Dalteparin Sodium

1 INDICATIONS AND USAGE FRAGMIN is a low molecular weight heparin (LMWH) indicated for • Prophylaxis of ischemic complications of unstable angina and non-Q-wave myocardial infarction ( 1.1 ) • Prophylaxis of deep vein thrombosis (DVT) in abdominal surgery, hip replacement surgery or medical patients with severely restricted mobility during acute illness ( 1.2 ) • 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 ( 1.3 ) • Treatment of symptomatic venous thromboembolism (VTE) to reduce the recurrence in pediatric patients from birth (gestational age at least 35 weeks) ( 1.4 ) • Limitations of Use FRAGMIN is not indicated for the acute treatment of VTE ( 1.5 ) 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 indicated for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE): • In patients undergoing hip replacement surgery [see Clinical Studies (14.2) ] ; • In patients undergoing abdominal surgery who are at risk for thromboembolic complications [see Clinical Studies (14.3) ] ; • In medical patients who are at risk for thromboembolic complications due to severely restricted mobility during acute illness [see Clinical Studies (14.4) ] . 1.3 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 [see Clinical Studies (14.5) ] . 1.4 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) . 1.5 Limitations of Use FRAGMIN is not indicated for the acute treatment of VTE.

2 DOSAGE AND ADMINISTRATION Indication Dosing Regimen Unstable angina and non-Q-wave MI 120 units/kg subcutaneous every 12 hours (with aspirin) ( 2.1 ) 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 ( 2.2 ) 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 ( 2.2 ) Preoperative start – Evening Before Surgery 5,000 units subcutaneous followed by 5,000 units subcutaneous 4 hours to 8 hours after surgery ( 2.2 ) DVT prophylaxis in medical patients 5,000 units subcutaneous once daily ( 2.2 ) Extended treatment of VTE in adult patients with cancer Month 1: 200 units/kg subcutaneous once daily ( 2.3 ) Months 2 to 6: 150 units/kg subcutaneous once daily ( 2.3 ) Treatment of VTE in pediatric patients (see Table 5 ) ( 2.4 ) 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 ( 2.7 ) 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. 2.3 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 [see Warnings and Precaution (5) and Adverse Reactions (6.1) ] . 2.4 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 [see Clinical Pharmacology (12.3) and Clinical Studies (14.5) ] . The 3.8 mL multiple-dose vials of FRAGMIN contain 14 mg/mL of benzyl alcohol [see Warnings and Precautions (5.3) ] . Whenever possible, administer benzyl alcohol-free formulations (prefilled syringes) in pediatric patients [see Warnings and Precautions (5.3) and Use in Specific Populations (8.4) ] . The 10,000 units/4 mL (2,500 units/mL) single-dose vials are preservative-free. For treatment of neonates, use this vial presentation. 2.5 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 . 2.6 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 (12.3) ] . 2.7 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

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) ] Most common adverse reactions (>1%) are: bleeding (including hemorrhage), thrombocytopenia (Type I), hematoma at the injection site, pain at the injection site, transient elevation of transaminases ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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 7 Major Bleeding Reactions in Unstable Angina and Non-Q-Wave Myocardial Infarction Indication Dosing Regimen Unstable Angina and Non-Q-Wave MI FRAGMIN 120 units/kg/12 hours subcutaneous Treatment was administered for 5 days to 8 days. n (%) Heparin Heparin intravenous infusion for at least 48 hours, APTT 1.5 to 2 times control, then 12,500 units subcutaneously every 12 hours for 5 days to 8 days. intravenous and subcutaneous n (%) Placebo every 12 hours subcutaneous n (%) Major Bleeding Reactions Aspirin (75 mg 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. 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 8 Bleeding Reactions Following Hip Replacement Surgery Indication FRAGMIN vs Warfarin Sodium FRAGMIN vs Heparin Dosing Regimen Dosing Regimen Hip Replacement Surgery FRAGMIN Includes three treated patients who did not undergo a surgical procedure. 5,000 units once daily subcutaneous Warfarin Sodium 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. oral FRAGMIN Includes two treated patients who did not undergo a surgical procedure. 5,000 units once daily subcutaneous Heparin 5,000 units three times a day subcutaneous n (%) n (%) n (%) n (%) Major Bleeding Reactions 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. 7/274 (2.6) 1/279 (0.4) 0 3/69 (4.3) Other Bleeding Reactions Occurred at a rate of at least 2% in the group treated with FRAGMIN 5,000 units once daily. 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 units and 5,000 units administered once daily to abdominal surgery patients. Table 9 Bleeding Reactions Following Abdominal Surgery Indication FRAGMIN vs Placebo FRAGMIN vs FRAGMIN Dosing Regimen Dosing Regimen Abdominal Surgery FRAGMIN 2,500 units once daily subcutaneous n (%) Placebo once daily subcutaneous n (%) FRAGMIN 2,500 units once daily subcutaneous n (%) FRAGMIN 5,000 units 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 units once daily subcutaneous n (%) Heparin 5,000 units twice daily subcutaneous n (%) FRAGMIN 5,000 units once daily subcutaneous n (%) Heparin 5,000 units 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 units once daily to FRAGMIN 2,500 units 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 units once daily to heparin 5,000 units 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 units once daily subcutaneous n (%) Placebo once daily subcutaneous n (%) Major Bleeding Reactions 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. 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) 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. Study period FRAGMIN 200 units/kg (max. 18,000 units) subcutaneous once daily x 1 month, then 150 units/kg (max. 18,000 units) subcutaneous once daily x 5 months OAC FRAGMIN 200 units/kg (max 18,000 units) subcutaneous once daily x 5 to 7 days and OAC for 6 months (target INR 2 to 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 to 4 332 9 (2.7) 17 (5.1) 321 1 (0.3) 12 (3.7) Weeks 5 to 28 297 9 (3.0) 26 (8.8) 267 8 (3) 40 (15) 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 units once daily vs 11.8% of patients treated with heparin 5,000 units 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 units once daily vs 13% of patients treated with heparin 5,000 units 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 4 th dose and then periodically to determine whether dose adjustments were required, using 25 units/kg increments, to achieve a target anti-Xa level of 0.5 units/mL to 1.0 units/mL. The median time on treatment with FRAGMIN was 86 days (range 2 days 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 ≥2g/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%). Neonatal Patients No controlled clinical trials have been conducted with FRAGMIN in neonatal patients with VTE; however, data are available from a non‑interventional retrospective medical chart review study of 16 neonates with VTE in the UK who were admitted to hospital between January 2010 and December 2021 and were treated with FRAGMIN. The mean (±SD) duration of dalteparin treatment was 62±30 days. For these 16 neonatal patients, the mean (±SD) daily dose of dalteparin at initiation was 365±196 units/kg (median:309 units/kg). The mean (±SD) daily dose of dalteparin including dose at initiation and dose changes was 575±320 units/kg (median: 450 units/kg). After the initial dose, all patients required one or more dose changes; 15 of 16 patients required dose increases due to anti-Xa level being initially below the target range of 0.5 units/mL to 1 units/mL. The safety profile in neonates was similar to other pediatric patients. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval 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 Metabolism and nutrition disorders: Hyperkalemia

