8.7 Renal Impairment
 
No dedicated renal impairment trial for KADCYLA has been conducted. Based on the population pharmacokinetics, as well as analysis of Grade 3 or greater adverse drug reactions and dose modifications, dose adjustments of KADCYLA are not needed in patients with mild (creatinine clearance [CLcr] 60 to 89 mL/min) or moderate (CLcr 30 to 59 mL/min) renal impairment. No dose adjustment can be recommended for patients with severe renal impairment (CLcr less than 30 mL/min) because of the limited data available [see Clinical Pharmacology (12.3)].
 

8.8 Hepatic Impairment
 
In vitro studies in human liver microsomes indicates that DM1 is metabolized by CYP3A4/5. The influence of hepatic impairment on the pharmacokinetics of ado-trastuzumab emtansine conjugate has not been determined.
 

10 OVERDOSAGE
 
There is no known antidote for overdose of KADCYLA. In clinical trials, overdose of KADCYLA has been reported at approximately two times the recommended dose which resulted in Grade 2 thrombocytopenia (resolved 4 days later) and one death. In the fatal case, the patient incorrectly received KADCYLA at 6 mg/kg and died approximately 3 weeks following the overdose; a cause of death and a causal relationship to KADCYLA were not established.
 

11 DESCRIPTION
 
KADCYLA (ado-trastuzumab emtansine) is a HER2-targeted antibody-drug conjugate (ADC) which contains the humanized anti-HER2 IgG1, trastuzumab, covalently linked to the microtubule inhibitory drug DM1 (a maytansine derivative) via the stable thioether linker MCC (4-[N-maleimidomethyl] cyclohexane-1-carboxylate). Emtansine refers to the MCC-DM1 complex.
 
The antibody trastuzumab, is a well characterized recombinant monoclonal antibody product produced by mammalian (Chinese hamster ovary) cells, and the small molecule components (DM1 and MCC) are produced by chemical synthesis. Ado-trastuzumab emtansine contains an average of 3.5 DM1 molecules per antibody. Ado-trastuzumab emtansine has the following chemical structure:
 

Note: The bracketed structure is DM1 plus MCC which represents the emtansine component. The n is, on average, 3.5 DM1 molecules per trastuzumab (Mab) molecule.
 
KADCYLA (ado-trastuzumab emtansine) is a sterile, white to off-white preservative free lyophilized powder in single-use vials. Each vial contains 100 mg or 160 mg ado-trastuzumab emtansine. Following reconstitution, each single-use vial contains ado-trastuzumab emtansine (20 mg/mL), polysorbate 20 [0.02% (w/v)], sodium succinate (10 mM), and sucrose [6% (w/v)] with a pH of 5.0 and density of 1.026 g/mL. The resulting solution containing 20 mg/mL ado-trastuzumab emtansine is administered by intravenous infusion following dilution.
 

12 CLINICAL PHARMACOLOGY
 

12.1 Mechanism of Action
 
Ado-trastuzumab emtansine is a HER2-targeted antibody-drug conjugate. The antibody is the humanized anti-HER2 IgG1, trastuzumab. The small molecule cytotoxin, DM1, is a microtubule inhibitor. Upon binding to sub-domain IV of the HER2 receptor, ado-trastuzumab emtansine undergoes receptor-mediated internalization and subsequent lysosomal degradation, resulting in intracellular release of DM1-containing cytotoxi