FRAGMIN Injection (dalteparin sodium injection) is a sterile, low molecular weight heparin. It is available in single-dose, prefilled syringes preassembled with a needle guard device, and multiple-dose vials. With reference to the W.H.O. First International Low Molecular Weight Heparin Reference Standard, each syringe contains either 2,500 units, 5,000 units, 7,500 units, 10,000 units, 12,500 units, 15,000 units or 18,000 anti-Xa international units (units), equivalent to 16 mg, 32 mg, 48 mg, 64 mg, 80 mg, 96 mg or 115.2 mg dalteparin sodium, respectively. Each multiple-dose vial contains 25,000 anti-Xa units per 1 mL (equivalent to 160 mg dalteparin sodium), for a total of 95,000 anti-Xa units per vial. Each single-dose vial contains 2,500 anti-Xa units per 1 mL (equivalent to 16 mg dalteparin sodium) for a total of 10,000 anti-Xa units per vial. Each prefilled syringe also contains Water for Injection and sodium chloride, when required, to maintain physiologic ionic strength. The prefilled syringes are preservative-free. Each multiple-dose vial also contains Water for Injection and 14 mg of benzyl alcohol per mL as a preservative. The pH of both formulations is 5.0 to 7.5. When necessary, the pH of FRAGMIN is adjusted with hydrochloric acid and/or sodium hydroxide . Dalteparin sodium is produced through controlled nitrous acid depolymerization of sodium heparin from porcine intestinal mucosa followed by a chromatographic purification process. It is composed of strongly acidic sulfated polysaccharide chains (oligosaccharide, containing 2,5-anhydro-D-mannitol residues as end groups) with an average molecular weight of 5,000 and about 90% of the material within the range 2,000–9,000. The molecular weight distribution is: <3000 daltons 3.0–15% 3,000 to 8,000 daltons 65.0–78.0% >8,000 daltons 14.0–26.0% Structural Formula Chemical Structure

FRAGMIN is a low molecular weight heparin (LMWH) indicated for • Prophylaxis of ischemic complications of unstable angina and non-Q-wave myocardial infarction • Prophylaxis of deep vein thrombosis (DVT) in abdominal surgery, hip replacement surgery or medical patients with severely restricted mobility during acute illness • Extended treatment of symptomatic venous thromboembolism (VTE) to reduce the recurrence in adult patients with cancer. In these patients, the FRAGMIN therapy begins with the initial VTE treatment and continues for six months • Treatment of symptomatic venous thromboembolism (VTE) to reduce the recurrence in pediatric patients from birth (gestational age at least 35 weeks) • Limitations of Use FRAGMIN is not indicated for the acute treatment of VTE 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

Prophylaxis of Deep Vein Thrombosis FRAGMIN is indicated for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE): • In patients undergoing hip replacement surgery ; • In patients undergoing abdominal surgery who are at risk for thromboembolic complications ; • In medical patients who are at risk for thromboembolic complications due to severely restricted mobility during acute illness

Extended Treatment of Symptomatic Venous Thromboembolism (VTE) in Adult Patients with Cancer FRAGMIN is indicated for the extended treatment of symptomatic venous thromboembolism (VTE) (proximal DVT and/or PE), to reduce the recurrence of VTE in adult patients with cancer. In these patients, the FRAGMIN therapy begins with the initial VTE treatment and continues for six months

Treatment of Symptomatic Venous Thromboembolism (VTE) in Pediatric Patients FRAGMIN is indicated for the treatment of symptomatic venous thromboembolism (VTE) to reduce the recurrence of VTE in pediatric patients from birth (gestational age at least 35 weeks)

Limitations of Use FRAGMIN is not indicated for the acute treatment of VTE.

FRAGMIN (dalteparin sodium) injection is a sterile, aqueous, clear, colorless or straw-colored solution for injection, available in the following dosage forms and strengths: • Injection: 2,500 units/ 0.2 mL, 5,000 units/ 0.2 mL, 7,500 units/ 0.3 mL, 12,500 units/ 0.5 mL, 15,000 units/ 0.6 mL, and 18,000 units/ 0.72 mL sterile, single-dose, prefilled syringes preassembled with a needle guard device. • Injection: 10,000 units/mL sterile, single-dose, graduated syringes preassembled with a needle guard device. • Injection: 95,000 units/ 3.8 mL (25,000 units/mL) sterile, multiple-dose vials. • Injection: 10,000 units/ 4 mL (2,500 units/mL) sterile, single-dose vials. • Injection: 2,500 units/ 0.2 mL, 5,000 units/ 0.2 mL, 7,500 units/ 0.3 mL, 12,500 units/ 0.5 mL, 15,000 units/ 0.6 mL, and 18,000 units/ 0.72 mL single-dose prefilled syringes • Injection: 10,000 units/mL single-dose graduated syringes • Injection: 95,000 units/ 3.8 mL (25,000 units/mL) multiple-dose vials • Injection: 10,000 units/ 4 mL (2,500 units/mL) single-dose vials

