Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Samsung Bioepis NL B.V., Olof Palmestraat 10, 2616 LR Delft, The Netherlands
Ontruzant is indicated for the treatment of adult patients with HER2 positive metastatic breast cancer (MBC):
Ontruzant is indicated for the treatment of adult patients with HER2 positive early breast cancer (EBC):
Ontruzant should only be used in patients with metastatic or early breast cancer whose tumours have either HER2 overexpression or HER2 gene amplification as determined by an accurate and validated assay (see sections 4.4 and 5.1).
Ontruzant in combination with capecitabine or 5-fluorouracil and cisplatin is indicated for the treatment of adult patients with HER2 positive metastatic adenocarcinoma of the stomach or gastro-oesophageal junction who have not received prior anti-cancer treatment for their metastatic disease.
Ontruzant should only be used in patients with metastatic gastric cancer (MGC) whose tumours have HER2 overexpression as defined by IHC2+ and a confirmatory SISH or FISH result, or by an IHC3+ result. Accurate and validated assay methods should be used (see sections 4.4 and 5.1).
HER2 testing is mandatory prior to initiation of therapy (see sections 4.4 and 5.1). Ontruzant treatment should only be initiated by a physician experienced in the administration of cytotoxic chemotherapy (see section 4.4), and should be administered by a healthcare professional only.
Ontruzant intravenous formulation is not intended for subcutaneous administration and should be administered via an intravenous infusion only.
In order to prevent medication errors, it is important to check the vial labels to ensure that the medicinal product being prepared and administered is Ontruzant (trastuzumab) and not another trastuzumab-containing product (e.g. trastuzumab emtansine or trastuzumab deruxtecan).
The recommended initial loading dose is 8 mg/kg body weight. The recommended maintenance dose at three-weekly intervals is 6 mg/kg body weight, beginning three weeks after the loading dose.
The recommended initial loading dose of Ontruzant is 4 mg/kg body weight. The recommended weekly maintenance dose of Ontruzant is 2 mg/kg body weight, beginning one week after the loading dose.
In the pivotal trials (H0648g, M77001), paclitaxel or docetaxel was administered the day following the first dose of trastuzumab (for dose, see the Summary of Product Characteristics (SmPC) for paclitaxel or docetaxel) and immediately after the subsequent doses of trastuzumab if the preceding dose of trastuzumab was well tolerated.
In the pivotal trial (BO16216) trastuzumab and anastrozole were administered from day 1. There were no restrictions on the relative timing of trastuzumab and anastrozole at administration (for dose, see the SmPC for anastrozole or other aromatase inhibitors).
As a three-weekly regimen the recommended initial loading dose of Ontruzant is 8 mg/kg body weight. The recommended maintenance dose of Ontruzant at three-weekly intervals is 6 mg/kg body weight, beginning three weeks after the loading dose.
As a weekly regimen (initial loading dose of 4 mg/kg followed by 2 mg/kg every week) concomitantly with paclitaxel following chemotherapy with doxorubicin and cyclophosphamide.
See section 5.1 for chemotherapy combination dosing.
The recommended initial loading dose is 8 mg/kg body weight. The recommended maintenance dose at three-weekly intervals is 6 mg/kg body weight, beginning three weeks after the loading dose.
Patients with MBC or MGC should be treated with Ontruzant until progression of disease. Patients with EBC should be treated with Ontruzant for 1 year or until disease recurrence, whichever occurs first; extending treatment in EBC beyond one year is not recommended (see section 5.1).
No reductions in the dose of trastuzumab were made during clinical trials. Patients may continue therapy during periods of reversible, chemotherapy-induced myelosuppression but they should be monitored carefully for complications of neutropenia during this time. Refer to the SmPC for paclitaxel, docetaxel or aromatase inhibitor for information on dose reduction or delays.
If left ventricular ejection fraction (LVEF) percentage drops ≥10 points from baseline AND to below 50%, treatment should be suspended and a repeat LVEF assessment performed within approximately 3 weeks. If LVEF has not improved, or has declined further, or if symptomatic congestive heart failure (CHF) has developed, discontinuation of Ontruzant should be strongly considered, unless the benefits for the individual patient are deemed to outweigh the risks. All such patients should be referred for assessment by a cardiologist and followed up.
If the patient has missed a dose of Ontruzant by one week or less, then the usual maintenance dose (weekly regimen: 2 mg/kg; three-weekly regimen: 6 mg/kg) should be administered as soon as possible. Do not wait until the next planned cycle. Subsequent maintenance doses should be administered 7 days or 21 days later according to the weekly or three-weekly schedules, respectively.
If the patient has missed a dose of Ontruzant by more than one week, a re-loading dose of Ontruzant should be administered over approximately 90 minutes (weekly regimen: 4 mg/kg; three-weekly regimen: 8 mg/kg) as soon as possible. Subsequent Ontruzant maintenance doses (weekly regimen: 2 mg/kg; three-weekly regimen 6 mg/kg respectively) should be administered 7 days or 21 days later according to the weekly or three-weekly schedules respectively.
Dedicated pharmacokinetic studies in the elderly and those with renal or hepatic impairment have not been carried out. In a population pharmacokinetic analysis, age and renal impairment were not shown to affect trastuzumab disposition.
There is no relevant use of Ontruzant in the paediatric population.
