Pertuzumab

Each vial of Pertuzumab drug product contains a total of 420 mg Pertuzumab.

Excipients/Inactive Ingredients: L-histidine, glacial acetic acid, sucrose, polysorbate 20 and sterile water for injection.

Metastatic Breast Cancer (MBC)

Pertuzumab is indicated for use in combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.

Neoadjuvant Treatment Of Breast Cancer

Pertuzumab is indicated for use in combination with trastuzumab and docetaxel for the neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either greater than 2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer. This indication is based on demonstration of an improvement in pathological complete response rate. No data are available demonstrating improvement in event-free survival or overall survival.

Limitations Of Use

• The safety of Pertuzumab as part of a doxorubicin-containing regimen has not been established.
• The safety of Pertuzumab administered for greater than 6 cycles for early breast cancer has not been established.

Pertuzumab injection is used to treat breast cancer that has spread to other parts of the body. It is used together with other cancer medicines, docetaxel and trastuzumab, and only in patients with HER2-positive breast cancer. The HER2 protein is produced by some breast tumors. Pertuzumab interferes with the growth of this protein, which is eventually destroyed by the body. It is a monoclonal antibody.

Pertuzumab is also used as part of a complete treatment regimen for early breast cancer before surgery.

Pertuzumab is to be given only by or under the immediate supervision of your doctor.

Recommended Doses And Schedules

The initial dose of Pertuzumab is 840 mg administered as a 60-minute intravenous infusion, followed every 3 weeks by a dose of 420 mg administered as an intravenous infusion over 30 to 60 minutes.

When administered with Pertuzumab, the recommended initial dose of trastuzumab is 8 mg/kg administered as a 90-minute intravenous infusion, followed every 3 weeks by a dose of 6 mg/kg administered as an intravenous infusion over 30 to 90 minutes.

Pertuzumab, trastuzumab, and docetaxel should be administered sequentially. Pertuzumab and trastuzumab can be given in any order. Docetaxel should be administered after Pertuzumab and trastuzumab. An observation period of 30 to 60 minutes is recommended after each Pertuzumab infusion and before commencement of any subsequent infusion of trastuzumab or docetaxel.

Metastatic Breast Cancer (MBC)

When administered with Pertuzumab, the recommended initial dose of docetaxel is 75 mg/m² administered as an intravenous infusion. The dose may be escalated to 100 mg/m administered every 3 weeks if the initial dose is well tolerated.

Neoadjuvant Treatment Of Breast Cancer

Pertuzumab should be administered every 3 weeks for 3 to 6 cycles as part of one of the following treatment regimens for early breast cancer :

• Four preoperative cycles of Pertuzumab in combination with trastuzumab and docetaxel followed by 3 postoperative cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC) as given in Study 2
• Three preoperative cycles of FEC alone followed by 3 preoperative cycles of Pertuzumab in combination with docetaxel and trastuzumab as given in Study 3
• Six preoperative cycles of Pertuzumab in combination with docetaxel, carboplatin, and trastuzumab (TCH) (escalation of docetaxel above 75 mg/m² is not recommended) as given in Study 3

Following surgery, patients should continue to receive trastuzumab to complete 1 year of treatment. There is insufficient evidence to recommend continued use of Pertuzumab for greater than 6 cycles for early breast cancer. There is insufficient evidence to recommend concomitant administration of an anthracycline with Pertuzumab, and there are no safety data to support sequential use of doxorubicin with Pertuzumab.

Dose Modification

For delayed or missed doses, if the time between two sequential infusions is less than 6 weeks, the 420 mg dose of Pertuzumab should be administered. Do not wait until the next planned dose. If the time between two sequential infusions is 6 weeks or more, the initial dose of 840 mg Pertuzumab should be re-administered as a 60-minute intravenous infusion followed every 3 weeks thereafter by a dose of 420 mg administered as an intravenous infusion over 30 to 60 minutes.

Pertuzumab should be discontinued if trastuzumab treatment is discontinued.

