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  • CLASSES

    Other Hematological Agents

    DEA CLASS

    Rx

    DESCRIPTION

    Parenteral von Willebrand factor-directed antibody fragment
    Used for acquired thrombotic thrombocytopenic purpura, in combination with plasma exchange and immunosuppressive therapy
    Associated with increased risk of bleeding

    COMMON BRAND NAMES

    CABLIVI

    HOW SUPPLIED

    CABLIVI Intravenous Inj Pwd: 11mg
    CABLIVI Subcutaneous Inj Pwd: 11mg

    DOSAGE & INDICATIONS

    For the treatment of acquired thrombotic thrombocytopenia purpura (aTTP), in combination with plasma exchange and immunosuppressive therapy.
    Intravenous dosage (initial dose)
    Adults

    11 mg IV once at least 15 minutes prior to plasma exchange on the first day of treatment.

    Subcutaneous dosage (maintenance dose)
    Adults

    11 mg subcutaneously once daily starting after the completion of plasma exchange on day 1 and continuing for 30 days after the last daily plasma exchange. Treatment may be extended for a maximum of 28 days after the initial treatment course if signs of persistent underlying disease remain present (e.g., suppressed ADAMTS13 activity concentrations). Discontinue caplacizumab if more than 2 recurrences of aTTP occur while on therapy.[63940]

    MAXIMUM DOSAGE

    Adults

    11 mg/dose IV or subcutaneously.

    Geriatric

    11 mg/dose IV or subcutaneously.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration whenever solution and container permit. The reconstituted solution should be clear and colorless.
    If a dose is missed during the plasma exchange period, give the dose as soon as possible. If a dose is missed after the plasma exchange period, administer the dose within 12 hours of the scheduled time of administration; beyond 12 hours, skip the dose and administer the next daily dose according to the usual dosing schedule.[63940]
     
    Reconstitution
    Ensure the caplacizumab vial and diluent syringe are at room temperature.
    Reconstitute the caplacizumab vial using the provided syringe containing 1 mL of Sterile Water for Injection to yield an 11 mg/mL single-dose solution.
    Attach the vial adapter to the caplacizumab vial.
    Attach the syringe to the vial adapter by twisting it clockwise until it cannot twist any further.
    Slowly push the syringe plunger down until the syringe is empty. Do not remove the syringe from the vial adapter.
    Gently swirl the vial until the cake or powder is completely dissolved; do not shake.
    Withdraw all the reconstituted solution from the vial into the syringe.
    Storage: Use immediately. If not, use within 4 hours after reconstitution when stored in the refrigerator at 2 to 8 degrees C (36 to 46 degrees F).[63940]

    Intravenous Administration

    The first dose of caplacizumab should be administered by a healthcare provider as a bolus IV injection.
    Connect the glass syringe to a standard Luer lock (and not a needleless connector), and flush with either 0.9% Sodium Chloride Injection or 5% Dextrose Injection.[63940]

    Subcutaneous Administration

    After the first IV dose, administer subsequent caplacizumab doses subcutaneously in the abdomen.
    Avoid injections around the navel. Do not administer consecutive injections in the same abdominal quadrant.
    Patients or caregivers may inject caplacizumab subcutaneously after proper training on preparation and administration techniques.[63940]

    STORAGE

    CABLIVI:
    - Discard unused portion. Do not store for later use.
    - Do not freeze
    - May be stored at room temperature not exceeding 86 degrees F for up to 2 months
    - Product stored at controlled room temperature should not be returned to a refrigerator
    - Protect from light
    - Reconstituted product should be refrigerated (36 to 46 degrees F) and used within 4 hours if not used immediately
    - See package insert for detailed storage information
    - Store in carton
    - Store unreconstituted product in refrigerator (36 to 46 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Caplacizumab is contraindicated in patients with a previous severe hypersensitivity reaction to caplacizumab or any of the excipients.

    Bleeding, coagulopathy, dental work, hemophilia, surgery

    Caplacizumab increases the risk of bleeding, particularly in patients with an underlying coagulopathy (e.g., hemophilia, other coagulation factor deficiencies) and with concomitant use of drugs that affect hemostasis and coagulation. Interrupt use if clinically significant bleeding occurs. Administer von Willebrand factor concentrate if rapid correction of hemostasis is required. Monitor patients closely for signs of bleeding if caplacizumab is restarted. Withhold caplacizumab for 7 days prior to elective surgery, dental procedures (dental work), or other invasive interventions. Consider administration of von Willebrand factor concentrate to correct hemostasis if emergency surgery is needed. Monitor patients closely for bleeding after risk of surgical bleeding has resolved and caplacizumab is resumed.[63940]

    Hepatic disease

    Closely monitor patients with severe hepatic disease for bleeding due to a potential increased risk of bleeding. No formal studies with caplacizumab have been conducted in patients with severe acute or chronic hepatic impairment.[63940]  

    Pregnancy

    All patients receiving caplacizumab, including pregnant women, are at risk for bleeding. In utero exposure may also increase the risk of bleeding in the fetus and neonate. Closely monitor pregnant women and neonates born to those receiving the drug for bleeding. There are no available data on caplacizumab use in human pregnancy to inform a drug-associated risk of major birth defects and miscarriage. In animal reproduction studies, there was no evidence of adverse developmental outcomes in guinea pigs at exposures approximately 30 times the AUC in humans at the recommended dose.

