曲妥珠单抗注射液Kadcyla

【Function and Indications】
Kadcyla, a trastuzumab injection, is expected to make up for the shortcomings of Herceptin.

Kadcyla, a trastuzumab injection, is a combination of a HER2-targeted antibody and a microtubule inhibitor indicated as a single agent for the treatment of patients with HER2-positive, metastatic breast cancer who have previously received trastuzumab and a taxane, either separately or in combination. Patients should have any of the following conditions:
(1) Previous treatment for metastatic disease, or
(2) Disease recurrence during or within 6 months of completion of adjuvant therapy.

【Model and Specifications】
The vial of lyophilized powder contains 100 mg per vial or 160 mg per vial.

【Usage and Dosage】
(1) For intravenous infusion only. Do not use intravenous push or bolus injections. Do not use glucose (5%) solution.

(2) The recommended dose of KADCYLA is 3.6 mg/kg intravenous infusion every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity. Do not administer KADCYLA at doses greater than 3.6 mg/kg. Do not substitute KADCYLA or trastuzumab.
(3) Management of adverse events (infusion-related reactions, hepatotoxicity, left ventricular dysfunction, thrombocytopenia, pulmonary toxicity, or peripheral neuropathy) may require temporary interruption, dose reduction, or discontinuation of KADCYLA treatment.

[Clinical Studies]
To prevent medication errors, it is important to check vial labels to ensure that KADCYLA (ado-trastuzumab emtansine) and not trastuzumab is being prepared and administered.
Administration:
● Administer KADCYLA only as an intravenous infusion using a 0.22 μm inline protein-free polyethersulfone (PES) filter. Do not administer as an intravenous push or bolus.
● Do not mix KADCYLA with other drug products or administer as an infusion.
● To improve traceability of biopharmaceutical products, the brand name of the administered product should be clearly recorded (or stated) in the patient’s file.
Reconstitution:
● Use aseptic technique for reconstitution and preparation of dosing solutions. Chemotherapy should be reconstituted using appropriate methods.
● Using 1 sterile syringe, slowly inject 5 mL of Sterile Water for Injection into a 100 mg KADCYLA vial, or 8 mL of Sterile Water for Injection into a 160 mg KADCYLA vial to produce a solution containing 20 mg/mL. Gently swirl the vial until completely dissolved. Do not shake. Inspect the reconstituted solution for particles and discoloration.
● The reconstituted solution should be clear to slightly opaque and free of visible particles. The reconstituted solution should be colorless to light brown. Do not use if visible particles are present or if it is cloudy or discolored.
● Reconstituted frozen vials should be used immediately after reconstitution with Sterile Water for Injection. If not used immediately, reconstituted KADCYLA vials may be stored in a refrigerator at 2ºC to 8ºC (36°F to 46°F) for up to 4 hours; discard unused KADCYLA after 4 hours. Do not freeze. .
● The reconstituted product does not contain preservatives and is intended for single use only.
Dilution:
Determine the correct dose (mg) of KADCYLA [see Dosage and Administration (2.1)]
● Calculate the volume of KADCYLA solution needed to reconstitute the 20 mg/mL solution.
● Withdraw this amount from the vial and add to an infusion bag containing 250 mL of 0.9% Sodium Chloride for Injection. Do not use dextrose (5%) solution. .
● Gently invert the bag to mix the solution to avoid foaming.
● The diluted KADCYLA infusion solution should be used immediately. If not used immediately, the solution may be stored at 2°C to 8°C (36°F to 46°F) for up to 4 hours before use. Do not freeze or shake.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of another drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
KADCYLA has been evaluated as a single agent in clinical trials of 884 patients with HER2-positive metastatic breast cancer. The most common (frequency ≥ 25%) adverse drug reactions (ADRs) in 884 patients treated with Kadcyla were fatigue, nausea, musculoskeletal pain, thrombocytopenia, headache, increased transaminases, and constipation.
The adverse drug reactions previously described were identified in a randomized trial (Study 1) in patients treated with HER2-positive metastatic breast cancer [see Clinical Studies (14.1)]. Patients were randomized to receive KADCYLA or lapatinib plus capecitabine. The median duration of study treatment was 7.6 months for patients in the KADCYLA-treated group and 5.5 months and 5.3 months for patients treated with lapatinib and capecitabine, respectively. 211 patients (43.1%) in the KADCYLA-treated group experienced ≥ Grade 3 adverse events compared to 289 patients (59.2%) in the lapatinib plus capecitabine-treated group. Dose modifications for KADCYLA were permitted [see Dosage and Administration (2.2)]. Thirty-two patients (6.5%) discontinued KADCYLA due to adverse events, compared to 41 patients (8.4%) who discontinued lapatinib, and 51 patients (10.5%) who discontinued capecitabine due to adverse events. The most common adverse events leading to KADCYLA withdrawal were thrombocytopenia and increased transaminases. Adverse events led to dose reductions in 80 patients (16.3%) treated with KADCYLA. The most frequent adverse events leading to dose reductions of KADCYLA (in ≥ 1% of patients) included thrombocytopenia, increased transaminases, and peripheral neuropathy. Adverse events leading to dose delays in 116 (23.7%) of KADCYLA-treated patients occurred. The most frequent adverse events leading to dose delays in KADCYLA (in ≥ 1% of patients) were neutropenia, thrombocytopenia, leukopenia, fatigue, increased transaminases, and pyrexia.
Adverse drug reactions (ADRs) were reported in KADCYLA-treated patients (n=490) in the randomized trial (Study 1). Table 7 shows selected laboratory abnormalities. The most common adverse drug reactions (ADRs) with KADCYLA (frequency > 25%) in randomized trials were nausea, fatigue, musculoskeletal pain, thrombocytopenia, increased transaminases, headache, and constipation. The most common NCI–CTCAE (version 3) ≥ Grade 3 adverse drug reactions (frequency > 2%) were thrombocytopenia, increased transaminases, anemia, hypokalemia, peripheral neuropathy, and fatigue.

