Caplacizumab
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Zach Leibowitz [2]
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Overview
Caplacizumab is a von Willebrand factor (vWF)-directed antibody fragment that is FDA approved for the treatment of adult patients with acquired thrombotic thrombocytopenia purpura (aTTP), in combination with plasma exchange and immunosuppressive therapy. Common adverse reactions include epistaxis, headache, and gingival bleeding.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Indication
- Caplacizumab is indicated for the treatment of adult patients with acquired thrombotic thrombocytopenia purpura (aTTP), in combination with plasma exchange and immunosuppressive therapy.
Dosages
- For injection: 11 mg as a white lyophilized powder in a single-dose vial.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding caplacizumab Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
Non–Guideline-Supported Use
There is limited information regarding caplacizumab Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
The safety and effectiveness of caplacizumab in pediatric patients have not been established.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding caplacizumab Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
Non–Guideline-Supported Use
There is limited information regarding caplacizumab Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
Contraindications
- Caplacizumab is contraindicated in patients with a previous severe hypersensitivity reaction to caplacizumab-yhdp or to any of the excipients. Hypersensitivity reactions have included urticaria.
Warnings
Bleeding
- Caplacizumab increases the risk of bleeding. In clinical studies, severe bleeding adverse reactions of epistaxis, gingival bleeding, upper gastrointestinal hemorrhage, and metrorrhagia were each reported in 1% of subjects. Overall, bleeding events occurred in approximately 58% of patients on caplacizumab versus 43% of patients on placebo.
- The risk of bleeding is increased in patients with underlying coagulopathies (e.g. hemophilia, other coagulation factor deficiencies). It is also increased with concomitant use of caplacizumab with drugs affecting hemostasis and coagulation.
- Interrupt use of caplacizumab if clinically significant bleeding occurs. If needed, von Willebrand factor concentrate may be administered to rapidly correct hemostasis. If caplacizumab is restarted, monitor closely for signs of bleeding.
- Withhold caplacizumab for 7 days prior to elective surgery, dental procedures or other invasive interventions. If emergency surgery is needed, the use of von Willebrand factor concentrate may be considered to correct hemostasis. After the risk of surgical bleeding has resolved, and caplacizumab is resumed, monitor closely for signs of bleeding.
Adverse Reactions
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 reflect the rates observed in practice.
- The safety of caplacizumab was evaluated in two placebo-controlled clinical studies (HERCULES, in which 71 patients received caplacizumab; and TITAN, in which 35 patients received caplacizumab). The data described below and in the Warnings and Precautions reflect exposure to caplacizumab during the blinded periods of both studies, which include 106 patients with aTTP who received at least one dose, age 18 to 79 years, of whom 69% were female and 73% were White. The median treatment duration with caplacizumab was 35 days (range 1–77 days).
- The most frequently reported adverse reactions (>15%) were epistaxis, headache and gingival bleeding. Seven patients (7%) in the caplacizumab group experienced an adverse reaction leading to study drug discontinuation. None of the adverse reactions leading to discontinuation were observed in more than 1% of patients.
- Among 106 patients treated with caplacizumab during the TITAN and HERCULES studies, serious bleeding adverse reactions reported in ≥2% patients included epistaxis (4%) and subarachnoid hemorrhage (2%).
- Adverse reactions that occurred in ≥2% of patients treated with caplacizumab and more frequently than in those treated with placebo across the pooled data from the two trials are summarized in Table 1. Urticaria was seen during plasma exchange.
Immunogenicity
- As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to caplacizumab-yhdp in the studies described below, with the incidence of antibodies in other studies, or to other products, may be misleading.
- The prevalence of pre-existing antibodies binding to caplacizumab-yhdp observed during clinical studies and during evaluation of commercially available human samples varied between 4% and 63%. In aTTP patients, pre-existing antibodies can be produced by the patient or can originate from donor plasma during plasma exchange. No clinically apparent impact of these pre-existing antibodies on clinical efficacy or safety was found. Treatment-emergent anti-drug antibodies (TE ADA) against caplacizumab-yhdp were detected in 3% of patients treated with caplacizumab in the HERCULES study. In the HERCULES study, TE ADA were further characterized as having neutralizing potential. There was no clinically apparent impact on clinical efficacy or safety.
Postmarketing Experience
There is limited information regarding Caplacizumab Postmarketing Experience in the drug label.
