Fragmin (Page 4 of 13)

5.2 Thrombocytopenia

Heparin-induced thrombocytopenia can occur with the administration of FRAGMIN. The incidence of this complication is unknown at present. In clinical practice, cases of thrombocytopenia with thrombosis, amputation and death have been observed [see Contraindications (4)]. Closely monitor thrombocytopenia of any degree.

In FRAGMIN clinical trials supporting non-cancer indications, platelet counts of <50,000/mm3 occurred in <1% of patients.

In the clinical trial of adult patients with cancer and acute symptomatic VTE treated for up to 6 months in the FRAGMIN treatment arm, platelet counts of <100,000/mm3 occurred in 13.6% of patients, including 6.5% who also had platelet counts less than 50,000/mm3. In the same clinical trial, thrombocytopenia was reported as an adverse event in 10.9% of patients in the FRAGMIN arm and 8.1% of patients in the Oral Anti-Coagulant (OAC) arm. FRAGMIN dose was decreased or interrupted in patients whose platelet counts fell below 100,000/mm3.

In the clinical trial of pediatric patients with or without cancer with acute symptomatic VTE treated for up to 3 months with FRAGMIN, platelet counts of <100,000/mm3 occurred in 37% of patients, including 21% who also had platelet counts less than 50,000/mm3. In the same clinical trial, thrombocytopenia was reported as an adverse reaction in 21% of patients. FRAGMIN dose was interrupted in patients whose platelet counts fell below 50,000/mm3.

5.3 Risk of Serious Adverse Reactions in Neonates and Infants due to Benzyl Alcohol Preservative

Use preservative-free FRAGMIN in neonates and infants.

Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and low-birth weight infants treated with medications that contain the preservative benzyl alcohol. The “gasping syndrome” is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. When prescribing FRAGMIN in infants, consider the combined daily metabolic load of benzyl alcohol from all sources including FRAGMIN multiple-dose vial (contains 14 mg of benzyl alcohol per mL) and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known [see Use in Specific Populations (8.4)]. Because benzyl alcohol may cross the placenta, use caution when administering FRAGMIN preserved with benzyl alcohol to pregnant women. If anticoagulation with FRAGMIN is needed during pregnancy, use preservative-free formulations where possible [see Use in Specific Populations (8.1)].

5.4 Laboratory Tests

Periodic routine complete blood counts, including platelet count, blood chemistry, and stool occult blood tests are recommended during the course of treatment with FRAGMIN. When administered at recommended prophylaxis doses, routine coagulation tests such as Prothrombin Time (PT) and Activated Partial Thromboplastin Time (APTT) are relatively insensitive measures of FRAGMIN activity and, therefore, unsuitable for monitoring the anticoagulant effect of FRAGMIN. Monitor anti-Xa level periodically in pediatric patients. Anti-Xa may be used to monitor the anticoagulant effect of FRAGMIN, such as in patients with severe renal impairment or if abnormal coagulation parameters or bleeding occurs during FRAGMIN therapy.

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)]
Benzyl Alcohol Preservative Risk to Premature Infants [see Warnings and Precautions (5.3)]

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 7 summarizes major bleeding reactions that occurred with FRAGMIN, heparin, and placebo in clinical trials of unstable angina and non-Q-wave myocardial infarction.

Table 6 Major Bleeding Reactions in Unstable Angina and Non-Q-Wave Myocardial Infarction
Indication Dosing Regimen
Unstable Angina and Non-Q-Wave MI FRAGMIN 120 IU/kg/12 hr subcutaneous * n (%) Heparin intravenous and subcutaneous n (%) Placebo every 12 hr subcutaneous n (%)
*
Treatment was administered for 5 to 8 days.
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.
Aspirin (75 to 165 mg per day) and beta blocker therapies were administered concurrently.
§
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.

Major Bleeding Reactions , §

15/1497 (1.0)

7/731 (1.0)

4/760 (0.5)

Hip Replacement Surgery

Table 8 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 7 Bleeding Reactions Following Hip Replacement Surgery
Indication FRAGMIN vs Warfarin Sodium FRAGMIN vs Heparin
Dosing Regimen Dosing Regimen
Hip Replacement Surgery FRAGMIN * 5,000 IU once daily subcutaneous Warfarin Sodium oral FRAGMIN 5,000 IU once daily subcutaneous Heparin 5,000 U three times a day subcutaneous
n (%) n (%) n (%) n (%)
*
Includes three treated patients who did not undergo a surgical procedure.
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.
Includes two treated patients who did not undergo a surgical procedure.
§
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.
Occurred at a rate of at least 2% in the group treated with FRAGMIN 5,000 IU once daily.

