PERJETA Concentrate for solution for infusion Ref.[8913] Active ingredients: Pertuzumab

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.

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:

Dose modification

Dose reductions are not recommended for Perjeta or trastuzumab. For details regarding trastuzumab, please refer to the summary of product characteristics (SmPC).

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 SmPC.

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 and safety of Perjeta were observed in patients ≥65 and <65 years of age with the exception of diarrhoea, which had an increased incidence in patients ≥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.

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).

The maximum tolerated dose of pertuzumab has not been determined. In clinical trials, single doses higher than 25 mg/kg (1727 mg) have not been tested.

In case of overdose, patients must be closely monitored for signs or symptoms of adverse reactions and appropriate symptomatic treatment instituted.

Unopened vial: 2 years.

Diluted solution: Chemical and physical in-use stability has been demonstrated for 24 hours at 30°C. From a microbiological point of view, the product 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 normally not be longer than 24 hours at 2°C to 8°C, unless dilution has taken place in controlled and validated aseptic conditions.

Store in a refrigerator (2°C-8°C).

Do not freeze.

Keep the vial in the outer carton in order to protect from light.

For storage conditions after dilution of the medicinal product, see section 6.3.

Vial (Type I glass) with a stopper (butyl rubber) containing 14 ml of solution.

Pack of 1 vial.

Perjeta does not contain any antimicrobial preservative. Therefore, care must be taken to ensure the sterility of the prepared solution for infusion and should be prepared by a healthcare professional.

Perjeta is for single use only.

The vial must not be shaken. 14 ml of Perjeta concentrate should be withdrawn from the vial and diluted into a 250 ml PVC or non-PVC polyolefin infusion bag of sodium chloride 9 mg/ml (0.9%) solution for infusion. After dilution, one ml of solution should contain approximately 3.02 mg of pertuzumab (840 mg/278 ml) for the initial dose where two vials are required and approximately 1.59 mg of pertuzumab (420 mg/264 ml) for the maintenance dose where one vial is required. The bag should be gently inverted to mix the solution in order to avoid foaming.

Parenteral medicinal products should be inspected visually for particulates and discolouration prior to administration. If particulates or discoloration are observed, the solution should not be used. Once the infusion is prepared it should be administered immediately (see section 6.3).

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Perjeta is compatible with polyvinylchloride (PVC) or non-PVC polyolefin bags including polyethylene.