Drug Interactions
Concomitant Use of Anticoagulants
- Concomitant use of caplacizumab with any anticoagulant may increase the risk of bleeding. Assess and monitor closely for bleeding with concomitant use.
Use in Specific Populations
Pregnancy
Risk Summary
- There are no available data on caplacizumab use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. However, there are potential risks of hemorrhage in the mother and fetus associated with use of caplacizumab. In animal reproduction studies, there was no evidence of adverse developmental outcomes with intramuscular administration of caplacizumab-yhdp during organogenesis in guinea pigs at exposures approximately 30 times the AUC in humans at the recommended subcutaneous injection dose of 11 mg.
- All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The background rate of major birth defects and miscarriage in the indicated population is unknown. In the U.S. general population, the estimated background rate of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Clinical Considerations
- Caplacizumab may increase the risk of bleeding in the fetus and neonate. Monitor neonates for bleeding.
- All patients receiving caplacizumab, including pregnant women, are at risk for bleeding. Pregnant women receiving caplacizumab should be carefully monitored for evidence of excessive bleeding.
Data
- Two separate reproduction studies were conducted in pregnant guinea pigs with administration of caplacizumab-yhdp during the organogenesis period.
- In an embryo-fetal development study, caplacizumab-yhdp was administered intramuscularly at doses up to 20 mg/kg/day from gestational day (GD) 6 to GD 41 in guinea pigs. No maternal toxicity or adverse developmental outcomes were observed.
- In a toxicokinetic study assessing the exposure of caplacizumab-yhdp in the dams and fetuses, caplacizumab-yhdp was administered once daily to female guinea pigs at doses up to 40 mg/kg/day (corresponding to a drug exposure of approximately 30 times the AUC in humans at the recommended dose of 11 mg) by intramuscular injection from GD 6 to GD 41 or GD 61. Exposure to caplacizumab-yhdp was observed in the dams and fetuses, with no effects on embryo-fetal development.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Caplacizumab in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Caplacizumab during labor and delivery.
Nursing Mothers
- There is no information regarding the presence of caplacizumab-yhdp in human milk, the effects on the breastfed child or the effects on milk production.
- The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for caplacizumab and any potential adverse effects on the breastfed child from caplacizumab, or from the underlying maternal condition.
Pediatric Use
- The safety and effectiveness of caplacizumab in pediatric patients have not been established.
Geriatic Use
- Clinical studies of caplacizumab did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
Gender
There is no FDA guidance on the use of Caplacizumab with respect to specific gender populations.
Race
There is no FDA guidance on the use of Caplacizumab with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Caplacizumab in patients with renal impairment.
Hepatic Impairment
- No formal studies with caplacizumab have been conducted in patients with severe acute or chronic hepatic impairment and no data regarding the use of caplacizumab in these populations are available. Due to a potential increased risk of bleeding, use of caplacizumab in patients with severe hepatic impairment requires close monitoring for bleeding.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Caplacizumab in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Caplacizumab in patients who are immunocompromised.
Administration and Monitoring
Administration
Recommended Dose and Schedules
- Caplacizumab should be administered upon initiation of plasma exchange therapy. The recommended dose of caplacizumab is as follows:
- First day of treatment: 11 mg bolus intravenous injection at least 15 minutes prior to plasma exchange followed by an 11 mg subcutaneous injection after completion of plasma exchange on day 1.
- Subsequent days of treatment during daily plasma exchange: 11 mg subcutaneous injection once daily following plasma exchange.
- Treatment after plasma exchange period: 11 mg subcutaneous injection once daily continuing for 30 days following the last daily plasma exchange. If after initial treatment course, sign(s) of persistent underlying disease such as suppressed ADAMTS13 activity levels remain present, treatment may be extended for a maximum of 28 days.
- Discontinue caplacizumab if the patient experiences more than 2 recurrences of aTTP, while on caplacizumab.
Missed Dose
- If a dose of caplacizumab is missed during the plasma exchange period, it should be given as soon as possible. If a dose of caplacizumab is missed after the plasma exchange period, it can be administered within 12 hours of the scheduled time of administration. Beyond 12 hours, the missed dose should be skipped and the next daily dose administered according to the usual dosing schedule.
Discontinuation for Surgery and Other Interventions
- Withhold caplacizumab treatment 7 days prior to elective surgery, dental procedures, or other invasive interventions.
Reconstitution and Administration Instructions
- The first dose of caplacizumab should be administered by a healthcare provider as a bolus intravenous injection. Administer subsequent 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 the preparation and administration of caplacizumab, including aseptic technique.
