Caplacizumab is a parenteral von Willebrand factor-directed antibody fragment indicated for the treatment of adults with acquired thrombotic thrombocytopenic purpura (aTTP), in combination with plasma exchange and immunosuppressive therapy. The efficacy of caplacizumab was established based on time to platelet count response (platelet count of 150,000/mm3 or more with discontinuation of daily plasma exchange within 5 days). Median time to platelet count normalization was shorter with caplacizumab than with placebo (2.69 days [95% CI, 1.89 to 2.83] vs. 2.88 days [95% CI, 2.68 to 3.56], p = 0.01). Treatment resulted in a lower number of patients with TTP-related death (0 vs. 3) and TTP recurrence (3 vs. 28). The proportion of patients with TTP recurrence in the overall study period (which included the treatment period and the 28-day follow-up period) was significantly lower in the treatment group (13%) compared to the placebo group (38%). Caplacizumab reduced the burden of care by reducing the number of plasma exchange sessions, length of hospital stay, and length of stay in the intensive care unit. Caplacizumab increases the risk of bleeding; severe or serious bleeding events reported in caplacizumab-treated patients included epistaxis, gingival bleeding, upper gastrointestinal bleeding, metrorrhagia, and subarachnoid hemorrhage. Life-threatening, fatal bleeding has been reported with postmarketing use.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific 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.
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).
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.
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.
Cases of life-threatening and fatal bleeding have been reported with postmarketing use of caplacizumab. Interrupt use if clinically significant bleeding occurs. Administer von Willebrand factor concentrate if rapid correction of hemostasis is required. Closely monitor patients for signs of bleeding if caplacizumab is restarted. Overall, bleeding events occurred in approximately 58% of caplacizumab-treated patients compared to 43% of patients given placebo during clinical trials. Epistaxis (29%) and gingival bleeding (16%) were among the most common adverse reactions reported during clinical trials. Severe bleeding adverse reactions of epistaxis, gingival bleeding, upper GI bleeding, and metrorrhagia were each reported in 1% of patients. Serious bleeding adverse reactions included epistaxis (4%) and subarachnoid hemorrhage (2%). Injection site hemorrhage (6%), catheter site hemorrhage (6%), rectal hemorrhage (4%), abdominal wall hematoma (3%), hematuria (4%), vaginal bleeding (5%), and menorrhagia (4%) were also reported.
Headache (21%), paresthesias (12%), back pain (7%), and myalgia (6%) were reported in patients treated with caplacizumab during clinical trials.
Fatigue (15%), fever (13%), urinary tract infection (6%), and dyspnea (9%) were reported in patients treated with caplacizumab during clinical trials. Urticaria (14%) was seen during plasma exchange.
An injection site reaction including pruritus (3%), hemorrhage (6%), and erythema have been reported in patients treated with caplacizumab.
Antibody formation can occur with caplacizumab use. The prevalence of preexisting antibodies binding to caplacizumab observed during clinical trials and evaluation of commercially available human samples varied between 4% and 63%. In aTTP patients, preexisting antibodies can be produced by the patient or can originate from donor plasma during plasma exchange. No clinically apparent impact of these preexisting antibodies on clinical efficacy or safety was found. Treatment-emergent antidrug antibodies against caplacizumab were detected in 3% of caplacizumab-treated patients in the HERCULES study. These antibodies were characterized as having neutralizing potential; however, there was no clinically apparent impact on efficacy or safety. The observed incidence of antibody positivity may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease.
Caplacizumab is contraindicated in patients with a previous severe hypersensitivity reaction to caplacizumab or any of the excipients.
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.
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.
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.
For the treatment of acquired thrombotic thrombocytopenia purpura in combination with plasma exchange and immunosuppressive therapy:
NOTE: Caplacizumab has been designated orphan drug status for this indication.
Intravenous or Subcutaneous dosage:
Adults: 11 mg IV as a single dose at least 15 minutes prior to plasma exchange, followed by 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 acquired thrombotic thrombocytopenia purpura occur while on therapy. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Maximum Dosage Limits:
-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.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
Abciximab: (Major) Avoid concomitant use of caplacizumab and platelet inhibitors when possible. Assess and monitor closely for bleeding if use together is necessary. Interrupt use of caplacizumab if clinically significant bleeding occurs.
Acetaminophen; Aspirin, ASA; Caffeine: (Major) Avoid concomitant use of caplacizumab and aspirin when possible. Assess and monitor closely for bleeding if use together is necessary. Interrupt use of caplacizumab if clinically significant bleeding occurs.
Acetaminophen; Aspirin: (Major) Avoid concomitant use of caplacizumab and aspirin when possible. Assess and monitor closely for bleeding if use together is necessary. Interrupt use of caplacizumab if clinically significant bleeding occurs.
