ess were not observed between elderly patients and younger patients.
11 DESCRIPTION
HERCEPTIN HYLECTA is a combination of trastuzumab and hyaluronidase. Trastuzumab is a humanized IgG1kappa monoclonal antibody that selectively binds with high affinity to the extracellular domain of the humanepidermal growth factor receptor 2 protein, HER2. Trastuzumab is produced by recombinant DNA technology ina mammalian cell (Chinese Hamster Ovary) culture. Trastuzumab has a molecular weight of approximately 148kDa.
Hyaluronidase (recombinant human) is an endoglycosidase used to increase the dispersion and absorption of coadministereddrugs when administered subcutaneously. It is a glycosylated single-chain protein produced bymammalian (Chinese Hamster Ovary) cells containing a DNA plasmid encoding for a soluble fragment of humanhyaluronidase (PH20). Hyaluronidase (recombinant human) has a molecular weight of approximately 61 kDa.
HERCEPTIN HYLECTA (trastuzumab and hyaluronidase) injection is a sterile, preservative-free, colorless toyellowish, clear to opalescent solution supplied in single-dose vials for subcutaneous administration.
HERCEPTIN HYLECTA is supplied as 600 mg trastuzumab and 10,000 units hyaluronidase per 5 mL in singledosevials. Each mL of solution contains trastuzumab (120 mg), hyaluronidase (2,000 units), L-histidine (0.39mg), L-histidine hydrochloride monohydrate (3.67 mg), L-methionine (1.49 mg), polysorbate 20 (0.4 mg), α,αtrehalose dihydrate (79.45 mg), and Water for Injection.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The HER2 (or c-erbB2) proto-oncogene encodes a transmembrane receptor protein of 185 kDa, which isstructurally related to the epidermal growth factor receptor. Trastuzumab has been shown, in both in vitro assaysand in animals, to inhibit the proliferation of human tumor cells that overexpress HER2.
Trastuzumab is a mediator of antibody-dependent cellular cytotoxicity (ADCC). In vitro, trastuzumab-mediatedADCC has been shown to be preferentially exerted on HER2 overexpressing cancer cells compared with cancercells that do not overexpress HER2.
Hyaluronan is a polysaccharide found in the extracellular matrix of the subcutaneous tissue. It is depolymerizedby the naturally occurring enzyme hyaluronidase. Unlike the stable structural components of the interstitialmatrix, hyaluronan has a half-life of approximately 0.5 days. Hyaluronidase increases permeability of the subcutaneous tissue by depolymerizing hyaluronan. In the doses administered, hyaluronidase in HERCEPTINHYLECTA acts transiently and locally.
The effects of hyaluronidase are reversible and permeability of the subcutaneous tissue is restored within 24 to48 hours.
Hyaluronidase has been shown to increase the absorption rate of a trastuzumab product into the systemiccirculation when given in the subcutis of Göttingen Minipigs.
12.2 Pharmacodynamics
Cardiac Electrophysiology
The effects of trastuzumab on electrocardiographic (ECG) endpoints, including QTc interval duration, wereeva luated in patients with HER2-positive solid tumors. Trastuzumab had no clinically relevant effect on the QTcinterval duration and there was no apparent relationship between serum trastuzumab concentrations and change
in QTcF interval duration in patients with HER2-positive solid tumors.
12.3 Pharmacokinetics
Trastuzumab exposure following su |
