Posology : מינונים

4.2     Posology and method of administration

Perjeta should only be initiated under the supervision of a physician experienced in the administration of anti-cancer agents. Perjeta should be administered by a healthcare professional prepared to manage anaphylaxis and in an environment where full resuscitation facilities are immediately available.

Posology

Patients treated with Perjeta must have HER2-positive tumour status, defined as a score of 3+ by immunohistochemistry (IHC) and/or a ratio of ≥ 2.0 by in situ hybridisation (ISH) assessed by a validated test.


EMEA/H/C/0002547/II/0066 (05.2023) 1    Perjeta PI_Ver 9.0
To ensure accurate and reproducible results, the testing must be performed in a specialised laboratory, which can ensure validation of the testing procedures. For full instructions on assay performance and interpretation please refer to the package leaflets of validated HER2 testing assays.

The recommended initial loading dose of pertuzumab is 840 mg administered as a 60 minute intravenous infusion, followed every 3 weeks thereafter by a maintenance dose of 420 mg administered over a period of 30 to 60 minutes. An observation period of 30 - 60 minutes is recommended after completion of each infusion. The observation period should be completed prior to any subsequent infusion of trastuzumab or chemotherapy (see section 4.4).

Perjeta and trastuzumab should be administered sequentially and not mixed in the same infusion bag. Perjeta and trastuzumab can be given in any order. When administered with Perjeta the recommendation is to follow a 3 weekly schedule for trastuzumab administered as either: 
•   an IV infusion with an initial loading dose of trastuzumab 8 mg/kg body weight followed every 3 weeks thereafter by a maintenance dose of 6 mg/kg body weight or
• a fixed subcutaneous dose of trastuzumab by injection (600 mg) every 3 weeks irrespective of the patient’s body weight.

In patients receiving a taxane, Perjeta and trastuzumab should be administered prior to the taxane.

When administered with Perjeta, docetaxel can be started at 75 mg/m2, and subsequently escalated to 100 mg/m2 depending on the chosen regimen and tolerability of the initial dose. Alternatively, docetaxel can be given at 100 mg/m2 on a 3 weekly schedule from the start, again depending on the chosen regimen. If a carboplatin-based regimen is used, the recommended dose for docetaxel is 75 mg/m2 throughout (no dose escalation). When administered with Perjeta in the adjuvant setting, the recommended dose of paclitaxel is 80 mg/m2 once weekly for 12 weekly cycles.

In patients receiving an anthracycline-based regimen, Perjeta and trastuzumab should be administered following completion of the entire anthracycline regimen (see section 4.4).

Metastatic breast cancer

Perjeta should be administered in combination with trastuzumab and docetaxel . Treatment with Perjeta and trastuzumab may continue until disease progression or unmanageable toxicity even if treatment with docetaxel is discontinued.

Early breast cancer

In the neoadjuvant setting, Perjeta should be administered for 3 to 6 cycles in combination with trastuzumab and chemotherapy, as part of a complete treatment regimen for early breast cancer (see section 5.1).

In the adjuvant setting, Perjeta should be administered in combination with trastuzumab for a total of one year (up to 18 cycles or until disease recurrence, or unmanageable toxicity, whichever occurs first) as part of a complete regimen for early breast cancer and regardless of the timing of surgery. Treatment should include standard anthracycline- and/or taxane-based chemotherapy. Perjeta and trastuzumab should start on Day 1 of the first taxane-containing cycle and should continue even if chemotherapy is discontinued.

Delayed or missed doses

For recommendations on delayed or missed doses, please refer to Table 1 below.


Table 1       Recommendations regarding delayed or missed doses
Time between two         Perjeta                                         trastuzumab sequential                                             IV                        SC infusions
< 6 weeks                The 420 mg dose of            The 6 mg/kg dose of         The fixed dose of pertuzumab should be          trastuzumab IV should       600mg trastuzumab administered as soon as       be administered as soon     SC should be possible. Do not wait         as possible. Do not wait    administered as soon until the next planned        until the next planned      as possible.
dose. Thereafter, revert to   dose. Thereafter, revert    Do not wait until the the original planned          to the original planned     next planned dose.
schedule.                     schedule.

