FRAGMIN, Dalteparin Sodium Form

Dalteparin (Fragmin®) is a low molecular weight heparin (LMWH). ____ For Health Insurance Marketplace (HIM), if request is through pharmacy benefit, Fragmin 95,000 units/3.8 mL is non-formulary and should not be approved using these criteria; refer to the formulary exception policy, HIM.PA.103.
FDA Approved Indication(s) Fragmin is indicated: • For prophylaxis of ischemic complications in unstable angina and non-Q-wave myocardial infarction, when concurrently administered with aspirin therapy; • For prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE): o In patients undergoing hip replacement surgery; o In patients undergoing abdominal surgery who are at risk for thromboembolic complications; o In medical patients who are at risk for thromboembolic complications due to severely restricted mobility during acute illness; • For 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. • For treatment of symptomatic venous thromboembolism (VTE) to reduce the recurrence in pediatric patients 1 month of age and older. Limitation(s) of use: Fragmin is not indicated for the acute treatment of VTE. Policy/Criteria Provider must submit documentation (including such as office chart notes, lab results or other clinical information) supporting that member has met all approval criteria. It is the policy of health plans affiliated with Centene Corporation® that Fragmin is medically necessary when the following criteria are met: I. Initial Approval Criteria A. Thrombosis/Thromboembolism (must meet all):

1. Any of the following indications (a, b, or c): Page 1 of 10

   CLINICAL POLICY Dalteparin a. Thrombosis or thromboembolism prevention associated with any of the following conditions: i. Cancer (see Appendix D); ii. Unstable angina or myocardial infarction; iii. Atrial fibrillation or prosthetic heart valve; iv. Major surgery - orthopedic or non-orthopedic; v. Critical illness related to ICU admissions or events; vi. Restricted mobility associated with acute illnesses or conditions; vii. Implanted devices-vascular (e.g., central venous access device, umbilical venous catheter, devices/fistulas related to hemodialysis, ventricular assist devices); b. Thrombosis or thromboembolism treatment; c. Short-term prophylaxis for transition to or from oral anticoagulation;

   2. Failure of a trial of enoxaparin unless (a, b, or c): a. Enoxaparin is contraindicated; b. History of clinically significant adverse effects to enoxaparin; c. The requested use is FDA labeled for dalteparin but not for enoxaparin (i.e., VTE treatment in patients with cancer, treatment of symptomatic VTE in pediatrics). Approval duration:
      Medicaid – 6 months
      HIM – 6 months (refer to HIM.PA.103 for Fragmin 95,000 units/3.8 mL) Commercial – 6 months or to the member’s renewal date, whichever is longer *Includes off-label use for adults and pediatrics. B. Anticoagulation in Pregnancy: Ante- and Postpartum (off-label) (must meet all):
   3. Any of the following indications: a. Acute venous thrombosis during current pregnancy; b. Prior venous thrombosis; c. Receiving long-term therapy with a vitamin K antagonist (e.g., warfarin); d. Prosthetic heart valve; e. Inherited thrombophilia; f. Antiphospholipid antibody syndrome; g. Development of severe ovarian hyperstimulation syndrome post assisted reproduction; h. Cesarean section – current pregnancy and request is for the postpartum period. i. Any other indication not listed here that is listed in section I.A.
   4. Member is pregnant or < 6 months postpartum;

2. Failure of a trial of enoxaparin, unless contraindicated or clinically significant adverse effects are experienced. Approval duration: HIM – Antepartum (to estimated delivery date); postpartum (6 months) (refer to HIM.PA.103 for Fragmin 95,000 units/3.8 mL) Medicaid/Commercial – Antepartum (to estimated delivery date); postpartum (6 months) Page 2 of 10

   CLINICAL POLICY Dalteparin C. Other diagnoses/indications (must meet 1 or 2):

   1. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, and CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or
   2. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid. II. Continued Therapy A. Thrombosis/Thromboembolism (must meet all):
3. Member meets one of the following (a or b): a. Currently receiving medication via Centene benefit or member has previously met initial approval criteria; b. Member is currently receiving medication and is enrolled in a state and product with continuity of care regulations (refer to state specific addendums for CC.PHARM.03A and CC.PHARM.03B);
4. Member is responding positively to therapy;