Dose reductions are not recommended for Pertuzumab.

For docetaxel dose modifications, see relevant prescribing information.

Left Ventricular Ejection Fraction (LVEF)

Withhold Pertuzumab and trastuzumab dosing for at least 3 weeks for either:

• a drop in LVEF to less than 45% or
• LVEF of 45% to 49% with a 10% or greater absolute decrease below pretreatment values

Pertuzumab may be resumed if the LVEF has recovered to greater than 49% or to 45% to 49% associated with less than a 10% absolute decrease below pretreatment values.

If after a repeat assessment within approximately 3 weeks, the LVEF has not improved, or has declined further, Pertuzumab and trastuzumab should be discontinued, unless the benefits for the individual patient are deemed to outweigh the risks.

Infusion-Related Reactions

The infusion rate of Pertuzumab may be slowed or interrupted if the patient develops an infusion-related reaction.

Hypersensitivity Reactions/Anaphylaxis

The infusion should be discontinued immediately if the patient experiences a serious hypersensitivity reaction.

Preparation For Administration

Administer as an intravenous infusion only. Do not administer as an intravenous push or bolus. Do not mix Pertuzumab with other drugs.

Preparation

Prepare the solution for infusion, using aseptic technique, as follows:

• Parenteral drug products should be inspected visually for particulates and discoloration prior to administration.

• Withdraw the appropriate volume of Pertuzumab solution from the vial(s).
• Dilute into a 250 mL 0.9% sodium chloride PVC or non-PVC polyolefin infusion bag.
• Mix diluted solution by gentle inversion. Do not shake.
• Administer immediately once prepared.
• If the diluted infusion solution is not used immediately, it can be stored at 2°C to 8°C for up to 24 hours.
• Dilute with 0.9% Sodium Chloride injection only. Do not use dextrose (5%) solution.

How supplied

Dosage Forms And Strengths

Pertuzumab (Pertuzumab) 420 mg/14 mL (30 mg/mL) in a single-use vial

Storage And Handling

Pertuzumab is supplied as a 420 mg/14 mL (30 mg/mL) single-use vial containing preservativefree solution. NDC 50242-145-01.

Store vials in a refrigerator at 2°C to 8°C (36°F to 46°F) until time of use.

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

DO NOT FREEZE. DO NOT SHAKE.

Manufactured by: Genentech, Inc., A Member of the Roche Group, 1 DNA Way, South San Francisco, CA 94080-4990. Revised: Mar 2016

See also:
What is the most important information I should know about Pertuzumab?

Pertuzumab can cause birth defects or death to the unborn baby. Do not use if you are pregnant.

Before receiving Pertuzumab, tell your doctor if you have heart disease, congestive heart failure, a history of heart attack, or any allergies or breathing problems. You may not be able to receive Pertuzumab, or you may need a dosage adjustment or special tests during treatment.

Some people receiving a Pertuzumab injection have had a reaction to the infusion (when the medicine is injected into the vein). Tell your caregiver right away if you feel dizzy, nauseated, light-headed, weak, itchy, or short of breath during the injection.

Use Pertuzumab as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Pertuzumab is given as an injection at your doctor's office, hospital, or clinic.
• Do not use Pertuzumab if it contains particles, is cloudy or discolored, or if the vial is cracked or damaged.
• Keep this product, as well as syringes and needles, out of the reach of children and pets. Do not reuse needles, syringes, or other materials. Ask your health care provider how to dispose of these materials after use. Follow all local rules for disposal.
• If you miss a dose of Pertuzumab, contact your doctor right away.

Ask your health care provider any questions you may have about how to use Pertuzumab.

Use: Labeled Indications

Breast cancer, metastatic: Treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (in combination with trastuzumab and docetaxel) in patients who have not received prior anti-HER2 therapy or chemotherapy to treat metastatic disease.