- Ensure the caplacizumab vial and diluent syringe are at room temperature.
- Reconstitute caplacizumab before administration using the provided syringe containing 1 mL Sterile Water for Injection, USP, to yield an 11 mg/mL single-dose solution.
- Using aseptic technique throughout the preparation of the solution, attach the vial adapter to the vial containing caplacizumab.
- Remove the plastic cap from the syringe and attach it 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.
- Visually inspect that the reconstituted solution is clear and colorless.
- Withdraw all of the clear, colorless reconstituted solution from the vial into the syringe. Label the caplacizumab syringe.
- Administer the full amount of reconstituted solution.
- For the initial intravenous injection, if using an intravenous line, the glass syringe should be connected to a standard Luer lock (and not a needleless connector) and flushed with either 0.9% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP.
- Use the caplacizumab solution immediately. If not, use caplacizumab within 4 hours after reconstitution when stored in the refrigerator at 2°C to 8°C (36°F to 46°F).
Monitoring
There is limited information regarding Caplacizumab Monitoring in the drug label.
IV Compatibility
There is limited information regarding the compatibility of Caplacizumab and IV administrations.
Overdosage
- In case of overdose, based on the pharmacological action of caplacizumab, there is the potential for an increased risk of bleeding. Close monitoring for signs and symptoms of bleeding is recommended. If needed, the use of von Willebrand factor concentrate could be considered to correct hemostasis.
Pharmacology
Mechanism of Action
- Caplacizumab-yhdp targets the A1-domain of vWF, and inhibits the interaction between vWF and platelets, thereby reducing both vWF-mediated platelet adhesion and platelet consumption.
Structure
There is limited information regarding Caplacizumab Structure in the drug label.
Pharmacodynamics
- Ristocetin cofactor (RICO) activity was used to assess vWF activity. Subcutaneous doses of caplacizumab-yhdp at greater than or equal to the approved recommended dosage to healthy subjects and patients with aTTP decreased RICO activity levels to below 20% approximately 4 hours post-dose. RICO activity returned to baseline values within 7 days of drug discontinuation.
- Caplacizumab-yhdp decreased vWF antigen and factor VIII:C levels. These reductions were transient and returned to baseline upon cessation of treatment.
Pharmacokinetics
- Caplacizumab-yhdp pharmacokinetics depends on the expression of the target vWF and are not dose proportional. Higher levels of vWF antigen increase the fraction of drug-target complex retained in the circulation. Steady-state was reached following the first administration of caplacizumab in healthy subjects, with minimal accumulation. Following a single subcutaneous dose of 10 mg caplacizumab-yhdp to healthy subjects the mean (CV%) peak concentration (Cmax) was 528 (20%) ng/mL and AUC0–24 was 7951 (16%). Following subcutaneous dosing of 10 mg caplacizumab-yhdp daily for 14 days to healthy subjects, the mean (CV%) Cmax was 348 (30%) ng/mL and AUC0–τ was 6808 (26%) hr∙ng/mL.
Absorption
- The bioavailability of subcutaneous caplacizumab-yhdp is approximately 90%.
- The maximum concentration was observed 6 to 7 hours after subcutaneous dosing of 10 mg caplacizumab-yhdp once daily in healthy subjects.
Distribution
- Caplacizumab-yhdp central volume of distribution is 6.33 L in patients with aTTP.
Elimination
- The half-life of caplacizumab-yhdp is concentration and target-level dependent.
Metabolism
- The available data suggest target-bound caplacizumab-yhdp is metabolized within the liver. Because caplacizumab-yhdp is a monoclonal antibody fragment, it is expected to be catabolized by various proteolytic enzymes.
Excretion
- The available nonclinical data suggest unbound caplacizumab-yhdp is cleared renally.
Antidrug Antibodies
- No clinically significant differences in the pharmacokinetics of caplacizumab-yhdp were observed in patients with pre-existing or treatment-emergent anti-drug antibodies.
Specific Populations
- No clinically significant differences in the pharmacokinetics of caplacizumab-yhdp were observed based on age (18 to 79 years), sex (66% females), race (White [83%] and Black [17%]), blood group (O [41%] and other groups [59%]), or renal impairment (mild [CrCl: 60 to 90 mL/min], moderate [CrCl: 30 to 60 mL/min] or severe [CrCl: 15 to 30 mL/min]). The effect of hepatic impairment on the pharmacokinetics of caplacizumab-yhdp is unknown.
