Fragmin

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 a…

5 WARNINGS AND PRECAUTIONS • Hemorrhage: Use caution in conditions with increased risk of hemorrhage ( 5.1 ) • Thrombocytopenia: Monitor thrombocytopenia of any degree closely ( 5.2 ) • Benzyl Alcohol Preservative: Do not use multiple-dose formulations in neonates and infants as they contain benzyl alcohol ( 5.3 ) • Laboratory Tests: Periodic blood counts recommended ( 5.4 ) 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 [see Boxed Warning , Adverse Reactions (6.2) , and Drug Interactions (7) ] . 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 [see Clinical Pharmacology (12.3) ]. 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) [see Clinical Pharmacology (12.3) ]. 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, bacteria…

4 CONTRAINDICATIONS FRAGMIN is contraindicated in: • Patients with active major bleeding. • Patients with a history of heparin induced thrombocytopenia or heparin induced thrombocytopenia with thrombosis. • Patients with prior hypersensitivity to dalteparin sodium (e.g., pruritis, rash, anaphylactic reactions) [see Adverse Reactions (6.1) ] . • Patients undergoing Epidural/Neuraxial anesthesia, do not administer FRAGMIN [see Boxed Warning and Warnings and Precautions (5.1) ] ; o As a treatment for unstable angina and non-Q-wave MI. o For prolonged VTE prophylaxis. • Patients with prior hypersensitivity to heparin or pork products. • Active major bleeding ( 4 ) • History of heparin induced thrombocytopenia or heparin induced thrombocytopenia with thrombosis ( 4 ) • Hypersensitivity to dalteparin sodium ( 4 , 6.1 ) • In patients undergoing Epidural/Neuraxial anesthesia, do not administer FRAGMIN ( 5.1 ) o As a treatment for unstable angina and non-Q-wave MI o For prolonged VTE prophylaxis ( 4 ) • Hypersensitivity to heparin or pork products ( 4 )

7 DRUG INTERACTIONS The use of FRAGMIN in patients receiving oral anticoagulants, platelet inhibitors, and thrombolytic agents may increase the risk of bleeding [see Warnings and Precautions (5) ] . The use of FRAGMIN in patients receiving oral anticoagulants, platelet inhibitors, and thrombolytic agents may increase the risk of bleeding ( 7 )

8.1 Pregnancy Risk Summary Available data from published literature and postmarketing reports have not reported a clear association with FRAGMIN and adverse developmental outcomes. There are risks to the mother associated with untreated VTE in pregnancy, and a potential for adverse effects on the preterm infant when FRAGMIN is used in pregnancy (see Clinical Considerations ) . In animal reproduction studies, there was no evidence of embryo-fetal toxicity or teratogenicity when dalteparin sodium was administered to pregnant rats and rabbits during organogenesis at doses 2 to 4 times (rats) and 4 times (rabbits) the human dose of 100 units/kg dalteparin based on the body surface area (see Data ) . Because animal reproduction studies are not always predictive of human response, FRAGMIN should be used during pregnancy only if clearly needed. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Published data describe that women with a previous history of VTE in pregnancy are at higher risk for recurrence during subsequent pregnancies compared to those with no risk factor for VTE (4.5% versus 2.7% respectively, relative risk 1.7, 95% CI: 1.0–2.8). Fetal/Neonatal Adverse Reactions Cases of "gasping syndrome" have occurred in premature infants when large amounts of benzyl alcohol have been administered (99 mg/kg/day to 404 mg/kg/day). The 3.8 mL multiple-dose vials of FRAGMIN contain 14 mg/mL of benzyl alcohol [see Warnings and Precautions (5.3) ] . Data Animal Data In reproductive and developmental toxicity studies, pregnant rats and rabbits received dalteparin sodium during organogenesis at intravenous doses up to 2,400 units/kg (14,160 units/m 2 ) (rats) and 4,800 units/kg (40,800 units/m 2 ) (rabbits). These exposures were 2 to 4 times (rats) and 4 times (rabbits) the human dose of 100 units/kg dalteparin based on the body surface area. These studies revealed no evidence of teratogenicity or embryo-fetal toxicity.

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…