Acetaminophen; Aspirin; Diphenhydramine: (Major) Avoid concomitant use of caplacizumab and aspirin when possible. Assess and monitor closely for bleeding if use together is necessary. Interrupt use of caplacizumab if clinically significant bleeding occurs.
Anagrelide: (Major) Avoid concomitant use of caplacizumab and platelet inhibitors when possible. Assess and monitor closely for bleeding if use together is necessary. Interrupt use of caplacizumab if clinically significant bleeding occurs.
Anticoagulants: (Major) Avoid concomitant use of caplacizumab and anticoagulants when possible. Assess and monitor closely for bleeding if use together is necessary. Interrupt use of caplacizumab if clinically significant bleeding occurs.
Antithrombin III: (Major) Avoid concomitant use of caplacizumab and anticoagulants when possible. Assess and monitor closely for bleeding if use together is necessary. Interrupt use of caplacizumab if clinically significant bleeding occurs.
Apixaban: (Major) Avoid concomitant use of caplacizumab and anticoagulants when possible. Assess and monitor closely for bleeding if use together is necessary. Interrupt use of caplacizumab if clinically significant bleeding occurs.
Argatroban: (Major) Avoid concomitant use of caplacizumab and anticoagulants when possible. Assess and monitor closely for bleeding if use together is necessary. Interrupt use of caplacizumab if clinically significant bleeding occurs.
Aspirin, ASA: (Major) Avoid concomitant use of caplacizumab and aspirin when possible. Assess and monitor closely for bleeding if use together is necessary. Interrupt use of caplacizumab if clinically significant bleeding occurs.
Aspirin, ASA; Butalbital; Caffeine: (Major) Avoid concomitant use of caplacizumab and aspirin when possible. Assess and monitor closely for bleeding if use together is necessary. Interrupt use of caplacizumab if clinically significant bleeding occurs.
Aspirin, ASA; Caffeine: (Major) Avoid concomitant use of caplacizumab and aspirin when possible. Assess and monitor closely for bleeding if use together is necessary. Interrupt use of caplacizumab if clinically significant bleeding occurs.
Aspirin, ASA; Caffeine; Orphenadrine: (Major) Avoid concomitant use of caplacizumab and aspirin when possible. Assess and monitor closely for bleeding if use together is necessary. Interrupt use of caplacizumab if clinically significant bleeding occurs.
Aspirin, ASA; Carisoprodol; Codeine: (Major) Avoid concomitant use of caplacizumab and aspirin when possible. Assess and monitor closely for bleeding if use together is necessary. Interrupt use of caplacizumab if clinically significant bleeding occurs.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Major) Avoid concomitant use of caplacizumab and aspirin when possible. Assess and monitor closely for bleeding if use together is necessary. Interrupt use of caplacizumab if clinically significant bleeding occurs.
Aspirin, ASA; Dipyridamole: (Major) Avoid concomitant use of caplacizumab and aspirin when possible. Assess and monitor closely for bleeding if use together is necessary. Interrupt use of caplacizumab if clinically significant bleeding occurs. (Major) Avoid concomitant use of caplacizumab and platelet inhibitors when possible. Assess and monitor closely for bleeding if use together is necessary. Interrupt use of caplacizumab if clinically significant bleeding occurs.
Aspirin, ASA; Omeprazole: (Major) Avoid concomitant use of caplacizumab and aspirin when possible. Assess and monitor closely for bleeding if use together is necessary. Interrupt use of caplacizumab if clinically significant bleeding occurs.
Aspirin, ASA; Oxycodone: (Major) Avoid concomitant use of caplacizumab and aspirin when possible. Assess and monitor closely for bleeding if use together is necessary. Interrupt use of caplacizumab if clinically significant bleeding occurs.
Betrixaban: (Major) Avoid concomitant use of caplacizumab and anticoagulants when possible. Assess and monitor closely for bleeding if use together is necessary. Interrupt use of caplacizumab if clinically significant bleeding occurs.
Bivalirudin: (Major) Avoid concomitant use of caplacizumab and anticoagulants when possible. Assess and monitor closely for bleeding if use together is necessary. Interrupt use of caplacizumab if clinically significant bleeding occurs.
Butalbital; Aspirin; Caffeine; Codeine: (Major) Avoid concomitant use of caplacizumab and aspirin when possible. Assess and monitor closely for bleeding if use together is necessary. Interrupt use of caplacizumab if clinically significant bleeding occurs.
Cangrelor: (Major) Avoid concomitant use of caplacizumab and cangrelor when possible. Assess and monitor closely for bleeding if use together is necessary. Interrupt use of caplacizumab if clinically significant bleeding occurs.
