levant.
Drug Interaction Studies
There have been no formal drug interaction studies performed with trastuzumab in humans. Clinicallysignificant interactions between trastuzumab and concomitant medications used in clinical trials have not beenobserved.Paclitaxel and doxorubicin: Concentrations of paclitaxel and doxorubicin and their major metabolites (i.e., 6-αhydroxyl-paclitaxel [POH], and doxorubicinol [DOL], respectively) were not altered in the presence oftrastuzumab when used as combination therapy in clinical trials. Trastuzumab concentrations were not alteredas part of this combination therapy.
Docetaxel and carboplatin: When intravenous trastuzumab was administered in combination with docetaxel orcarboplatin, neither the plasma concentrations of docetaxel or carboplatin nor the plasma concentrations oftrastuzumab were altered.
Cisplatin and capecitabine: In a drug interaction substudy conducted in patients in Study BO18255, thepharmacokinetics of cisplatin, capecitabine and their metabolites were not altered when administered incombination with intravenous trastuzumab.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
HERCEPTIN HYLECTA contains trastuzumab and hyaluronidase.
Trastuzumab has not been tested for carcinogenicity potential.
No evidence of mutagenic activity was observed when trastuzumab was tested in the standard Ames bacterial andhuman peripheral blood lymphocyte mutagenicity assays at concentrations of up to 5000 mcg/mL. In an in vivomicronucleus assay, no evidence of chromosomal damage to mouse bone marrow cells was observed followingbolus intravenous doses of up to 118 mg/kg of trastuzumab.
A fertility study was conducted in female cynomolgus monkeys at doses up to 25 times the weekly recommendedhuman dose of 2 mg/kg of intravenous trastuzumab and has revealed no evidence of impaired fertility, asmeasured by menstrual cycle duration and female sex hormone levels.
Hyaluronidases are found in most tissues of the body. Long-term animal studies have not been performed to assessthe carcinogenic or mutagenic potentialofhyaluronidase. In addition, when hyaluronidase (recombinant human)was administered to cynomolgus monkeys for 39 weeks at dose levels up to 220,000 U/kg, which is > 670 times
higher than the human dose, no evidence of toxicity to the male or female reproductive system was found throughperiodic monitoring of in-life parameters, e.g., semen analyses, hormone levels, menstrual cycles, and also fromgross pathology, histopathology and organ weight data.
14 CLINICAL STUDIES
The comparability between HERCEPTIN HYLECTA administered subcutaneously and intravenoustrastuzumab was established in the HannaH study. The HannaH study was conducted in patients with HER2overexpressing breast cancer in the neoadjuvant and adjuvant settings with co-primary endpoints ofpathological complete response (pCR) and the PK endpoint of Ctrough at cycle 7 [see Clinical Pharmacology(12.3)].
14.1 Adjuvant Breast Cancer
HERCEPTIN HYLECTA
HannaH
The HannaH study (NCT00950300) was a randomized, multicenter, open-label, clinical trial in 596 patients withHER2-positive operable or locally advanced breast cancer (LABC), including inflammatory breast cancer. HER2positivity was defined as IHC 3+ or ISH+. Patients were randomized to receive 8 cycles of either HERCEPTINHYLECTA or intravenous tr |