Major Bleeding Reactions §

7/274 (2.6)

1/279 (0.4)

0

3/69 (4.3)

Other Bleeding Reactions Hematuria

8/274 (2.9)

5/279 (1.8)

0

0

Wound Hematoma

6/274 (2.2)

0

0

0

Injection Site Hematoma

3/274 (1.1)

NA

2/69 (2.9)

7/69 (10.1)

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 9 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 8 Bleeding Reactions Following Abdominal Surgery
Indication FRAGMIN vs Placebo FRAGMIN vs FRAGMIN
Dosing Regimen Dosing Regimen
Abdominal Surgery FRAGMIN 2,500 IU once daily subcutaneous n (%) Placebo once daily subcutaneous n (%) FRAGMIN 2,500 IU once daily subcutaneous n (%) FRAGMIN 5,000 IU once daily subcutaneous n (%)

Postoperative Transfusions

14/182(7.7)

13/182(7.1)

89/1,025(8.7)

125/1,033(12.1)

Wound Hematoma

2/79(2.5)

2/77(2.6)

1/1,030(0.1)

4/1,039(0.4)

Reoperation Due to Bleeding

1/79(1.3)

1/78(1.3)

2/1,030(0.2)

13/1,038(1.3)

Injection Site Hematoma

8/172(4.7)

2/174(1.1)

36/1,026(3.5)

57/1,035(5.5)

Table 9 Cont. Bleeding Reactions Following Abdominal Surgery
Indication FRAGMIN vs Heparin
Dosing Regimen
Abdominal Surgery FRAGMIN 2,500 IU once daily subcutaneous n (%) Heparin 5,000 U twice daily subcutaneous n (%) FRAGMIN 5,000 IU once daily subcutaneous n (%) Heparin 5,000 U twice daily subcutaneous n (%)

Postoperative Transfusions

26/459(5.7)

36/454(7.9)

81/508(15.9)

63/498(12.7)

Wound Hematoma

16/467(3.4)

18/467(3.9)

12/508(2.4)

6/498(1.2)

Reoperation Due to Bleeding

2/392(0.5)

3/392(0.8)

4/508(0.8)

2/498(0.4)

Injection Site Hematoma

1/466(0.2)

5/464(1.1)

36/506(7.1)

47/493(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 10 summarizes major bleeding reactions that occurred in a clinical trial of medical patients with severely restricted mobility during acute illness.

Table 10 Bleeding Reactions in Medical Patients with Severely Restricted Mobility During Acute Illness
Indication Dosing Regimen
Medical Patients with Severely Restricted Mobility FRAGMIN 5,000 IU once daily subcutaneous n (%) Placebo once daily subcutaneous n (%)
*
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.

Major Bleeding Reactions * at Day 14

8/1,848 (0.4)

0/1,833 (0)

Major Bleeding Reactions * at Day 21

9/1,848 (0.5)

3/1,833 (0.2)

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 11 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 11 Bleeding Reactions (Major and Any) (As treated population)*
Study period FRAGMIN 200 IU/kg (max. 18,000 IU) subcutaneous once daily × 1 month, then 150 IU/kg (max. 18,000 IU) subcutaneous once daily × 5 months OAC FRAGMIN 200 IU/kg (max 18,000 IU) subcutaneous once daily × 5–7 days and OAC for 6 months (target INR 2–3)
Number at risk Patients with Major Bleeding n (%) Patients with Any Bleeding n (%) Number at risk Patients with Major Bleeding n (%) Patients with Any Bleeding n (%)
*
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.

Total during study

338

19 (5.6)

46 (13.6)

335

12 (3.6)

62 (18.5)

Week 1

338

4 (1.2)

15 (4.4)

335

4 (1.2)

12 (3.6)

Weeks 2–4

332

9 (2.7)

17 (5.1)

321

1 (0.3)

12 (3.7)

Weeks 5–28

297

9 (3.0)

26 (8.8)

267

8 (3.0)

40 (15.0)

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.

Pediatric Patients with Symptomatic VTE

The data below reflect exposure to FRAGMIN from two studies in pediatric patients from newborn to less than 18 years of age with or without cancer and symptomatic VTE (n = 50). Patients were started on FRAGMIN using age and weight-based dosing via subcutaneous injection twice daily. Anti-Xa levels were measured prior to the 4th dose and then periodically to determine whether dose adjustments were required, using 25 IU/kg increments, to achieve a target anti-Xa level of 0.5 – 1.0 IU/mL. The median time on treatment with FRAGMIN was 86 days (range 2 to 170 days).

In pediatric patients with symptomatic VTE, the most common (greater than 10%) adverse reactions were injection site bruising (30%), contusion (12%), and epistaxis (10%).

Major bleeding was defined as any fatal bleeding, clinically overt bleeding with a decrease in hemoglobin of ≥2gm/dl in 24 hours, overt bleeding deemed by the attending physician to be unrelated to the subject’s underlying condition and accompanied by blood product administration, overt bleeding that was retroperitoneal, intracranial, intraspinal, intraocular, or intraarticular, or overt bleeding deemed by the attending physician to necessitate permanent discontinuation of trial medication. Major bleeding (intestinal hematoma) occurred in one patient (2%). Discontinuation due to adverse reactions occurred in 12% of patients, most often due to thrombocytopenia (4%).

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