Cablivi

1 INDICATIONS AND USAGE CABLIVI is indicated for the treatment of adult and pediatric patients 12 years of age and older with acquired thrombotic thrombocytopenic purpura (aTTP), in combination with plasma exchange and immunosuppressive therapy. CABLIVI is a von Willebrand factor (vWF)-directed antibody fragment indicated for the treatment of adult and pediatric patients 12 years of age and older with acquired thrombotic thrombocytopenic purpura (aTTP), in combination with plasma exchange and immunosuppressive therapy. ( 1 )

2 DOSAGE AND ADMINISTRATION CABLIVI should be administered upon the initiation of plasma exchange therapy. The recommended dose of CABLIVI is as follows: ( 2.1 ) 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 treatment during daily plasma exchange: 11 mg subcutaneous injection once daily following plasma exchange. Treatment after the plasma exchange period: 11 mg subcutaneous injection once daily for 30 days beyond the last 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. The first dose should be administered by a healthcare provider as a bolus intravenous injection. Administer subsequent doses subcutaneously in the abdomen. ( 2.3 ) 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 Administer the first dose of CABLIVI intravenously before the initial plasma exchange. If the administration of the first intravenous dose of CABLIVI is missed and plasma exchange is already administered, administer the first CABLIVI dose intravenously and administer the next dose subcutaneously on the following day according to the usual dosing schedule. 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. Adult patients may self-inject, or adult caregivers may inject CABLIVI subcutaneously after proper instruction on the preparation and administration of CABLIVI, including aseptic technique [see Instructions for Use ] if a healthcare provider determines that it is appropriate. In pediatric patients 12 years of age and older, CABLIVI must be administered by a healthcare provider or an adult caregiver. If the carton was not stored at room temperature, allow the CABLIVI vial and diluent syringe to reach room temperature [25°C to 30°C (77°F to 86°F)] by holding them in your hands for 10 seconds. Do not use any other way to warm up the vial and syringe. 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 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).

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) ] . Previous severe hypersensitivity reaction to caplacizumab-yhdp or any of the excipients. ( 4 )

5 WARNINGS AND PRECAUTIONS Hemorrhage: Serious and fatal bleeding can occur. Risk of bleeding is increased in patients with underlying coagulopathies or on concomitant antiplatelet agents or anticoagulants. If clinically significant bleeding occurs, interrupt treatment. Withhold CABLIVI 7 days prior to elective surgery, dental procedures, or other invasive interventions. ( 5.1 ) 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, thrombolytic drugs, heparin, 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.

7 DRUG INTERACTIONS Concomitant use of anticoagulants or antiplatelet agents with CABLIVI may increase the risk of bleeding. Monitor closely for bleeding with concomitant use. ( 7 ) Concomitant Use of Anticoagulants, Thrombolytic Drugs, Heparin or Antiplatelet Agents Concomitant use of CABLIVI with any anticoagulant, thrombolytic drugs, heparin 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) ] .

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) ] In adults, the most common adverse reactions (incidence >15%) are epistaxis, headache, and gingival bleeding. In pediatric patients, the most frequently reported adverse reactions are epistaxis and tachycardia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Ablynx US at 1-800-745-4447 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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. TITAN and HERCULES 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) Pediatric Patients The safety of CABLIVI in patients aged ≤18 years with aTTP was evaluated in an observational, retrospective chart review (OBS17325) [see Clinical Studies (14) ] . The most commonly reported events were epistaxis in 4 (13.3%) patients and tachycardia in 4 (13.3%) patients. One serious bleeding adverse reaction (hemorrhage urinary tract) was reported. The adverse reaction profile in pediatric patients 12 years and older with aTTP was consistent with that in adults. 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 reactions including injection site pain, injection site bruising and injection site erythema

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.