Breast cancer, early (adjuvant): Adjuvant treatment of HER2-positive early breast cancer at high risk of recurrence (in combination with trastuzumab and chemotherapy).

Breast cancer, early (neoadjuvant): Neoadjuvant treatment of locally advanced, inflammatory, or early stage HER2-positive, breast cancer (either greater than 2 cm in diameter or node positive) in combination with trastuzumab and chemotherapy (as part of a complete treatment regimen for early breast cancer).

See also:
What other drugs will affect Pertuzumab?

A sub-study in 37 patients in the pivotal trial CLEOPATRA showed no evidence of drug-drug interaction between Pertuzumab and Herceptin (trastuzumab) and between Pertuzumab and docetaxel. In addition no clinical relevant pharmacokinetic interaction of co-administered docetaxel or Herceptin (trastuzumab) on Pertuzumab was evident based on the population pharmacokinetics analysis. This lack of drug-drug interaction was confirmed by pharmacokinetic data from the NEOSPHERE study. Four studies have evaluated the effects of Pertuzumab on the pharmacokinetics of co-administered cytotoxic agents, docetaxel, gemcitabine, erlotinib and capecitabine, respectively. There was no evidence of any pharmacokinetics interaction between Pertuzumab and any of these agents. The pharmacokinetics of Pertuzumab in these studies were comparable to those observed in single-agent studies.

See also:
What are the possible side effects of Pertuzumab?

Clinical Trials: The safety of Pertuzumab has been evaluated in more than 1600 patients either in the pivotal Phase III trial CLEOPATRA or in phase I and II trials conducted in patients with various malignancies and predominantly treated with Pertuzumab in combination with other antineoplastic agents. The safety of Pertuzumab in the phase I and II studies was generally consistent with that observed in the CLEOPATRA trial, though the incidence and most common ADRs varied depending on whether Pertuzumab was administered as monotherapy or on the concomitant anti-neoplastic agent(s) studied.

Metastatic Breast Cancer: Table 4 summarises the adverse drug reactions (ADRs) from the pivotal clinical trial CLEOPATRA in which Pertuzumab was given in combination with Herceptin (trastuzumab) and docetaxel vs placebo in combination with Herceptin (trastuzumab) and docetaxel. As Pertuzumab is used with Herceptin (trastuzumab) and docetaxel it is difficult to ascertain the causal relationship of an adverse reaction to a particular drug. The safety profile for Pertuzumab remains unchanged with an additional year of follow-up (median total follow-up of 30 months) in CLEOPATRA.

The most common ADRs (≥50%) seen in Pertuzumab in combination with Herceptin and docetaxel were diarrhoea, alopecia and neutropenia. The most common NCI-CTCAE (version 3) grade 3-4 ADRs (>10%) were neutropenia, febrile neutropenia and leukopenia. An increased incidence of febrile neutropenia was observed for Asian patients in both treatment arms compared with patients of other races and from other geographic regions. Among Asian patients, the incidence of febrile neutropenia was higher in the Pertuzumab-treated group (26%) compared with the placebo-treated group (12%).

The following categories of frequency have been used: Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000).

The following clinically relevant ADRs were reported in <10% of the Pertuzumab treated group.

Infections and Infestations: Paronychia (3.5% in the placebo-treated group/7.1% in the Pertuzumab-treated group).

Respiratory, Thoracic and Mediastinal Disorders: Pleural effusion (5.8% in the placebo-treated group/5.2% in the treated group).

Cardiac Disorders: Left Ventricular Dysfunction (8.3% in the placebo treated group/4.4% in the Pertuzumab treated group) including Symptomatic Left Ventricular Systolic Dysfunction (CHF) (1.8% in the placebo treated group/1.0% in the Pertuzumab treated group).

Immune System Disorders: Hypersensitivity (5.0% in placebo treated group/6.4% in the Pertuzumab treated group). Drug hypersensitivity (3.8% in the placebo treated group/4.4% in the Pertuzumab treated group).

