OGIVRI: Package Insert and Label Information (Page 6 of 10)
11 DESCRIPTION
Trastuzumab-dkst is a humanized IgG1 kappa monoclonal antibody that selectively binds with high affinity to the extracellular domain of the human epidermal growth factor receptor 2 protein, HER2. Trastuzumab-dkst is produced by recombinant DNA technology in a mammalian cell (Chinese Hamster Ovary) culture.
Ogivri (trastuzumab-dkst) for injection is a sterile, off-white to pale yellow, preservative-free lyophilized powder with a cake-like appearance, for injection, for intravenous administration.
Each multiple-dose vial of Ogivri delivers 420 mg trastuzumab-dkst, D-sorbitol (322.6 mg), L-Histidine (6.0 mg), Histidine hydrochloride monohydrate (9.4 mg) and Polyethylene glycol 3350/Macrogol 3350 (94.1 mg). Hydrochloric acid or sodium hydroxide may be used to adjust the pH of the formulation buffer. Reconstitution with 20 mL of the appropriate diluent (BWFI or SWFI) yields a solution containing 21 mg/mL trastuzumab-dkst that delivers 20 mL (420 mg trastuzumab-dkst), at a pH of approximately 6. If Ogivri is reconstituted with SWFI without preservative, the reconstituted solution is considered single-dose.
Each single-dose vial of Ogivri delivers 150 mg trastuzumab-dkst, D-sorbitol (115.2 mg), L-Histidine (2.16 mg), L-Histidine hydrochloride monohydrate (3.36 mg) and Polyethylene glycol 3350/Macrogol 3350 (33.6 mg). Hydrochloric acid or sodium hydroxide may be used to adjust the pH of the formulation buffer. Reconstitution with 7.4 mL of sterile water for injection (SWFI) yields a solution containing 21 mg/mL trastuzumab-dkst that delivers 7.15 mL (150 mg trastuzumab-dkst), at a pH of approximately 6.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The HER2 (or c-erbB2) proto-oncogene encodes a transmembrane receptor protein of 185 kDa, which is structurally related to the epidermal growth factor receptor. Trastuzumab products have been shown, in both in vitro assays and in animals, to inhibit the proliferation of human tumor cells that overexpress HER2.
Trastuzumab products are mediators of antibody-dependent cellular cytotoxicity (ADCC). In vitro , trastuzumab product-mediated ADCC has been shown to be preferentially exerted on HER2 overexpressing cancer cells compared with cancer cells that do not overexpress HER2.
12.2 Pharmacodynamics
Cardiac Electrophysiology
The effects of trastuzumab on electrocardiographic (ECG) endpoints, including QTc interval duration, were evaluated in patients with HER2 positive solid tumors. Trastuzumab had no clinically relevant effect on the QTc interval 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
The pharmacokinetics of trastuzumab were evaluated in a pooled population pharmacokinetic (PK) model analysis of 1,582 subjects with primarily breast cancer and metastatic gastric cancer (MGC) receiving intravenous trastuzumab. Total trastuzumab clearance increases with decreasing concentrations due to parallel linear and non-linear elimination pathways.
Although the average trastuzumab exposure was higher following the first cycle in breast cancer patients receiving the three-weekly schedule compared to the weekly schedule of trastuzumab, the average steady-state exposure was essentially the same at both dosages. The average trastuzumab
exposure following the first cycle and at steady state as well as the time to steady state was higher in breast cancer patients compared to MGC patients at the same dosage; however, the reason for this exposure difference is unknown. Additional predicted trastuzumab exposure and PK parameters following the first trastuzumab cycle and at steady state exposure are described in Tables 7 and 8, respectively.
Population PK based simulations indicate that following discontinuation of trastuzumab, concentrations in at least 95% of breast cancer patients and MGC patients will decrease to approximately 3% of the population predicted steady-state trough serum concentration (approximately 97% washout) by 7 months [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1, 8.3)].
| Schedule | Primary tumor type | N | Cmin (µg/mL) | Cmax (µg/mL) | AUC0-21days (µg.day/mL) |
| 8 mg/kg + 6 mg/kg q3w | Breast cancer | 1195 | 29.4 (5.8 to 59.5) | 178 (117 to 291) | 1373 (736 to 2245) |
| MGC | 274 | 23.1 (6.1 to50.3) | 132 (84.2 to 225) | 1109 (588 to 1938) | |
| 4 mg/kg + 2 mg/kg qw | Breast cancer | 1195 | 37.7 (12.3 to 70.9) | 88.3 (58 to 144) | 1066 (586 to 1754) |
| Schedule | Primary tumor type | N | Cmin,ss * (µg/mL) | Cmax,ss † (µg/mL) | AUCss ,0-21days (µg.day/mL) | Time to steady-state (week) | Total CL range at steady-state (L/day) |
| 8 mg/kg + 6 mg/kg q3w | Breast cancer | 1195 | 47.4 (5 to 115) | 179 (107 to 309) | 1794 (673 to 3618) | 12 | 0.173 to 0.283 |
| MGC | 274 | 32.9 (6.1 to 88.9) | 131 (72.5 to 251) | 1338 (557 to 2875) | 9 | 0.189 to 0.337 | |
| 4 mg/kg + 2 mg/kg qw | Breast cancer | 1195 | 66.1 (14.9 to 142) | 109 (51.0 to 209) | 1765 (647 to 3578) | 12 | 0.201 to 0.244 |
Specific Populations
Based on a population pharmacokinetic analysis, no clinically significant differences were observed in the pharmacokinetics of trastuzumab based on age (<65 (n = 1294); ≥65 (n = 288)), race (Asian (n = 264); non-Asian (n = 1324)) and renal impairment (mild (creatinine clearance [CLcr] 60 to 90 mL/min) (n = 636) or moderate (CLcr 30 to 60 mL/min) (n = 133)). The pharmacokinetics of trastuzumab products in patients with severe renal impairment, end-stage renal disease with or without hemodialysis, or hepatic impairment is unknown.