5. Continued use is limited to any of the following indications (a, b, or c): a. Venous thrombosis prophylaxis or treatment in the presence of cancer; b. Past history of failed anticoagulation therapy (clot development) on a non- LMWH (e.g., failed therapy on heparin, fondaparinux, warfarin, apixaban, dabigatran, edoxaban, rivaroxaban); LMWHs include enoxaparin and dalteparin c. Any other indication in section I.A where bridging to warfarin is inappropriate or member has a contraindication to warfarin and extended (indefinite duration) anticoagulation therapy is required. Approval duration:
   Medicaid – 6 months HIM - 6 months (refer to HIM.PA.103 for Fragmin 95,000 units/3.8 mL) Commercial – 6 months or to the member’s renewal date, whichever is longer . B. Anticoagulation in Pregnancy: Ante- and Postpartum (off-label) (must meet all):

   1. Member meets one of the following (a or b): a. Currently receiving medication via Centene benefit or member has previously met initial approval criteria; Page 3 of 10

   CLINICAL POLICY Dalteparin b. Member is currently receiving medication and is enrolled in a state and product with continuity of care regulations (refer to state specific addendums for CC.PHARM.03A and CC.PHARM.03B);

6. Member is responding positively to therapy;

7. See Section II.A for continued anticoagulation therapy beyond 6 months postpartum. Approval duration: HIM – Antepartum (to estimated delivery date); postpartum (6 months) (refer to HIM.PA.103 for Fragmin 95,000 units/3.8 mL) Medicaid/Commercial – Antepartum (to estimated delivery date); postpartum (6 months) C. Other diagnoses/indications (must meet 1 or 2):

   1. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, and CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or
   2. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 2 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid.
      III. Diagnoses/Indications for which coverage is NOT authorized: A. Non-FDA approved indications, which are not addressed in this policy, unless there is sufficient documentation of efficacy and safety according to the off label use policies – CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid, or evidence of coverage documents. IV. Appendices/General Information
      Appendix A: Abbreviation/Acronym Key
      DVT: deep vein thrombosis LMWH: low molecular weight heparin
      NCCN: National Comprehensive Cancer Network
      PE: pulmonary embolism
      STEMI: ST-elevated myocardial infarction
      VTE: venous thromboembolism (typically refers to DVT or PE) Page 4 of 10

   CLINICAL POLICY Dalteparin Appendix B: Therapeutic Alternatives This table provides a listing of preferred alternative therapy recommended in the approval criteria. The drugs listed here may not be a formulary agent for all relevant lines of business and may require prior authorization. Drug Name Dosing Regimen Dose Limit/ Maximum Dose Dose as specified; duration may vary. enoxaparin (Lovenox®) Adults: DVT prophylaxis in abdominal surgery 40 mg SC once daily DVT prophylaxis in knee replacement surgery 30 mg SC every 12 hours DVT prophylaxis in hip replacement surgery 30 mg SC every 12 hours or 40 mg SC once daily DVT prophylaxis in medical patients 40 mg SC once daily Inpatient treatment or acute DVT with or without PE 1 mg/kg SC every 12 hours or 1.5 mg/kg SC once daily Outpatient treatment of acute DVT without PI 1 mg/kg SC every 12 hours Unstable angina and non-Q wave MI 1 mg/kg SC every 12 hours (with aspirin) Acute STEMI in patient < 75 years of age 30 mg single IV bolus plus a 1 mg/kg SC dose followed by 1 mg/kg SC every 12 hours (with aspirin) Acute STEMI in patient ≥ 75 years of age 0.75 mg/kg SC every 12 hours (no bolus) (with aspirin) Therapeutic alternatives are listed as Brand name® (generic) when the drug is available by brand name only and generic (Brand name®) when the drug is available by both brand and generic. Appendix C: Contraindications/Boxed Warnings • Contraindication(s): o Active major bleeding o History of heparin induced thrombocytopenia or heparin induced thrombocytopenia with thrombosis o Hypersensitivity to dalteparin sodium (e.g., pruritis, rash, anaphylactic reactions) o In patients undergoing epidural/neuraxial anesthesia, do not administer Fragmin o As a treatment for unstable angina and non-Q-wave MI o For prolonged VTE prophylaxis o Hypersensitivity to heparin or pork products • Boxed warning(s): spinal/epidural hematomas Page 5 of 10

