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Fragmin

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These highlights do not include all the information needed to use FRAGMIN® safely and effectively. See full prescribing information for FRAGMIN. FRAGMIN (dalteparin sodium injection) for Subcutaneous Use Only Initial U

WARNING: SPINAL/EPIDURAL HEMATOMAS

Epidural or spinal hematomas may occur in patients who are anticoagulated with low molecular weight heparins (LMWH) or heparinoids and are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include:

Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary.

Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis [see Warnings and Precautions ( 5.1 ) and Drug Interactions ( 7 )].

1 INDICATIONS AND USAGE

1.1 Prophylaxis of Ischemic Complications in Unstable Angina and Non-Q-Wave Myocardial Infarction

FRAGMIN® Injection is indicated for the prophylaxis of ischemic complications in unstable angina and non-Q-wave myocardial infarction, when concurrently administered with aspirin therapy [see Clinical Studies ( 14.1 )].

1.2 Prophylaxis of Deep Vein Thrombosis

FRAGMIN is also indicated for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE):

1.3 Extended Treatment of Symptomatic Venous Thromboembolism in Patients with Cancer

FRAGMIN is also indicated for the extended treatment of symptomatic venous thromboembolism (VTE) (proximal DVT and/or PE), to reduce the recurrence of VTE in patients with cancer. In these patients, the FRAGMIN therapy begins with the initial VTE treatment and continues for six months [see Clinical Studies ( 14.5 )].

Limitations of Use

FRAGMIN is not indicated for the acute treatment of VTE.

2 DOSAGE AND ADMINISTRATION

FRAGMIN is administered by subcutaneous injection. It must not be administered by intramuscular injection.

FRAGMIN Injection should not be mixed with other injections or infusions unless specific compatibility data are available that support such mixing.

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. [see Warnings and Precautions ( 5 )].

2.1 Adult Dosage

Prophylaxis of Ischemic Complications in Unstable Angina and Non-Q-Wave Myocardial Infarction : In patients with unstable angina or non-Q-wave myocardial infarction, the recommended dose of FRAGMIN Injection is 120 IU/kg of body weight, but not more than 10,000 IU, subcutaneously every 12 hours with concurrent oral aspirin (75 to 165 mg once daily) therapy. Treatment should be continued until the patient is clinically stabilized. The usual duration of administration is 5 to 8 days. Concurrent aspirin therapy is recommended except when contraindicated.

Table 1 lists the volume of FRAGMIN, based on the 9.5 mL multiple-dose vial (10,000 IU/mL), to be administered for a range of patient weights.

Prophylaxis of Venous Thromboembolism Following Hip Replacement Surgery : Table 2 presents the dosing options for patients undergoing hip replacement surgery. The usual duration of administration is 5 to 10 days after surgery; up to 14 days of treatment with FRAGMIN have been well tolerated in clinical trials.

Abdominal Surgery : In patients undergoing abdominal surgery with a risk of thromboembolic complications, the recommended dose of FRAGMIN is 2500 IU administered by subcutaneous injection once daily, starting 1 to 2 hours prior to surgery and repeated once daily postoperatively. The usual duration of administration is 5 to 10 days.

In patients undergoing abdominal surgery associated with a high risk of thromboembolic complications, such as malignant disorder, the recommended dose of FRAGMIN is 5000 IU subcutaneously the evening before surgery, then once daily postoperatively. The usual duration of administration is 5 to 10 days. Alternatively, in patients with malignancy, 2500 IU of FRAGMIN can be administered subcutaneously 1 to 2 hours before surgery followed by 2500 IU subcutaneously 12 hours later, and then 5000 IU once daily postoperatively. The usual duration of administration is 5 to 10 days.

Medical Patients During Acute Illness : In medical patients with severely restricted mobility during acute illness, the recommended dose of FRAGMIN is 5000 IU administered by subcutaneous injection once daily. In clinical trials, the usual duration of administration was 12 to 14 days.