≥ 6 weeks                The 840 mg loading dose       The loading dose of of pertuzumab should be       8 mg/kg of trastuzumab re-administered as a 60       IV should be re- minute infusion, followed     administered over by a maintenance dose of      approximately
420 mg IV administered        90 minutes, followed by every 3 weeks thereafter.     a maintenance dose of
6 mg/kg IV administered every 3 weeks thereafter.


Dose modification
Dose reductions are not recommended for Perjeta or trastuzumab. For details regarding trastuzumab, please refer to the Prescribing Information.

Patients may continue therapy during periods of reversible chemotherapy-induced myelosuppression but they should be monitored carefully for complications of neutropenia during this time. For docetaxel and other chemotherapy dose modifications, see relevant presecribing information.

If trastuzumab treatment is discontinued, treatment with Perjeta should be discontinued.

Left ventricular dysfunction
Perjeta and trastuzumab should be withheld for at least 3 weeks for any signs and symptoms suggestive of congestive heart failure. Perjeta should be discontinued if symptomatic heart failure is confirmed (see section 4.4 for more details).

Patients with metastatic breast cancer

Patients should have a pre-treatment left ventricular ejection fraction (LVEF) of ≥ 50%. Perjeta and trastuzumab should be withheld for at least 3 weeks for:
 a drop in LVEF to less than 40%
 a LVEF of 40%-45% associated with a fall of ≥ 10% points below pre-treatment value.
Perjeta and trastuzumab may be resumed if the LVEF has recovered to > 45% or to 40-45% associated with a difference of < 10% points below pre-treatment values.

Patients with early breast cancer

Patients should have a pre-treatment LVEF of ≥ 55% (≥ 50% after completion of the anthracycline component of chemotherapy, if given). Perjeta and trastuzumab should be withheld for at least 3 weeks for: 
•     a drop in LVEF to less than 50% associated with a fall of ≥ 10% points below pre-treatment values.

Perjeta and trastuzumab may be resumed if the LVEF has recovered to ≥50% or to a difference of < 10% points below pre-treatment values.
Elderly patients
No overall differences in efficacy of Perjeta were observed in patients ≥ 65 and < 65 years of age. No dose adjustment is necessary in the elderly population ≥ 65 years of age. Limited data are available in patients > 75 years of age. Please see section 4.8 for assessment of safety of Perjeta in elderly patients.

Renal impairment
Dose adjustments of pertuzumab are not needed in patients with mild or moderate renal impairment. No dose recommendations can be made for patients with severe renal impairment because of the limited pharmacokinetic data available (see section 5.2).

Hepatic impairment
The safety and efficacy of Perjeta have not been studied in patients with hepatic impairment. No specific dose recommendations can be made.

Paediatric population
The safety and efficacy of Perjeta in children and adolescents below 18 years of age have not been established. There is no relevant use of Perjeta in the paediatric population in the indication of breast cancer.

Method of administration
Perjeta is administered intravenously by infusion. It should not be administered as an intravenous push or bolus. For instructions on dilution of Perjeta prior to administration, see sections 6.2 and 6.6.

For the initial dose, the recommended infusion period is 60 minutes. If the first infusion is well tolerated, subsequent infusions may be administered over a period of 30 minutes to 60 minutes (see section 4.4).

Infusion reactions

The infusion rate may be slowed or interrupted if the patient develops an infusion reaction (see section 4.8).
The infusion may be resumed when symptoms abate. Treatment including oxygen, beta agonists, antihistamines, rapid i.v. fluids and antipyretics may also help alleviate symptoms.

Hypersensitivity reactions/anaphylaxis

The infusion should be discontinued immediately and permanently if the patient experiences a NCI-CTCAE Grade 4 reaction (anaphylaxis), bronchospasm or acute respiratory distress syndrome (see section 4.4).