Cilostazol: (Major) Avoid concomitant use of caplacizumab and platelet inhibitors when possible. Assess and monitor closely for bleeding if use together is necessary. Interrupt use of caplacizumab if clinically significant bleeding occurs.
Clopidogrel: (Major) Avoid concomitant use of caplacizumab and platelet inhibitors when possible. Assess and monitor closely for bleeding if use together is necessary. Interrupt use of caplacizumab if clinically significant bleeding occurs.
Dabigatran: (Major) Avoid concomitant use of caplacizumab and anticoagulants when possible. Assess and monitor closely for bleeding if use together is necessary. Interrupt use of caplacizumab if clinically significant bleeding occurs.
Dalteparin: (Major) Avoid concomitant use of caplacizumab and anticoagulants when possible. Assess and monitor closely for bleeding if use together is necessary. Interrupt use of caplacizumab if clinically significant bleeding occurs.
Dipyridamole: (Major) Avoid concomitant use of caplacizumab and platelet inhibitors when possible. Assess and monitor closely for bleeding if use together is necessary. Interrupt use of caplacizumab if clinically significant bleeding occurs.
Edoxaban: (Major) Avoid concomitant use of caplacizumab and anticoagulants when possible. Assess and monitor closely for bleeding if use together is necessary. Interrupt use of caplacizumab if clinically significant bleeding occurs.
Enoxaparin: (Major) Avoid concomitant use of caplacizumab and anticoagulants when possible. Assess and monitor closely for bleeding if use together is necessary. Interrupt use of caplacizumab if clinically significant bleeding occurs.
Eptifibatide: (Major) Avoid concomitant use of caplacizumab and platelet inhibitors when possible. Assess and monitor closely for bleeding if use together is necessary. Interrupt use of caplacizumab if clinically significant bleeding occurs.
Fondaparinux: (Major) Avoid concomitant use of caplacizumab and anticoagulants when possible. Assess and monitor closely for bleeding if use together is necessary. Interrupt use of caplacizumab if clinically significant bleeding occurs.
Heparin: (Major) Avoid concomitant use of caplacizumab and anticoagulants when possible. Assess and monitor closely for bleeding if use together is necessary. Interrupt use of caplacizumab if clinically significant bleeding occurs.
Pentosan: (Major) Avoid concomitant use of caplacizumab and anticoagulants when possible. Assess and monitor closely for bleeding if use together is necessary. Interrupt use of caplacizumab if clinically significant bleeding occurs.
Platelet Inhibitors: (Major) Avoid concomitant use of caplacizumab and platelet inhibitors when possible. Assess and monitor closely for bleeding if use together is necessary. Interrupt use of caplacizumab if clinically significant bleeding occurs.
Prasugrel: (Major) Avoid concomitant use of caplacizumab and platelet inhibitors when possible. Assess and monitor closely for bleeding if use together is necessary. Interrupt use of caplacizumab if clinically significant bleeding occurs.
Rivaroxaban: (Major) Avoid concomitant use of caplacizumab and anticoagulants when possible. Assess and monitor closely for bleeding if use together is necessary. Interrupt use of caplacizumab if clinically significant bleeding occurs.
Ticagrelor: (Major) Avoid concomitant use of caplacizumab and platelet inhibitors when possible. Assess and monitor closely for bleeding if use together is necessary. Interrupt use of caplacizumab if clinically significant bleeding occurs.
Tirofiban: (Major) Avoid concomitant use of caplacizumab and platelet inhibitors when possible. Assess and monitor closely for bleeding if use together is necessary. Interrupt use of caplacizumab if clinically significant bleeding occurs.
Vorapaxar: (Major) Avoid concomitant use of caplacizumab and platelet inhibitors when possible. Assess and monitor closely for bleeding if use together is necessary. Interrupt use of caplacizumab if clinically significant bleeding occurs.
Warfarin: (Major) Avoid concomitant use of caplacizumab and anticoagulants when possible. Assess and monitor closely for bleeding if use together is necessary. Interrupt use of caplacizumab if clinically significant bleeding occurs.
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. 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.
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.
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.
Affected cytochrome P450 isoenzymes and drug transporters: none
-Route-Specific Pharmacokinetics
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.
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.
-Special Populations
Hepatic Impairment
The effect of hepatic impairment on the pharmacokinetics of caplacizumab is unknown.
Renal Impairment
The pharmacokinetics of caplacizumab are not significantly influenced by renal impairment.
Geriatric
The pharmacokinetics of caplacizumab are not significantly influenced by age (18 to 79 years).
Gender Differences
The pharmacokinetics of caplacizumab are not significantly influenced by gender.
Ethnic Differences
The pharmacokinetics of caplacizumab are not significantly influenced by race.
Other
Blood Type
The pharmacokinetics of caplacizumab are not significantly influenced by blood type.