1. Dalteparin (Fragmin ® ) Anticoagulation Inpatient Management (AIM) Team 2009

2. Formulary update Understand dalteparin Mechanism of action Indications Pharmacokinetics Dose and Monitoring Warnings/contraindications Special considerations Obesity Renal impairment Latex allergies Bridging with warfarin Objectives

3. Formulary options for VTE Unfractionated heparin SQ IV infusion Low molecular weight heparin Enoxaparin (Lovenox ® ) Dalteparin (Fragmin ® )

4. Why the change? Dalteparin has been extensively studied as prophylaxis and treatment for venous thromboembolism (VTE) Data supporting its efficacy and safety suggest it has similar properties to enoxaparin Given the comparable efficacy and safety of dalteparin with enoxaparin, a change to dalteparin will create significant cost savings without any decline in clinical outcomes

5. All about the new agent…

6. Mechanism of action Low-molecular-weight-heparin (LMWH) Strongly inhibits both factor Xa and factor IIa (thrombin), with a higher ratio of antifactor Xa to antifactor IIa activity (Ratio=4)

7. Generic name Dalteparin Brand name Fragmin ® Manufacturer Eisai Drug Class Low Molecular Weight Heparin Approved by P&T March 2009 Replaces enoxaparin on formulary for VTE prophylaxis and treatment The Basics…

8. Clotting Cascade

9. Pharmacokinetics Absorption Bioavailability 81-93% Peak concentrations 4hrs Distribution Vd 40-60 mL/kg Metabolism Unknown Excretion T 1/2 2-5 hours pending ROA

10. Place in Therapy VTE prophylaxis VTE treatment Atrial Fibrillation Exception Acute Coronary Syndrome patients Neonates

11. Dosing Guide Prophylaxis Dalteparin 5000 international units (IU) subcutaneously daily Treatment Dalteparin 200 international units (IU)/kg SQ daily Dose based on Actual Body Weight (ABW)

12. Inpatient Dosing Patient Weight (kg)Dalteparin dose (IU/day) < 50 kgNot recommended 50.0 – 56.210,000 56.3 – 68.712,500 68.8 – 81.215,000 81.3 – 93.717,500 93.8 – 106.220,000 106.3 – 118.722,500 118.8 – 131.225,000 131.3 – 143.727,500 143.8 – 150.030,000 > 150.0 kgsNot recommended

13. Dosage formulations Multi-dose vials Dalteparin 25,000 international units/ml Use for Treatment doses Same syringe and process as Enoxaparin—VanishPoint Syringe Pre-filled syringes Dalteparin 5,000 international units syringes Use for Prophylaxis doses Sent with Cart fill

14. Dosing Key Points All subcutaneous injections administered at 1800 daily For both prophylaxis and treatment doses Available as 5000 international units prefilled syringes or drawn up syringes from the IV room Weight cap Minimum 50 kg Maximum 150 kg Doses should be rounded to the nearest 2500 international units Contraindicated in patients with CrCl <30 ml/min

15. How to inject Injection are administered subcutaneously Patient should be sitting or lying down Sites of injection U shaped area around the naval (preferred site) Upper outer quadrangle of buttock Upper outer side of thigh

16. How to inject With thumb and forefinger, pinch an inch at the site of injection, if unable to do so, move on to next site Do not expel air bubble in pre-filled syringes At a 45 to 90 degree angle, insert entire length of needle Doses of dalteparin are drawn up in VanishPoint syringes. http://www.vanishpoint.com/Simple4.aspx?PageID=174 http://www.vanishpoint.com/Simple4.aspx?PageID=174 Injection technique is same as the drawn up enoxaparin syringes from Pharmacy Dispose of syringe in Biohazard box

17. Monitoring Monitoring is not required for most of cases For special patient populations (obesity BMI >35, pregnancy, CrCl<30, etc), monitoring maybe considered Hematology consult should be called to assist with monitoring and mangement of such patients For Antifactor Xa level testing Blue top tubes should be labeled with the type of heparin the patient is on AND must have approval from Hematology Antifactor Xa level of 0.5 -1.5 for treatment Antifactor Xa levels may be drawn 4 hours after the third dose