12.3 Pharmacokinetics Adults Mean peak levels of plasma anti-Xa activity following single subcutaneous doses of 2,500 units, 5,000 units and 10,000 units were 0.19 ± 0.04 units/mL, 0.41 ± 0.07 units/mL and 0.82 ± 0.10 units/mL, respectively, and were attained in about 4 hours in most subjects. Absolute bioavailability in healthy volunteers, measured as the anti-Xa activity, was 87 ± 6%. Increasing the dose from 2,500 units to 10,000 units resulted in an overall increase in anti-Xa AUC that was greater than proportional by about one-third. Peak anti-Xa activity increased more or less linearly with dose over the same dose range. There appeared to be no appreciable accumulation of anti-Xa activity with twice-daily dosing of 100 units/kg subcutaneously for up to 7 days. The volume of distribution for dalteparin anti-Xa activity was 40 mL/kg to 60 mL/kg. The mean plasma clearances of dalteparin anti-Xa activity in normal volunteers following single intravenous bolus doses of 30 and 120 anti-Xa units/kg were 24.6 ± 5.4 mL/hr/kg and 15.6 ± 2.4 mL/hr/kg, respectively. The corresponding mean disposition half-lives were 1.47 ± 0.3 hours and 2.5 ± 0.3 hours. Following intravenous doses of 40 units/kg and 60 units/kg, mean terminal half-lives were 2.1 ± 0.3 hours and 2.3 ± 0.4 hours, respectively. Longer apparent terminal half-lives (3 hours to 5 hours) are observed following subcutaneous dosing, possibly due to delayed absorption. In patients with chronic renal insufficiency requiring hemodialysis, the mean terminal half-life of anti-Xa activity following a single intravenous dose of 5,000 units FRAGMIN was 5.7 ± 2.0 hours, i.e., considerably longer than values observed in healthy volunteers, therefore, greater accumulation can be expected in these patients. Pediatric Patients The pharmacokinetics of twice-daily subcutaneous dalteparin, measured as anti-Xa activity, was characterized in 89 pediatric patients with or without cancer from two clinical studies and 1 observational study. Dalteparin pharmacokinetics (PK) were described by a 1-compartment model with linear absorption and elimination and PK parameters are shown in Table 12. After correcting for the body weight, clearance (CL/F) decreased with increasing age, while volume of distribution at steady-state (V d /F) remained similar. The mean elimination half-life increased with age. Table 12 Pharmacokinetic Parameters of Dalteparin in Pediatric Population Abbreviations: CL=clearance; F=absolute bioavailability; SD=standard deviation; t ½β =elimination half-life; V d =volume of distribution. Parameter 3 Weeks to <8 Weeks ≥8 Weeks to <2 Years ≥2 Years to <8 Years ≥8 Years to <12 Years ≥12 Years to <20 Years Median Age (range) (years) 0.06 (0.04 – 0.14) 0.5 (0.2 – 1.91) 4.47 (2.01 – 7.6) 9.62 (8.01 – 10.5) 15.9 (12.0 – 19.5) Derived Mean (SD) CL/F (mL/h/kg) 55.8 (3.91) 40.4 (8.49) 26.7 (4.75) 22.4 (3.40) 18.8 (3.01) Derived Mean (SD) V d /F (mL/kg) 181 (15.3) 175 (55.3) 160 (25.6) 165 (27.3) 171 (38.9) Derived Mean (SD) t ½β (h) 2.25 (0.173) 3.02 (0.688) 4.27 (1.05) 5.11 (0.509) 6.28 (0.937)