Extended Treatment of Symptomatic Venous Thromboembolism in Patients with Cancer : In patients with cancer and symptomatic venous thromboembolism, the recommended dosing of FRAGMIN is as follows: for the first 30 days of treatment administer FRAGMIN 200 IU/kg total body weight subcutaneously once daily. The total daily dose should not exceed 18,000 IU. Table 3 lists the dose of FRAGMIN to be administered once daily during the first month for a range of patient weights

Month 1

Months 2 to 6

Administer FRAGMIN at a dose of approximately 150 IU/kg, subcutaneously once daily during Months 2 through 6. The total daily dose should not exceed 18,000 IU. Table 4 lists the dose of FRAGMIN to be administered once daily for a range of patient weights during months 2-6.

Safety and efficacy beyond six months have not been eva luated in patients with cancer and acute symptomatic VTE [see Warnings and Precautions ( 5 ) and Adverse Reactions ( 6.1 )].

Table 1
Volume of FRAGMIN to be Administered by Patient Weight, Based on 9.5 mL Vial (10,000 IU/mL)
Patient weight (lb)	< 110	110 to 131	132 to 153	154 to 175	176 to 197	≥198
Patient weight (kg)	< 50	50 to 59	60 to 69	70 to 79	80 to 89	≥90
Volume of FRAGMIN (mL)	0.55	0.65	0.75	0.90	1.0	1.0

Table 2
¹ Or later, if hemostasis has not been achieved. ² Up to 14 days of treatment was well tolerated in controlled clinical trials, where the usual duration of treatment was 5 to 10 days postoperatively. ³ Allow a minimum of 6 hours between this dose and the dose to be given on Postoperative Day 1. Adjust the timing of the dose on Postoperative Day 1 accordingly. ⁴ Allow approximately 24 hours between doses.
Dosing Options for Patients Undergoing Hip Replacement Surgery
	Dose of FRAGMIN to be Given Subcutaneously
Timing of First Dose of FRAGMIN	10 to 14 Hours Before Surgery	Within 2 Hours Before Surgery	4 to 8 Hours After Surgery¹	Postoperative Period²
Postoperative Start	---	---	2500 IU³	5000 IU once daily
Preoperative Start - Day of Surgery	---	2500 IU	2500 IU³	5000 IU once daily
Preoperative Start - Evening Before Surgery⁴	5000 IU	---	5000 IU	5000 IU once daily

Table 3
Dose of FRAGMIN to be Administered Subcutaneously by Patient Weight during the First Month
Body Weight (lbs)	Body Weight (kg)	FRAGMIN Dose (IU) (prefilled syringe) once daily
≤ 124	≤ 56	10,000
125 to 150	57 to 68	12,500
151 to 181	69 to 82	15,000
182 to 216	83 to 98	18,000
≥ 217	≥ 99	18,000

Table 4
Dose of FRAGMIN to be Administered Subcutaneously by Patient Weight during Months 2-6
Body Weight (lbs)	Body Weight (kg)	FRAGMIN Dose (IU) (prefilled syringe) once daily
≤ 124	≤ 56	7,500
125 to 150	57 to 68	10,000
151 to 181	69 to 82	12,500
182 to 216	83 to 98	15,000
≥ 217	≥ 99	18,000

2.2 Dose reductions for thrombocytopenia in patients with cancer and acute symptomatic VTE

In patients receiving FRAGMIN who experience platelet counts between 50,000 and 100,000/mm, reduce the daily dose of FRAGMIN by 2,500 IU until the platelet count recovers to ≥100,000/mm. In patients receiving FRAGMIN who experience platelet counts < 50,000/mm, discontinue FRAGMIN until the platelet count recovers above 50,000/mm.

2.3 Dose reductions for renal insufficiency in extended treatment of acute symptomatic venous thromboembolism in patients with cancer

In patients with severely impaired renal function (CrCl < 30 mL/min), monitor anti-Xa levels to determine the appropriate FRAGMIN dose. Target anti-Xa range is 0.5-1.5 IU/mL. When monitoring anti-Xa in these patients, perform sampling 4-6 hrs after FRAGMIN dosing and only after the patient has received 3-4 doses.