Drug Interaction Studies
There have been no formal drug interaction studies performed with trastuzumab products in humans. Clinically significant interactions between trastuzumab and concomitant medications used in clinical trials have not been observed.
Paclitaxel and doxorubicin
Concentrations of paclitaxel and doxorubicin and their major metabolites (i.e., 6-α hydroxyl-paclitaxel [POH], and doxorubicinol [DOL], respectively) were not altered in the presence of trastuzumab when used as combination therapy in clinical trials. Trastuzumab concentrations were not altered as part of this combination therapy.
Docetaxel and carboplatin
When trastuzumab was administered in combination with docetaxel or carboplatin, neither the plasma concentrations of docetaxel or carboplatin nor the plasma concentrations of trastuzumab were altered.
Cisplatin and capecitabine
In a drug interaction substudy conducted in patients in Study 7, the pharmacokinetics of cisplatin, capecitabine and their metabolites were not altered when administered in combination with trastuzumab.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Trastuzumab products have not been tested for carcinogenic potential.
No evidence of mutagenic activity was observed when trastuzumab was tested in the standard Ames bacterial and human peripheral blood lymphocyte mutagenicity assays, at concentrations of up to 5000 mcg/mL. In an in vivo micronucleus assay, no evidence of chromosomal damage to mouse bone marrow cells was observed following bolus 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 recommended human dose of 2 mg/kg of trastuzumab and has revealed no evidence of impaired fertility, as measured by menstrual cycle duration and female sex hormone levels.
14 CLINICAL STUDIES
14.1 Adjuvant Breast Cancer
The safety and efficacy of trastuzumab in women receiving adjuvant chemotherapy for HER2 overexpressing breast cancer were evaluated in an integrated analysis of two randomized, open-label, clinical trials (Studies 1 and 2) with a total of 4063 women at the protocol-specified final overall survival analysis, a third randomized, open-label, clinical trial (Study 3) with a total of 3386 women at definitive Disease-Free Survival analysis for one-year trastuzumab treatment versus observation, and a fourth randomized, open-label clinical trial with a total of 3222 patients (Study 4).
Studies 1 and 2
In Studies 1 and 2, breast tumor specimens were required to show HER2 overexpression (3+ by IHC) or gene amplification (by FISH). HER2 testing was verified by a central laboratory prior to randomization (Study 2) or was required to be performed at a reference laboratory (Study 1). Patients with a history of active cardiac disease based on symptoms, abnormal electrocardiographic, radiologic, or left ventricular ejection fraction findings or uncontrolled hypertension (diastolic > 100 mm Hg or systolic > 200 mm Hg) were not eligible.
Patients were randomized (1:1) to receive doxorubicin and cyclophosphamide followed by paclitaxel (AC → paclitaxel) alone or paclitaxel plus trastuzumab (AC → paclitaxel + trastuzumab). In both trials, patients received four 21-day cycles of doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2. Paclitaxel was administered either weekly (80 mg/m2) or every 3 weeks (175 mg/m2) for a total of 12 weeks in Study 1; paclitaxel was administered only by the weekly schedule in Study 2. Trastuzumab was administered at 4 mg/kg on the day of initiation of paclitaxel and then at a dose of 2 mg/kg weekly for a total of 52 weeks. Trastuzumab treatment was permanently discontinued in patients who developed congestive heart failure, or persistent/recurrent LVEF decline [see Dosage and Administration (2.3)]. Radiation therapy, if administered, was initiated after the completion of chemotherapy. Patients with ER+ and/or PR+ tumors received hormonal therapy. The primary endpoint of the combined efficacy analysis was Disease-Free Survival (DFS), defined as the time from randomization to recurrence, occurrence of contralateral breast cancer, other second primary cancer, or death. The secondary endpoint was overall survival (OS).
A total of 3752 patients were included in the joint efficacy analysis of the primary endpoint of DFS following a median follow-up of 2.0 years in the AC → paclitaxel + trastuzumab arm. The pre-planned final OS analysis from the joint analysis included 4063 patients and was performed when 707 deaths had occurred after a median follow-up of 8.3 years in the AC → paclitaxel + trastuzumab arm. The data from both arms in Study 1 and two of the three study arms in Study 2 were pooled for efficacy analyses. The patients included in the primary DFS analysis had a median age of 49 years (range, 22 to 80 years; 6% > 65 years), 84% were white, 7% black, 4% Hispanic, and 4% Asian/Pacific Islander. Disease characteristics included 90% infiltrating ductal histology, 38% T1, 744 91% nodal involvement, 27% intermediate and 66% high grade pathology, and 53% ER+ and/or PR+ tumors. Similar demographic and baseline characteristics were reported for the efficacy evaluable population, after 8.3 years of median follow-up in the AC → paclitaxel + trastuzumab arm.
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