Indication Dosing Regimen Unstable angina and non-Q-wave MI 120 units/kg subcutaneous every 12 hours (with aspirin) DVT prophylaxis in abdominal surgery 2,500 units subcutaneous once daily or 5,000 units subcutaneous once daily or 2,500 units subcutaneous followed by 2,500 units subcutaneous 12 hours later and then 5,000 units subcutaneous once daily DVT prophylaxis in hip replacement surgery Postoperative start – 2,500 units subcutaneous 4 hours to 8 hours after surgery, then 5,000 units subcutaneous once daily, or Preoperative start – day of surgery 2,500 units subcutaneous 2 hours before surgery followed by 2,500 units subcutaneous 4 hours to 8 hours after surgery, then 5,000 units subcutaneous once daily Preoperative start – Evening Before Surgery 5,000 units subcutaneous followed by 5,000 units subcutaneous 4 hours to 8 hours after surgery DVT prophylaxis in medical patients 5,000 units subcutaneous once daily Extended treatment of VTE in adult patients with cancer Month 1: 200 units/kg subcutaneous once daily Months 2 to 6: 150 units/kg subcutaneous once daily Treatment of VTE in pediatric patients Age Group Starting Dose Birth (gestational age at least 35 weeks) to less than 2 Years 150 units/kg twice daily 2 Years to less than 8 Years 125 units/kg twice daily 8 Years to less than 17 Years 100 units/kg twice daily Do not use as intramuscular injection. FRAGMIN should not be mixed with other injections or infusions 2.1 Recommended Dosage for 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 units/kg of body weight, but not more than 10,000 units, subcutaneously every 12 hours with concurrent oral aspirin (75 mg to 165 mg once daily) therapy. Treatment should be continued until the patient is clinically stabilized. The usual duration of administration is 5 days to 8 days. Concurrent aspirin therapy is recommended except when contraindicated. Table 1 lists the volume of FRAGMIN in mL (based on the 3.8 mL multiple-dose vial 25,000 units/mL) and quantity of FRAGMIN in units, to be administered for a range of patient weights. Table 1 Quantity and Volume of FRAGMIN to be Administered by Patient Weight Patient weight (kg) <50 kg 50 kg to 59 kg 60 kg to 69 kg 70 kg to 79 kg 80 kg to 89 kg ≥90 kg Quantity of FRAGMIN (units) 5,500 units 6,500 units 7,500 units 9,000 units 10,000 units 10,000 units Volume of FRAGMIN (mL) 95,000 units / 3.8 mL 0.22 mL 0.26 mL 0.3 mL 0.36 mL 0.4 mL 0.4 mL 2.2 Prophylaxis of Deep Vein Thrombosis Prophylaxis of VTE Following Hip Replacement Surgery : Table 2 presents the dosing options for patients undergoing hip replacement surgery. The usual duration of administration is 5 days to 10 days after surgery; up to 14 days of treatment with FRAGMIN have been well tolerated in clinical trials. Table 2 Dosing Options for Patients Undergoing Hip Replacement Surgery Timing of First Dose of FRAGMIN Dose of FRAGMIN to be Given Subcutaneously 10 Hours to 14 Hours Before Surgery Within 2 Hours Before Surgery 4 Hours to 8 Hours After Surgery Or later, if hemostasis has not been achieved. Postoperative Period Up to 14 days of treatment was well tolerated in controlled clinical trials, where the usual duration of treatment was 5 days to 10 days postoperatively. Postoperative Start --- --- 2,500 units 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. 5,000 units once daily Preoperative Start - Day of Surgery --- 2,500 units 2,500 units 5,000 units once daily Preoperative Start - Evening Before Surgery Allow approximately 24 hours between doses. 5,000 units --- 5,000 units 5,000 units once daily Abdominal Surgery: In patients undergoing abdominal surgery with a risk of thromboembolic complications, the recommended dose of FRAGMIN is 2,500 units administered by subcutaneous injection once daily, starting 1 hour to 2 hours prior to surgery and repeated once daily postoperatively. The usual duration of administration is 5 days 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 5,000 units subcutaneously the evening before surgery, then once daily postoperatively. The usual duration of administration is 5 days to 10 days. Alternatively, in patients with malignancy, 2,500 units of FRAGMIN can be administered subcutaneously 1 hour to 2 hours before surgery followed by 2,500 units subcutaneously 12 hours later, and then 5,000 units once daily postoperatively. The usual duration of administration is 5 days to 10 days. Medical Patients During Acute Illness: In medical patients with severely restricted mobility during acute illness, the recommended dose of FRAGMIN is 5,000 units administered by subcutaneous injection once daily. In clinical trials, the usual duration of administration was 12 days to 14 days

