8.5 Geriatric Use

Clinical studies of CABLIVI did not include sufficient numbers of subjects aged 65 and over todetermine whether they respond differently from younger subjects.

8.6 Hepatic Impairment

No formal studies with CABLIVI have been conducted in patients with severe acute or chronichepatic impairment and no data regarding the use of CABLIVI in these populations are available.

Due to a potential increased risk of bleeding, use of CABLIVI in patients with severe hepaticimpairment requires close monitoring for bleeding [see Warnings and Precautions (5.1)].

10 OVERDOSAGE

In case of overdose, based on the pharmacological action of CABLIVI, there is the potential foran increased risk of bleeding [see Warnings and Precautions (5.1)]. Close monitoring for signs

and symptoms of bleeding is recommended. If needed, the use of von Willebrand factorconcentrate could be considered to correct hemostasis.

11 DESCRIPTION

Caplacizumab-yhdp is a von Willebrand factor (vWF)-directed antibody fragment that consistsof two identical humanized building blocks, linked by a three-alanine linker. Caplacizumab-yhdp

is produced in Escherichia coli by recombinant DNA technology and has an approximatemolecular weight of 28 kDa.

CABLIVI (caplacizumab-yhdp) for injection is a sterile, white, preservative-free, lyophilizedpowder. Each single-dose vial delivers 11 mg caplacizumab-yhdp, anhydrous citric acid

(0.18 mg), polysorbate-80 (0.10 mg), sucrose (62 mg), and trisodium citrate dihydrate (4.91 mg).

After reconstitution with 1 mL of Sterile Water for Injection, USP, the final concentration is

11 mg/mL, at a pH of approximately 6.5.

12 CLINICAL PHARMACOLOGY

12.1 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.

12.2 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 healthysubjects and patients with aTTP decreased RICO activity levels to below 20% approximately 4hours 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 weretransient and returned to baseline upon cessation of treatment.

12.3 Pharmacokinetics

Caplacizumab-yhdp pharmacokinetics depends on the expression of the target vWF and are notdose proportional. 

Higher levels of vWF antigen increase the fraction of drug-target complexretained in the circulation. 

Steady-state was reached following the first administration ofCABLIVI in healthy subjects, with minimal accumulation. Following a single subcutaneous doseof 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 mgcaplacizumab-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%.