2.4 Administration

Subcutaneous injection technique: Patients should be sitting or lying down and FRAGMIN administered by deep subcutaneous injection. FRAGMIN may be injected in a U-shape area around the navel, the upper outer side of the thigh or the upper outer quadrangle of the buttock. The injection site should be varied daily. When the area around the navel or the thigh is used, using the thumb and forefinger, you must lift up a fold of skin while giving the injection. The entire length of the needle should be inserted at a 45 to 90 degree angle.

Inspect FRAGMIN prefilled syringes and vials visually for particulate matter and discoloration prior to administration

After first penetration of the rubber stopper, store the multiple-dose vials at room temperature for up to 2 weeks. Discard any unused solution after 2 weeks.

Instructions for using the prefilled single-dose syringes preassembled with needle guard devices

Fixed dose syringes: To ensure delivery of the full dose, do not expel the air bubble from the prefilled syringe before injection. Hold the syringe assembly by the open sides of the device. Remove the needle shield. Insert the needle into the injection area as instructed above. Depress the plunger of the syringe while holding the finger flange until the entire dose has been given. The needle guard will not be activated unless the entire dose has been given. Remove needle from the patient. Let go of the plunger and allow syringe to move up inside the device until the entire needle is guarded. Discard the syringe assembly in approved containers.

Graduated syringes: Hold the syringe assembly by the open sides of the device. Remove the needle shield. With the needle pointing up, prepare the syringe by expelling the air bubble and then continuing to push the plunger to the desired dose or volume, discarding the extra solution in an appropriate manner. Insert the needle into the injection area as instructed above. Depress the plunger of the syringe while holding the finger flange until the entire dose remaining in the syringe has been given. The needle guard will not be activated unless the entire dose has been given. Remove needle from the patient. Let go of the plunger and allow syringe to move up inside the device until the entire needle is guarded. Discard the syringe assembly in approved containers.

3 DOSAGE FORMS AND STRENGTHS

2,500 IU / 0.2 mL single-dose prefilled syringe

5,000 IU / 0.2 mL single-dose prefilled syringe

7,500 IU / 0.3 mL single-dose prefilled syringe

10,000 IU / 0.4 mL single-dose prefilled syringe

10,000 IU / 1 mL single-dose graduated syringe

12,500 IU / 0.5 mL single-dose prefilled syringe

15,000 IU / 0.6 mL single-dose prefilled syringe

18,000 IU / 0.72 mL single-dose prefilled syringe

95,000 IU / 3.8 mL multiple-dose vial

95,000 IU / 9.5 mL multiple-dose vial

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Hemorrhage

Spinal or epidural hematomas can occur with the associated use of low molecular weight heparins or heparinoids and neuraxial (spinal/epidural) anesthesia or spinal puncture [see Boxed Warning and Adverse Reactions (6.2)].

Use FRAGMIN with extreme caution in patients who have an increased risk of hemorrhage, such as those with severe uncontrolled hypertension, bacterial endocarditis, congenital or acquired bleeding disorders, active ulceration and angiodysplastic gastrointestinal disease, hemorrhagic stroke, or shortly after brain, spinal or ophthalmological surgery. FRAGMIN may enhance the risk of bleeding in patients with thrombocytopenia or platelet defects; severe liver or kidney insufficiency, hypertensive or diabetic retinopathy, and recent gastrointestinal bleeding. Bleeding can occur at any site during therapy with FRAGMIN.

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/mm occurred in < 1% of patients.

In the clinical trial of patients with cancer and acute symptomatic venous thromboembolism treated for up to 6 months in the FRAGMIN treatment arm, platelet counts of < 100,000/mm occurred in 13.6% of patients, including 6.5% who also had platelet counts less than 50,000/mm. 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 OAC arm. FRAGMIN dose was decreased or interrupted in patients whose platelet counts fell below 100,000/mm.

