Cablivi: Package Insert and Label Information

CABLIVI- caplacizumab
Genzyme Corporation

1 INDICATIONS AND USAGE

CABLIVI is indicated for the treatment of adult patients with acquired thrombotic thrombocytopenic purpura (aTTP), in combination with plasma exchange and immunosuppressive therapy.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dose and Schedules

CABLIVI should be administered upon initiation of plasma exchange therapy. The recommended dose of CABLIVI 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 CABLIVI if the patient experiences more than 2 recurrences of aTTP, while on CABLIVI.

Avoid concomitant use of antiplatelet agents or anticoagulants [see Warnings and Precautions (5.1)].

Missed Dose

If a dose of CABLIVI is missed during the plasma exchange period, it should be given as soon as possible. If a dose of CABLIVI 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.

2.2 Discontinuation for Surgery and Other Interventions

Withhold CABLIVI treatment 7 days prior to elective surgery, dental procedures, or other invasive interventions [see Warnings and Precautions (5.1)].

2.3 Reconstitution and Administration Instructions

The first dose of CABLIVI 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 CABLIVI subcutaneously after proper training on the preparation and administration of CABLIVI, including aseptic technique [see Instructions for Use].

• Ensure the CABLIVI vial and diluent syringe are at room temperature.
• Reconstitute CABLIVI 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 CABLIVI.
• 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 CABLIVI 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 CABLIVI solution immediately. If not, use CABLIVI within 4 hours after reconstitution when stored in the refrigerator at 2°C to 8°C (36°F to 46°F).

3 DOSAGE FORMS AND STRENGTHS

For injection: 11 mg as a white lyophilized powder in a single-dose vial.

4 CONTRAINDICATIONS

CABLIVI is contraindicated in patients with a previous severe hypersensitivity reaction to caplacizumab-yhdp or to any of the excipients. Hypersensitivity reactions have included urticaria [see Adverse Reactions (6.1)].

5 WARNINGS AND PRECAUTIONS

5.1 Hemorrhage

CABLIVI increases the risk of bleeding [see Adverse Reactions (6.1)].

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 CABLIVI versus 43% of patients on placebo.

​ In the postmarketing setting, cases of life-threatening and fatal bleeding were reported in patients receiving CABLIVI.

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 CABLIVI with drugs affecting hemostasis and coagulation [see Drug Interactions (7) and Clinical Pharmacology (12.3)].

​ Avoid concomitant use of CABLIVI with antiplatelet agents or anticoagulants. Interrupt use of CABLIVI if clinically significant bleeding occurs. If needed, von Willebrand factor concentrate may be administered to rapidly correct hemostasis. If CABLIVI is restarted, monitor closely for signs of bleeding.

Withhold CABLIVI 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 CABLIVI is resumed, monitor closely for signs of bleeding.

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are also discussed in other sections of the labeling:

• Hemorrhage [see Warnings and Precautions (5.1)]

6.1 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 CABLIVI was evaluated in two placebo-controlled clinical studies (HERCULES, in which 71 patients received CABLIVI; and TITAN, in which 35 patients received CABLIVI). The data described below and in the Warnings and Precautions reflect exposure to CABLIVI 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 CABLIVI 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 CABLIVI 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 CABLIVI 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 CABLIVI 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.

Table 1: Adverse Reactions in ≥2% of Patients Treated with CABLIVI and More Frequent than Placebo During the Blinded Periods of aTTP Studies (HERCULES and TITAN)

Adverse Reaction by Body System	CABLIVI(N=106)n (%)	Placebo(N=110)n (%)
Gastrointestinal disorders
Gingival bleeding	17 (16)	3 (3)
Rectal hemorrhage	4 (4)	0 (0)
Abdominal wall hematoma	3 (3)	1 (1)
General disorders and administration site conditions
Fatigue	16 (15)	10 (9)
Pyrexia	14 (13)	12 (11)
Injection site hemorrhage	6 (6)	1 (1)
Catheter site hemorrhage	6 (6)	5 (5)
Injection site pruritus	3 (3)	0 (0)
Musculoskeletal and connective tissue disorders
Back pain	7 (7)	4 (4)
Myalgia	6 (6)	2 (2)
Nervous system disorders
Headache	22 (21)	15 (14)
Paresthesia	13 (12)	11 (10)
Renal and urinary disorders
Urinary tract infection	6 (6)	4 (4)
Hematuria	4 (4)	3 (3)
Reproductive system and breast disorders
Vaginal hemorrhage	5 (5)	2 (2)
Menorrhagia	4 (4)	1 (1)
Respiratory, thoracic and mediastinal disorders
Epistaxis	31 (29)	6 (6)
Dyspnea	10 (9)	5 (5)
Skin and subcutaneous tissue disorders
Urticaria	15 (14)	7 (6)

6.2 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 CABLIVI 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 [see Clinical Pharmacology (12.3)].

6.3 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of CABLIVI. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to caplacizumab-yhdp exposure.

General disorders and administration site conditions:

• injection site erythema

7 DRUG INTERACTIONS

Concomitant Use of Anticoagulants or Antiplatelet Agents

Concomitant use of CABLIVI with any anticoagulant or antiplatelet agent may increase the risk of bleeding. Avoid concomitant use when possible. Assess and monitor closely for bleeding with concomitant use [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no available data on CABLIVI 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 CABLIVI (see Clinical Considerations). 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 (see Data).

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

Fetal/neonatal adverse reactions

CABLIVI may increase the risk of bleeding in the fetus and neonate. Monitor neonates for bleeding [see Warnings and Precautions (5.1)].

Maternal adverse reactions

All patients receiving CABLIVI, including pregnant women, are at risk for bleeding. Pregnant women receiving CABLIVI should be carefully monitored for evidence of excessive bleeding [see Warnings and Precautions (5.1)].

Data

Animal 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.