Precautions
(1) Pulmonary toxicity: Permanently discontinue KADCYLA in patients diagnosed with interstitial lung disease or pneumonitis.
(2) Infusion-related reactions, hypersensitivity reactions: Monitor for signs and symptoms during and after infusion. If major infusion-related reactions or hypersensitivity reactions occur, slow or interrupt the infusion and administer appropriate medical treatment. Permanently discontinue KADCYLA for life-threatening infusion-related reactions.
(3) Thrombocytopenia: Monitor platelet count before each administration of KADCYLA. Adjust dose as appropriate.
(4) Neurotoxicity: Monitor for signs and symptoms. Patients with grade 3 or 4 peripheral neuropathy should not be given the drug temporarily.

(5) HER2 testing: Testing should be performed by a laboratory with testing capabilities using an FDA-approved test.

[Adverse Reactions and Contraindications]
The most common adverse reactions include fatigue, nausea, muscle aches, bone aches, thrombocytopenia, headache, increased transaminases, and intestinal discomfort such as constipation.

[Contraindications]
This product is contraindicated in patients who are allergic to any component of this product.

[Pregnant Women’s Use]
Considering the importance of KADCYLA to the mother, KADCYLA should not be used during lactation, or KADCYLA should be discontinued before use.
KADCYLA may cause fetal harm when administered to pregnant women. There are no adequate and well-controlled studies of KADCYLA in pregnant women. Reproductive and developmental toxicology studies have not been conducted with ado-trastuzumab emtansine. However, both components of KADCYLA (trastuzumab and DM1) are known or suspected to cause fetal harm or death when administered to pregnant women. If KADCYLA is administered during pregnancy, or if patients are receiving KADCYLA, effective contraception should be used.

Pediatric Use
This drug should not be used to treat children.

Drug Interactions
No formal drug-drug interaction studies have been conducted with KADCYLA. In vitro studies indicate that DM1, the cytotoxic component of KADCYLA, is metabolized primarily by CYP3A4 and to a lesser extent by CYP3A5. Concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole) with KADCYLA should be avoided due to increased DM1 exposure and potential for toxicity. Consider other drugs with no or little potential to inhibit CYP3A4. If co-administration of strong CYP3A4 inhibitors cannot be avoided, consider delaying KADCYLA treatment when possible until the strong CYP3A4 inhibitor has been cleared from the circulation (approximately 3 elimination half-lives of the inhibitor). If a strong CYP3A4 inhibitor is co-administered and KADCYLA treatment cannot be delayed, patients should be closely monitored for adverse reactions.

[Storage]
Store in a freezer.

[Manufacturer]
Trastuzumab injection Kadcyla was developed by Roche Pharmaceuticals, Inc.