5.3 Benzyl Alcohol

Each multiple-dose vial of FRAGMIN contains benzyl alcohol as a preservative. Benzyl alcohol has been reported to be associated with a fatal "Gasping Syndrome" in premature infants. 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. Anti-Factor 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

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 incidence of hemorrhagic complications during treatment with FRAGMIN Injection has been low. The most commonly reported side effect is hematoma at the injection site. The risk for bleeding varies with the indication and may increase with higher doses.

Unstable Angina and Non-Q-Wave Myocardial Infarction

Table 5 summarizes major bleeding reactions that occurred with FRAGMIN, heparin, and placebo in clinical trials of unstable angina and non-Q-wave myocardial infarction.

Hip Replacement Surgery

Table 6 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.

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. None of the patients experienced retroperitoneal or intracranial hemorrhage or died of bleeding complications.

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 7 summarizes bleeding reactions that occurred in clinical trials which studied FRAGMIN 2500 and 5000 IU administered once daily to abdominal surgery patients.

In a trial comparing FRAGMIN 5000 IU once daily to FRAGMIN 2500 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 5000 IU once daily to heparin 5000 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 8 summarizes major bleeding reactions that occurred in a clinical trial of medical patients with severely restricted mobility during acute illness.

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).

Patients with Cancer and Acute Symptomatic Venous Thromboembolism

Table 9 summarizes the number of patients with bleeding reactions that occurred in the clinical trial of patients with cancer and acute symptomatic venous thromboembolism. 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.

Thrombocytopenia

[See Warnings and Precautions (5.2)]

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, the only non-bleeding event determined to be possibly or probably related to treatment with FRAGMIN and reported at a rate of at least 2% in the group treated with FRAGMIN, was reported in 4.5% of patients treated with FRAGMIN 5000 IU once daily vs 11.8% of patients treated with heparin 5000 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 5000 IU once daily vs 13% of patients treated with heparin 5000 U three times a day.

Table 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.
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 subcutaneous¹ n (%)	Heparin² intravenous and subcutaneous² n (%)	Placebo every 12 hr subcutaneous n (%)
Major Bleeding Reactions^3,4	15/1497 (1.0)	7/731 (1.0)	4/760 (0.5)

Table 6
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 5000 IU once daily.
Bleeding Reactions Following Hip Replacement Surgery
	FRAGMIN vs Warfarin Sodium		FRAGMIN vs Heparin
Indication	Dosing Regimen		Dosing Regimen
Hip Replacement Surgery	FRAGMIN ² 5000 IU once daily subcutaneous n (%)	Warfarin Sodium¹ oral n (%)	FRAGMIN ⁴ 5000 IU once daily subcutaneous n (%)	Heparin 5000 U three times a day subcutaneous n (%)
Major Bleeding Reactions³	7/274 (2.6)	1/279 (0.4)	0	3/69 (4.3)
Other Bleeding Reactions⁵ 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)

Table 7
Bleeding Reactions Following Abdominal Surgery
	FRAGMIN vs Placebo		FRAGMIN vs FRAGMIN
Indication	Dosing Regimen		Dosing Regimen
Abdominal Surgery	FRAGMIN 2500 IU once daily subcutaneous n (%)	Placebo once daily subcutaneous n (%)	FRAGMIN 2500 IU once daily subcutaneous n (%)	FRAGMIN 5000 IU once daily subcutaneous n (%)
Postoperative Transfusions	14/182 (7.7)	13/182 (7.1)	89/1025 (8.7)	125/1033 (12.1)
Wound Hematoma	2/79 (2.5)	2/77 (2.6)	1/1030 (0.1)	4/1039 (0.4)
Reoperation Due to Bleeding	1/79 (1.3)	1/78 (1.3)	2/1030 (0.2)	13/1038 (1.3)
Injection Site Hematoma	8/172 (4.7)	2/174 (1.1)	36/1026 (3.5)	57/1035 (5.5)

Table 7 Cont.
Bleeding Reactions Following Abdominal Surgery
	FRAGMIN vs Heparin
Indication	Dosing Regimen
Abdominal Surgery	FRAGMIN 2500 IU once daily subcutaneous n (%)	Heparin 5000 U twice daily subcutaneous n (%)	FRAGMIN 5000 IU once daily subcutaneous n (%)	Heparin 5000 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)