Ontruzant is for intravenous use. The loading dose should be administered as a 90-minute intravenous infusion. Administration as an intravenous push or bolus is prohibited. Ontruzant intravenous infusion should be administered by a healthcare provider prepared to manage anaphylaxis and an emergency kit should be available. Patients should be observed for at least six hours after the start of the first infusion and for two hours after the start of the subsequent infusions for symptoms like fever and chills or other infusion-related symptoms (see sections 4.4 and 4.8). Interruption or slowing the rate of the infusion may help control such symptoms. The infusion may be resumed when symptoms abate.
If the initial loading dose was well tolerated, the subsequent doses can be administered as a 30-minute infusion.
For instructions on reconstitution of Ontruzant intravenous formulation before administration, see section 6.6.
There is no experience with overdose in human clinical trials. Single doses of trastuzumab alone greater than 10 mg/kg have not been administered in the clinical trials; a maintenance dose of 10 mg/kg q3w following a loading dose of 8 mg/kg has been studied in a clinical trial with metastatic gastric cancer patients. Doses up to this level were well tolerated.
Unopened vials: 4 years.
After reconstitution and dilution: After aseptic reconstitution with sterile water for injections, chemical and physical stability of the reconstituted solution has been demonstrated for 7 days at 2°C-8°C.
After aseptic dilution in polyvinylchloride, polyethylene or polypropylene bags containing sodium chloride 9 mg/mL (0.9%) solution for injection, chemical and physical stability of Ontruzant has been demonstrated for up to 30 days at 2ºC-8ºC, and 24 hours at temperatures not exceeding 30°C.
From a microbiological point of view, the reconstituted solution and Ontruzant infusion solution should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user, and would not normally be longer than 24 hours at 2°C to 8°C, unless reconstitution and dilution have taken place under controlled and validated aseptic conditions.
Store in a refrigerator (2°C-8°C).
Do not freeze the reconstituted solution.
For storage conditions of the reconstituted and diluted medicinal product, see section 6.3 and 6.6.
Ontruzant 150 mg powder for concentrate for solution for infusion: One 15 mL clear glass type I vial with butyl rubber stopper laminated with a fluoro-resin film containing 150 mg of trastuzumab.
Each carton contains one vial.
Ontruzant 420 mg powder for concentrate for solution for infusion: One 40 mL clear glass type I vial with butyl rubber stopper laminated with a fluoro-resin film containing 420 mg of trastuzumab.
Each carton contains one vial.
Ontruzant is provided in sterile, preservative-free, non-pyrogenic, single use vials.
Appropriate aseptic technique should be used for reconstitution and dilution procedures. Care must be taken to ensure the sterility of prepared solutions. Since the medicinal product does not contain any anti-microbial preservative or bacteriostatic agents, aseptic technique must be observed.
Aseptic handling must be ensured when preparing the infusion. Preparation should be:
Ontruzant should be carefully handled during reconstitution. Causing excessive foaming during reconstitution or shaking the reconstituted solution may result in problems with the amount of Ontruzant that can be withdrawn from the vial.
The reconstituted solution should not be frozen.
Ontruzant 150 mg powder for concentrate for solution for infusion: Appropriate aseptic technique should be used. Each 150 mg vial of Ontruzant is reconstituted with 7.2 mL of sterile water for injection (not supplied). Use of other reconstitution solvents should be avoided. This yields a 7.4 mL solution for single-dose use, containing approximately 21 mg/mL trastuzumab, at a pH of approximately 6.0. A volume overage of 4% ensures that the labelled dose of 150 mg can be withdrawn from each vial.
Ontruzant 420 mg powder for concentrate for solution for infusion: Appropriate aseptic technique should be used. Each 420 mg vial of Ontruzant is reconstituted with 20 mL of sterile water for injection (not supplied). Use of other reconstitution solvents should be avoided. This yields a 21 mL solution for single-dose use, containing approximately 21 mg/mL trastuzumab, at a pH of approximately 6.0. A volume overage of 5% ensures that the labelled dose of 420 mg can be withdrawn from each vial.
| Ontruzant vial | Volume of sterile water for injections | Final concentration | ||
| 150 mg vial | + | 7.2 mL | = | 21 mg/mL |
| 420 mg vial | + | 20 mL | = | 21 mg/mL |
Slight foaming of the product upon reconstitution is not unusual. Allow the vial to stand undisturbed for approximately 5 minutes. The reconstituted Ontruzant results in a colourless to pale yellow transparent solution and should be essentially free of visible particulates.
Determine the volume of the solution required:
Volume (mL) = Body weight (kg) x dose (4 mg/kg for loading or 2 mg/kg for maintenance) / 21 (mg/mL, concentration of reconstituted solution)
Volume (mL) = Body weight (kg) x dose (8 mg/kg for loading or 6 mg/kg for maintenance) / 21 (mg/mL, concentration of reconstituted solution)
The appropriate amount of solution should be withdrawn from the vial using a sterile needle and syringe and added to an infusion bag containing 250 mL of 0.9% sodium chloride solution. Do not use with glucose-containing solutions (see section 6.2). The bag should be gently inverted to mix the solution in order to avoid foaming.
Parenteral medicinal products should be inspected visually for particulate matter and discoloration prior to administration.
No incompatibilities between Ontruzant and polyvinylchloride, polyethylene or polypropylene bags have been observed.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
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