    Breast-feeding

    There is no information regarding the presence of caplacizumab in human milk, the effects on the breast-fed child, or the effects on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for caplacizumab and any potential adverse effects on the breast-fed child from caplacizumab or the underlying maternal condition.[63940]

    ADVERSE REACTIONS

    Severe

    epistaxis / Delayed / 1.0-4.0
    GI bleeding / Delayed / 1.0-1.0

    Moderate

    bleeding / Early / 58.0-58.0
    dyspnea / Early / 9.0-9.0
    vaginal bleeding / Delayed / 5.0-5.0
    hematuria / Delayed / 4.0-4.0
    hematoma / Early / 3.0-3.0
    antibody formation / Delayed / Incidence not known

    Mild

    headache / Early / 21.0-21.0
    fatigue / Early / 15.0-15.0
    urticaria / Rapid / 14.0-14.0
    fever / Early / 13.0-13.0
    paresthesias / Delayed / 12.0-12.0
    back pain / Delayed / 7.0-7.0
    myalgia / Early / 6.0-6.0
    infection / Delayed / 6.0-6.0
    injection site reaction / Rapid / 3.0-6.0
    menorrhagia / Delayed / 4.0-4.0

    DRUG INTERACTIONS

    Anticoagulants: (Moderate) Assess and monitor closely for bleeding with concomitant use of caplacizumab and anticoagulants. Concomitant use of caplacizumab with any anticoagulant may increase the risk of bleeding. Interrupt caplacizumab use if clinically significant bleeding occurs.
    Antithrombin III: (Moderate) Assess and monitor closely for bleeding with concomitant use of caplacizumab and anticoagulants. Concomitant use of caplacizumab with any anticoagulant may increase the risk of bleeding. Interrupt caplacizumab use if clinically significant bleeding occurs.
    Apixaban: (Moderate) Assess and monitor closely for bleeding with concomitant use of caplacizumab and anticoagulants. Concomitant use of caplacizumab with any anticoagulant may increase the risk of bleeding. Interrupt caplacizumab use if clinically significant bleeding occurs.
    Argatroban: (Moderate) Assess and monitor closely for bleeding with concomitant use of caplacizumab and anticoagulants. Concomitant use of caplacizumab with any anticoagulant may increase the risk of bleeding. Interrupt caplacizumab use if clinically significant bleeding occurs.
    Betrixaban: (Moderate) Assess and monitor closely for bleeding with concomitant use of caplacizumab and anticoagulants. Concomitant use of caplacizumab with any anticoagulant may increase the risk of bleeding. Interrupt caplacizumab use if clinically significant bleeding occurs.
    Bivalirudin: (Moderate) Assess and monitor closely for bleeding with concomitant use of caplacizumab and anticoagulants. Concomitant use of caplacizumab with any anticoagulant may increase the risk of bleeding. Interrupt caplacizumab use if clinically significant bleeding occurs.
    Dabigatran: (Moderate) Assess and monitor closely for bleeding with concomitant use of caplacizumab and anticoagulants. Concomitant use of caplacizumab with any anticoagulant may increase the risk of bleeding. Interrupt caplacizumab use if clinically significant bleeding occurs.
    Dalteparin: (Moderate) Assess and monitor closely for bleeding with concomitant use of caplacizumab and anticoagulants. Concomitant use of caplacizumab with any anticoagulant may increase the risk of bleeding. Interrupt caplacizumab use if clinically significant bleeding occurs.
    Danaparoid: (Moderate) Assess and monitor closely for bleeding with concomitant use of caplacizumab and anticoagulants. Concomitant use of caplacizumab with any anticoagulant may increase the risk of bleeding. Interrupt caplacizumab use if clinically significant bleeding occurs.
    Desirudin: (Moderate) Assess and monitor closely for bleeding with concomitant use of caplacizumab and anticoagulants. Concomitant use of caplacizumab with any anticoagulant may increase the risk of bleeding. Interrupt caplacizumab use if clinically significant bleeding occurs.
    Edoxaban: (Moderate) Assess and monitor closely for bleeding with concomitant use of caplacizumab and anticoagulants. Concomitant use of caplacizumab with any anticoagulant may increase the risk of bleeding. Interrupt caplacizumab use if clinically significant bleeding occurs.
    Enoxaparin: (Moderate) Assess and monitor closely for bleeding with concomitant use of caplacizumab and anticoagulants. Concomitant use of caplacizumab with any anticoagulant may increase the risk of bleeding. Interrupt caplacizumab use if clinically significant bleeding occurs.
    Fondaparinux: (Moderate) Assess and monitor closely for bleeding with concomitant use of caplacizumab and anticoagulants. Concomitant use of caplacizumab with any anticoagulant may increase the risk of bleeding. Interrupt caplacizumab use if clinically significant bleeding occurs.
    Heparin: (Moderate) Assess and monitor closely for bleeding with concomitant use of caplacizumab and anticoagulants. Concomitant use of caplacizumab with any anticoagulant may increase the risk of bleeding. Interrupt caplacizumab use if clinically significant bleeding occurs.
    Lepirudin: (Moderate) Assess and monitor closely for bleeding with concomitant use of caplacizumab and anticoagulants. Concomitant use of caplacizumab with any anticoagulant may increase the risk of bleeding. Interrupt caplacizumab use if clinically significant bleeding occurs.
    Pentosan: (Moderate) Assess and monitor closely for bleeding with concomitant use of caplacizumab and anticoagulants. Concomitant use of caplacizumab with any anticoagulant may increase the risk of bleeding. Interrupt caplacizumab use if clinically significant bleeding occurs.
    Rivaroxaban: (Moderate) Assess and monitor closely for bleeding with concomitant use of caplacizumab and anticoagulants. Concomitant use of caplacizumab with any anticoagulant may increase the risk of bleeding. Interrupt caplacizumab use if clinically significant bleeding occurs.
    Tinzaparin: (Moderate) Assess and monitor closely for bleeding with concomitant use of caplacizumab and anticoagulants. Concomitant use of caplacizumab with any anticoagulant may increase the risk of bleeding. Interrupt caplacizumab use if clinically significant bleeding occurs.
    Warfarin: (Moderate) Assess and monitor closely for bleeding with concomitant use of caplacizumab and anticoagulants. Concomitant use of caplacizumab with any anticoagulant may increase the risk of bleeding. Interrupt caplacizumab use if clinically significant bleeding occurs.