Extended Treatment of Symptomatic Venous Thromboembolism (VTE) in Adult Patients with Cancer In adult patients with cancer and symptomatic VTE, the recommended dosing of FRAGMIN is as follows: for the first 30 days of treatment administer FRAGMIN 200 units/kg total body weight subcutaneously once daily. The total daily dose should not exceed 18,000 units. Table 3 lists the dose of FRAGMIN to be administered once daily during the first month for a range of patient weights. Month 1 Table 3 Dose of FRAGMIN to be Administered Subcutaneously by Patient Weight during the First Month Body Weight (kg) FRAGMIN Dose (units) (prefilled syringe) once daily ≤56 kg 10,000 units 57 kg to 68 kg 12,500 units 69 kg to 82 kg 15,000 units 83 kg to 98 kg 18,000 units ≥99 kg 18,000 units Months 2 to 6 Administer FRAGMIN at a dose of approximately 150 units/kg, subcutaneously once daily during Months 2 through 6. The total daily dose should not exceed 18,000 units. Table 4 lists the dose of FRAGMIN to be administered once daily for a range of patient weights during months 2 to 6. Table 4 Dose of FRAGMIN to be Administered Subcutaneously by Patient Weight during Months 2 to 6 Body Weight (kg) FRAGMIN Dose (units) (prefilled syringe) once daily ≤56 kg 7,500 units 57 kg to 68 kg 10,000 units 69 kg to 82 kg 12,500 units 83 kg to 98 kg 15,000 units ≥99 kg 18,000 units Safety and efficacy beyond six months have not been evaluated in patients with cancer and acute symptomatic VTE

Treatment of Symptomatic Venous Thromboembolism (VTE) in Pediatric Patients The recommended starting dose according to pediatric age is provided in Table 5. Table 5 Starting Doses for Pediatric Patients with Symptomatic VTE Age Group Starting Dose Birth (gestational age at least 35 weeks) to less than 2 Years 150 units/kg twice daily 2 Years to less than 8 Years 125 units/kg twice daily 8 Years to less than 17 Years 100 units/kg twice daily After initiation of FRAGMIN, measure anti-Xa level prior to the 4 th dose. Samples for anti-Xa level should be drawn 4 hours after administration of FRAGMIN. Adjust doses in increments of 25 units/kg to achieve target anti-Xa level between 0.5 units/mL and 1 unit/mL. Individualize the maintenance dose of FRAGMIN based on the dose that achieves target anti-Xa level collected 4 hours after administration of FRAGMIN . Monitor anti-Xa level periodically in pediatric patients to maintain anti-Xa level between 0.5 units/mL and 1 unit/mL . The 3.8 mL multiple-dose vials of FRAGMIN contain 14 mg/mL of benzyl alcohol . Whenever possible, administer benzyl alcohol-free formulations (prefilled syringes) in pediatric patients . The 10,000 units/4 mL (2,500 units/mL) single-dose vials are preservative-free. For treatment of neonates, use this vial presentation

Dose Reductions for Thrombocytopenia in Adult Patients with Cancer and in Pediatric Patients with Symptomatic VTE Dose reductions recommended in patients receiving FRAGMIN who experience thrombocytopenia are presented below in Table 6. Table 6 Platelet Count less than or equal to 50,000/mm 3 Platelet Count greater than 50,000/mm 3 up to 100,000/mm 3 Adults Discontinue FRAGMIN until platelet count recovers to above 50,000/mm 3 . Reduce the daily dose of FRAGMIN by 2,500 units until the platelet count recovers to greater or equal to 100,000/mm 3 . Children from birth (gestational age at least 35 weeks) to less than 17 Years Discontinue FRAGMIN until platelet count recovers to above 50,000/mm 3 . Reduce the daily dose of FRAGMIN by 50% until the platelet count recovers to greater or equal to 100,000/mm 3