   CLINICAL POLICY Dalteparin Appendix D: General Information • Per National Comprehensive Cancer Network (NCCN) guidelines for cancer-associated venous thromboembolic disease, dalteparin is recommended for: o Anticoagulation for management of acute superficial vein thrombosis, anticoagulation for acute DVT, acute catheter-related DVT, and/or acute pulmonary embolism, management of acute splanchnic vein thrombosis, or consider for management of chronic splanchnic vein thrombosis in cancer patients with no contraindication to anticoagulation (preferred for patients with gastric or gastroesophageal lesions):  administered as monotherapy  administered for at least 4 days given concurrently with warfarin until transition to warfarin monotherapy, prior to switching to edoxaban, prior to switching to dabigatran if preferred regimens not appropriate or unavailable
   o Anticoagulation for cancer patients following therapeutic anticoagulation failure with: heparin sodium, fondaparinux, warfarin sodium, apixaban, dabigatran, edoxaban, or rivaroxaban o Venous thromboembolism prophylaxis:  For adults with cancer (excluding basal/squamous cell skin cancer) or those for whom a clinical suspicion of cancer exists who are admitted for medical or surgical hospitalizations and no contraindication to anticoagulation
    For adults with cancer (excluding basal/squamous cell skin cancer) or those for whom a clinical suspicion of cancer exists who are admitted for surgical hospitalizations and requires preoperative dosing for high-risk surgery (e.g. abdominal/pelvic surgery) and no contraindication to anticoagulation
    For adults with advanced unresectable and metastatic pancreatic cancer receiving/starting systemic therapy for their cancer that are ambulatory with post- medical oncology discharge and assessed as intermediate or high risk for VTE based on Khorana score > 2
    For adults with cancer who are at risk in the ambulatory setting after discharge for up to 4 weeks postoperative following high-risk surgery (e.g. abdominal/pelvic)
   Maximum Dose Varies V. Dosage and Administration Indication Dosing Regimen Unstable angina and non-Q-wave MI DVT prophylaxis in abdominal surgery DVT prophylaxis in hip replacement surgery Adults: 120 IU/kg SC every 12 hours (with aspirin) Adults: 2,500 IU SC once daily or 5,000 IU SC once daily or 2,500 IU SC followed by 2,500 IU SC 12 hours later and then 5,000 IU SC once daily Adults:
   Postoperative start – 2,500 IU SC 4 to 8 hours after surgery, then 5,000 IU SC once daily or Preoperative start – day of surgery 2,500 IU SC 2 hours before surgery followed by 2,500 IU SC 4 to 8 hours after surgery, then 5,000 IU SC once daily Page 6 of 10

   CLINICAL POLICY Dalteparin Indication Dosing Regimen Maximum Dose DVT prophylaxis in medical Extended treatment of VTE in patients with cancer Treatment of VTE in pediatric patients Preoperative start – evening before surgery 5,000 IU SC followed by 5,000 IU SC 4 to 8 hours after surgery, then 5,000 IU once daily.
   Adults: 5,000 IU SC once daily Adults:
   Month 1: 200 IU/kg SC once daily
   Months 2 – 6: 150 IU/kg SC once daily Starting dose by age: 4 weeks to less than 2 years: 150 IU/kg SC BID 2 years to less than 8 years: 125 IU/kg SC BID 8 years to less than 17 years: 100 IU/kg SC BID Whenever possible, administer benzyl alcohol-free formulations (prefilled syringes) in pediatric patients.
   VI. Product Availability • Single-dose prefilled syringe: 2,500 IU/0.2 mL, 5,000 IU/0.2 mL, 7,500 IU/0.3 mL, 12,500 IU/0.5 mL, 15,000 IU/0.6 mL, 18,000 IU/0.72 mL • Single-dose graduated syringe: 10,000 IU/mL • Multiple-dose vial: 95,000 IU/3.8 mL • Single-dose vial: 10,000 IU/4 mL
   VII.