Drug Interaction Studies
- No dedicated drug-drug interaction studies with caplacizumab-yhdp have been conducted.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- No studies have been performed to evaluate the potential of caplacizumab-yhdp for carcinogenicity or genotoxicity.
- Animal reproduction studies assessing the effects of caplacizumab-yhdp on male and female fertility have not been conducted.
Clinical Studies
- The efficacy of caplacizumab for the treatment of adult patients with acquired thrombotic thrombocytopenia purpura (aTTP) in combination with plasma exchange and immunosuppressive therapy was established in a pivotal multicenter, randomized, double-blind, placebo-controlled trial (HERCULES) (NCT02553317).
- A total of 145 patients were enrolled in the HERCULES study; the median age was 45 (range: 18 to 79) years, 69% were female, 73% were White. Patients were randomized to either caplacizumab (n=72) or placebo (n=73). Patients in both groups received plasma exchange and immunosuppressive therapy. Patients were stratified according the severity of neurological involvement (Glasgow Coma Scale score ≤12 or 13 to 15). Patients with sepsis, infection with E. coli 0157, atypical hemolytic uremic syndrome, disseminated intravascular coagulation or congenital thrombotic thrombocytopenia purpura were not eligible for enrollment.
- Patients received a single 11 mg caplacizumab bolus intravenous injection or placebo prior to the first plasma exchange on study, followed by a daily subcutaneous injection of 11 mg caplacizumab or placebo after completion of plasma exchange, for the duration of the daily plasma exchange period and for 30 days thereafter. If after the initial treatment course, sign(s) of persistent underlying disease such as suppressed ADAMTS13 activity levels remained present, treatment was extended for 7 day intervals for a maximum of 28 days.
- The median treatment duration with caplacizumab was 35 days.
- The clinical trial protocol specified the caplacizumab dose as 10 mg, to be delivered by withdrawing all of the reconstituted solution from the vial and administering the full amount. A dose recovery study showed that the mean dose that can be withdrawn from a vial is 11 mg. Therefore, based on the dose recovery study, the mean dose delivered in the trial was 11 mg.
- The efficacy of caplacizumab in patients with aTTP was established based on time to platelet count response (platelet count ≥150,000/µL followed by cessation of daily plasma exchange within 5 days). Time to platelet count response was shorter among patients treated with caplacizumab, compared to placebo.
- Treatment with caplacizumab resulted in a lower number of patients with TTP-related death, recurrence of TTP, or at least one treatment-emergent major thromboembolic event (a composite endpoint) during the treatment period (see TABLE 2).
- The proportion of patients with a recurrence of TTP in the overall study period (the drug treatment period plus the 28-day follow-up period after discontinuation of drug treatment) was lower in the caplacizumab group (9/72 patients [13%]) compared to the placebo group (28/73 patients [38%] (p<0.001). In the 6 patients in the caplacizumab group who experienced a recurrence of TTP during the follow-up period (i.e., a relapse defined as recurrent thrombocytopenia after initial recovery of platelet count (platelet count ≥150,000/µL) that required reinitiation of daily plasma exchange, occurring after the 30-day post daily plasma exchange period), ADAMTS13 activity levels were <10% at the end of the study drug treatment, indicating that the underlying immunological disease was still active at the time caplacizumab was stopped.
How Supplied
- Caplacizumab (caplacizumab-yhdp) for injection is a sterile, white, preservative-free, lyophilized powder in a single-dose vial. Each carton (NDC 58468-0225-1) contains:
- one 11 mg caplacizumab single-dose vial (NDC 58468-0227-1)
- one 1 mL Sterile Water for Injection, USP, prefilled glass syringe (diluent for caplacizumab) (NDC 58468-0229-1)
- one sterile vial adapter
- one sterile hypodermic needle (30 gauge)
- two individually packaged alcohol swabs
Storage
- Store refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not freeze. Unopened vials may be stored in the original carton at room temperature up to 30°C (86°F) for a single period of up to 2 months. Do not return caplacizumab to the refrigerator after it has been stored at room temperature.
Images
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Patient Counseling Information
There is limited information regarding Caplacizumab Patient Counseling Information in the drug label.
Precautions with Alcohol
- Alcohol-caplacizumab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
Brand Names
Look-Alike Drug Names
- There is limited information regarding caplacizumab Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.