18. Warnings/Precautions Use with caution in patients with increased risk of hemorrhage Bleeding diathesis, thrombocytopenia, active ulceration/recent gastrointestinal bleeding, hemorrhagic stroke, severe liver/kidney insufficiency

19. Warnings/Precautions  Use caution in case of history of thrombocytopenia (Plt <50,000), platelet defects or heparin-induced thrombocytopenia- refer to hematology  Severe liver or kidney insufficiency  Shortly after (< 48h) brain, spinal or ophthalmological surgery  Not intended for IM use  Active major bleeding, or thrombocytopenia associated with positive in vitro tests for antiplatelet antibody  CrCl < 30 ml/min

20. Contraindications Spinal or epidural hematomas Hx heparin-induced thrombocytopenia (HIT) Known hypersensitivity to heparin or pork products Hypersensitivity to dalteparin, heparin or pork product Spinal/epidural catheter or hematoma Do not exchange with heparin or other low molecular weight heparins (LMWHs)

21. Reversal: Protamine Initial Dose 1 mg protamine for every 100 international units dalteparin given based on previous dose Given as slow infusion not to exceed 50mg over 10 minutes Should a second dose be given??? Measure aPTT 2-4 hours after initial infusion, if aPTT is prolonged may administer second dose 0.5mg Protamine for every 100 international units dalteparin based on previous dose

22. Reversal: Protamine aPTT may remain elevated following protamine administration Anti-Factor Xa activity is never completely neutralized with protamine Maximum 60-75% neutralization

23. Other information Pregnancy Category B May use as bridge therapy to warfarin Latex Allergy MDV and Pre-filled syringes are latex free Education materials are available on the nursing floors and at the Family/Patient Education Center Patient Assistance Program is available contact social worker Outpatient insurance coverage Yes, but may require prior authorization

24. Key Points to Remember Dalteparin for all indications except ACS and neonates Dose Prophylaxis 5000 international units subcutaneous daily Treatment 200 international units/kg subcutaneous daily Administered @ 1800, round to nearest 2500 international units Weights 50-150 kg Contraindicated in CrCl <30 ml/min Use caution in pt at high risk of bleeding Contraindicated in pts with epidurals Protamine may be used as reversal, but not complete Latex Free Education materials and patient assistance program available

25. Patient Education Education available as Dalteparin teaching kit from Patient Education Department DVD/video on ON-DEMAND channel Consults for AIM team may be requested if the patient requires further education

26. Discharge Dosing Inpatient dosing different from Outpatient dosing due to the availability of multi-dose vials Available Outpatient Pre-filled syringes 2500 IU 5000 IU 7500 IU 10,000 IU 12,5000 IU 15,000 IU 18,000 IU

27. Outpatient Dosing Weight (kg)Dalteparin pre-filled syringe ONCE daily dosing 50.0 – 56.210,000 IU 56.3 – 68.712,500 IU 68.8 – 81.215,000 IU 81.3 – 93.718,000 IU 93.8 – 112.520,000 IU 112.6 –137.525,000 IU 137.6 –150.030,000 IU Outpatient dosing adjusted to commmercially available pre-filled syringes

28. SCM Charting—Task List

29. When will this change happen? Effective DECEMBER 1, 2009 Enoxaparin  Dalteparin conversion Pharmacist receive reports of patients on enoxaparin and will notify MDs the morning of 12/1/09 There is no issue with patients on q12hr dosing and they receive the 0900 dose. The Dalteparin dose will begin at 1800 that day MDs have until 2pm to change the order to Dalteparin Please contact MDs if changes are not in by 2pm

30. References: British Journal of Haematology 2003;121:12. Dalteparin. Package Insert. Eisai Inc. 2007 Dunn CJ, et al.Drugs 2000:60(1):203 AIM team: pager 215-312-0021