Dose Reductions for Renal Insufficiency in Extended Treatment of Acute Symptomatic VTE in Adult 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 units/mL to 1.5 units/mL. When monitoring anti-Xa in these patients, perform sampling 4 hours to 6 hours after FRAGMIN dosing and only after the patient has received 3 to 4 doses [ see Clinical Pharmacology ]

Administration Latex Allergy: Persons with latex allergies should not handle the FRAGMIN prefilled syringe because the needle shield may contain natural rubber latex which may cause allergic reactions. 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. 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. Figure

• Hemorrhage: Use caution in conditions with increased risk of hemorrhage • Thrombocytopenia: Monitor thrombocytopenia of any degree closely • Benzyl Alcohol Preservative: Do not use multiple-dose formulations in neonates and infants as they contain benzyl alcohol • Laboratory Tests: Periodic blood counts recommended 5.1 Risk of Hemorrhage including Spinal/Epidural Hematomas Spinal or epidural hemorrhage and subsequent hematomas can occur with the associated use of low molecular weight heparins or heparinoids and neuraxial (spinal/epidural) anesthesia or spinal puncture. The risk of these events is higher with the use of post-operative indwelling epidural catheters, with the concomitant use of additional drugs affecting hemostasis such as NSAIDs, with traumatic or repeated epidural or spinal puncture, or in patients with a history of spinal surgery or spinal deformity . To reduce the potential risk of bleeding associated with the concurrent use of FRAGMIN and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of FRAGMIN . Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of FRAGMIN is low; however, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known. No additional hemostasis-altering medications should be administered due to the additive effects. Patients on preoperative FRAGMIN thromboprophylaxis can be assumed to have altered coagulation. The first postoperative FRAGMIN thromboprophylaxis dose (2,500 units) should be administered 6 hours to 8 hours postoperatively. The second postoperative dose (2,500 units or 5,000 units) should occur no sooner than 24 hours after the first dose. Placement or removal of a catheter should be delayed for at least 12 hours after administration of 2,500 units once daily of FRAGMIN, at least 15 hours after the administration of 5,000 units once daily of FRAGMIN, and at least 24 hours after the administration of higher doses (200 units/kg once daily, 120 units/kg twice daily) of FRAGMIN. Anti-Xa levels are still detectable at these time points, and these delays are not a guarantee that neuraxial hematoma will be avoided. Although a specific recommendation for timing of a subsequent FRAGMIN dose after catheter removal cannot be made, consider delaying this next dose for at least 4 hours, based on a benefit-risk assessment considering both the risk for thrombosis and the risk for bleeding in the context of the procedure and patient risk factors. For patients with creatinine clearance <30 mL/minute, additional considerations are necessary because elimination of FRAGMIN may be more prolonged; consider doubling the timing of removal of a catheter, at least 24 hours for the lower prescribed dose of FRAGMIN (2,500 units or 5,000 units once daily) and at least 48 hours for the higher dose (200 units/kg once daily, 120 units/kg twice daily) . Should the physician decide to administer anticoagulation in the context of epidural or spinal anesthesia/analgesia or lumbar puncture, frequent monitoring must be exercised to detect any signs and symptoms of neurological impairment such as midline back pain, sensory and motor deficits (numbness or weakness in lower limbs), bowel and/or bladder dysfunction. Instruct patients to report immediately if they experience any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected, initiate urgent diagnosis and treatment including consideration for spinal cord decompression even though such treatment may not prevent or reverse neurological sequelae. 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

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 . Closely monitor thrombocytopenia of any degree. In FRAGMIN clinical trials supporting non-cancer indications, platelet counts of <50,000/mm 3 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/mm 3 occurred in 13.6% of patients, including 6.5% who also had platelet counts less than 50,000/mm 3 . 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/mm 3 . 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/mm 3 occurred in 37% of patients, including 21% who also had platelet counts less than 50,000/mm 3 . 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/mm 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 . 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

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.

The use of FRAGMIN in patients receiving oral anticoagulants, platelet inhibitors, and thrombolytic agents may increase the risk of bleeding . The use of FRAGMIN in patients receiving oral anticoagulants, platelet inhibitors, and thrombolytic agents may increase the risk of bleeding