    PREGNANCY AND LACTATION

    Pregnancy

    All patients receiving caplacizumab, including pregnant women, are at risk for bleeding. In utero exposure may also increase the risk of bleeding in the fetus and neonate. Closely monitor pregnant women and neonates born to those receiving the drug for bleeding. There are no available data on caplacizumab use in human pregnancy to inform a drug-associated risk of major birth defects and miscarriage. In animal reproduction studies, there was no evidence of adverse developmental outcomes in guinea pigs at exposures approximately 30 times the AUC in humans at the recommended dose.

    There is no information regarding the presence of caplacizumab in human milk, the effects on the breast-fed child, or the effects on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for caplacizumab and any potential adverse effects on the breast-fed child from caplacizumab or the underlying maternal condition.[63940]

    MECHANISM OF ACTION

    Caplacizumab targets the A1-domain of von Willebrand factor (vWF) and inhibits the interaction between vWF and platelets, thus reducing both vWF-mediated platelet adhesion and platelet consumption.[63940] In acquired thrombotic thrombocytopenic purpura (aTTP), autoantibodies inhibit activity of the vWF-cleaving protease ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), which leads to unrestrained adhesion of vWF to platelets and microvascular thrombosis.[63946]

    PHARMACOKINETICS

    Caplacizumab is administered intravenously as an initial bolus, then subcutaneously thereafter. Caplacizumab pharmacokinetics depend on the expression of the target von Willebrand factor (vWF) and are not dose proportional. Higher concentrations of vWF antigen increase the fraction of drug-target complex retained in the circulation. Central volume of distribution is 6.33 L. Available data suggest target-bound caplacizumab is hepatically metabolized. Because caplacizumab is a monoclonal antibody fragment, it is expected to be catabolized by various proteolytic enzymes. Nonclinical data suggest unbound caplacizumab is renally eliminated. The half-life is concentration and target-level dependent.[63940]
     
    Ristocetin cofactor (RICO) activity was used to assess vWF activity during clinical trials. Caplacizumab decreased RICO activity concentrations to below 20% approximately 4 hours after subcutaneous administration. RICO activity returned to baseline values within 7 days of drug discontinuation. Caplacizumab also decreased vWF antigen factor and factor VIII:C concentrations; these reductions were transient and returned to baseline upon drug discontinuation.[63940]
     
    Affected cytochrome P450 isoenzymes and drug transporters: none

    Intravenous Route

    Steady-state was attained after the first administration of caplacizumab in healthy subjects, with minimal accumulation. The initial dose of caplacizumab is administered via IV bolus.[63940]

    Subcutaneous Route

    The bioavailability of subcutaneous caplacizumab is approximately 90%. Tmax occurs 6 to 7 hours after subcutaneous administration. Mean Cmax was 528 ng/mL and AUC was 7,951 ng x hour/mL after a single subcutaneous dose of 10 mg in healthy subjects. After once daily dosing for 14 days, mean Cmax was 348 ng/mL and AUC was 6,808 ng x hour/mL.