Table 8
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.
Bleeding Reactions in Medical Patients with Severely Restricted Mobility During Acute Illness
Indication	Dosing Regimen
Medical Patients with Severely Restricted Mobility	FRAGMIN 5000 IU once daily subcutaneous n (%)	Placebo once daily subcutaneous n (%)
Major Bleeding Reactions¹ at Day 14	8/1848 (0.4)	0/1833 (0)
Major Bleeding Reactions¹ at Day 21	9/1848 (0.5)	3/1833 (0.2)

Table 9
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.
Bleeding Reactions (Major and Any) (As treated population)¹
Study period	FRAGMIN 200 IU/kg (max. 18,000 IU) subcutaneous once daily x 1 month, then 150 IU/kg (max. 18,000 IU) subcutaneous once daily x 5 months			OAC FRAGMIN 200 IU/kg (max 18,000 IU) subcutaneous once daily x 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 (%)
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)

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 dalteparin sodium 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 ]

Skin necrosis has occurred. There have been cases of alopecia reported that improved on drug discontinuation.

7 DRUG INTERACTIONS

Use FRAGMIN with care in patients receiving oral anticoagulants, platelet inhibitors, and thrombolytic agents because of increased risk of bleeding [see Warning and Precautions ( 5 )].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B

There are no adequate and well-controlled studies of FRAGMIN use in pregnant women. In reproductive and developmental toxicity studies, pregnant rats and rabbits received dalteparin sodium at intravenous doses up to 2400 IU/kg (14,160 IU/m) (rats) and 4800 IU/kg (40,800 IU/m) (rabbits). These exposures were 2 to 4 times (rats) and 4 times (rabbits) the human dose of 100 IU/kg dalteparin based on the body surface area. No evidence of impaired fertility or harm to the fetuses occurred in these studies. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Cases of "Gasping Syndrome" have occurred in premature infants when large amounts of benzyl alcohol have been administered (99-404 mg/kg/day). The 9.5 mL and the 3.8 mL multiple-dose vials of FRAGMIN contain 14 mg/mL of benzyl alcohol [see Warnings and Precautions ( 5.3 )].

8.3 Nursing Mothers

Based on limited published data dalteparin is minimally excreted in human milk. One study of 15 lactating women receiving prophylactic doses of dalteparin, in the immediate postpartum period, detected small amounts of anti-Xa activity (range < 0.005 to 0.037 IU/mL) in breast milk that were equivalent to a milk/plasma ratio of <0.025-0.224. Oral absorption of LMWH is extremely low, but the clinical implications, if any, of this small amount of anticoagulant activity on a nursing infant are unknown. Caution should be exercised when FRAGMIN is administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Of the total number of patients in clinical studies of FRAGMIN, 5516 patients were 65 years of age or older and 2237 were 75 or older. No overall differences in effectiveness were observed between these subjects and younger subjects. Some studies suggest that the risk of bleeding increases with age. Postmarketing surveillance and literature reports have not revealed additional differences in the safety of FRAGMIN between elderly and younger patients. Give careful attention to dosing intervals and concomitant medications (especially antiplatelet medications) in geriatric patients, particularly in those with low body weight (< 45 kg) and those predisposed to decreased renal function [see Warnings and Precautions ( 5 ) and Clinical Pharmacology ( 12 )].

10 OVERDOSAGE

An excessive dosage of FRAGMIN Injection may lead to hemorrhagic complications. These may generally be stopped by slow intravenous injection of protamine sulfate (1% solution), at a dose of 1 mg protamine for every 100 anti-Xa IU of FRAGMIN given. If the APTT measured 2 to 4 hours after the first infusion remains prolonged, a second infusion of 0.5 mg protamine sulfate per 100 anti-Xa IU of FRAGMIN may be administered. Even with these additional doses of protamine, the APTT may remain more prolonged than would usually be found fo