ADRs Reported in Patients Receiving Pertuzumab and Herceptin (Trastuzumab) After Discontinuation of Docetaxel: In the pivotal trial CLEOPATRA, ADRs were reported less frequently after discontinuation of docetaxel treatment. After discontinuation of docetaxel, all ADRs in the Pertuzumab and Herceptin (trastuzumab) treatment group occurred in <10% of patients with the exception of diarrhoea (19.1%), upper respiratory tract infection (12.8%), rash (11.7%), headache (11.4%) and fatigue (11.1%).

Neoadjuvant Treatment of Breast Cancer: In NEOSPHERE, the most common ADRs (≥50%) seen in Pertuzumab in combination with Herceptin and docetaxel were alopecia and neutropenia. The most common NCI-CTCAE (version 3) grade 3-4 ADR (≥10%) was neutropenia.

In TRYPHAENA, when Pertuzumab was administered in combination with Herceptin and docetaxel for three cycles following three cycles of FEC, the most common ADRs (≥50%) were diarrhoea, nausea and alopecia. The most common NCI-CTCAE (version 3) grade 3-4 ADRs (≥10%) were neutropenia and leukopenia. Similarly, when Pertuzumab was administered in combination with TCH for six cycles, the most common ADRs (≥50%) were diarrhoea and alopecia. The most common NCI-CTCAE (version 3) grade 3-4 ADRs (≥10%) were neutropenia, febrile neutropenia, anaemia, leukopenia and diarrhoea.

Further Information on Selected Adverse Drug Reactions: Left Ventricular Dysfunction: In the pivotal trial CLEOPATRA, the incidence of LVD during study treatment was higher in the placebo treated group than the Pertuzumab treated group (8.3% and 4.4%, respectively). The incidence of symptomatic left ventricular systolic dysfunction was also lower in the Pertuzumab treated group (1.8% in the placebo treated group vs. 1.0% in the Pertuzumab treated group).

In NEOSPHERE the incidence of LVD (during the overall treatment period) was higher in the Pertuzumab treated groups (4.2%) than the Herceptin and docetaxel treated group (1.9%). There was one case of symptomatic left ventricular systolic dysfunction in the Pertuzumab and Herceptin treated group.

In TRYPHAENA the incidence of LVD (during the overall treatment period) was similar in the anthracycline and Pertuzumab treated groups and the Pertuzumab in combination with TCH treated group (8.8% and 7.9% respectively). The incidence of symptomatic left ventricular systolic dysfunction (congestive heart failure) in the anthracycline and Pertuzumab treated groups and the non-anthracycline Pertuzumab treated group was 0.7% and 1.3% respectively.

Infusion-Related Reactions: An infusion related reaction was defined in the pivotal Phase lll trial as any event reported as hypersensitivity, anaphylactic reaction, acute infusion reaction or cytokine release syndrome occurring during an infusion or on the same day as the infusion. In the pivotal trial CLEOPATRA, the initial dose of Pertuzumab was given the day before Herceptin (trastuzumab) and docetaxel to allow for the examination of Pertuzumab associated reactions. On the first day when only Pertuzumab was administered, the overall frequency of infusion related reactions was 9.8% in the placebo treated group and 13.0% in the Pertuzumab-treated group, with the majority of reactions being mild or moderate. The most common infusion related reactions (≥1.0%) in the Pertuzumab-treated group were pyrexia, chills, fatigue, headache, asthenia, hypersensitivity and vomiting.

During the second cycle when all drugs were administered on the same day, the most common infusion related reactions (≥1.0%) in the Pertuzumab-treated group were fatigue, drug hypersensitivity, dysgeusia, hypersensitivity, myalgia and vomiting.

In NEOSPHERE and TRYPHAENA, Pertuzumab was administered on the same day as the other study treatment drugs. Infusion-related reactions were consistent with those observed in CLEOPATRA, with a majority of reactions being mild or moderate.

Hypersensitivity Reactions/Anaphylaxis: In the pivotal trial CLEOPATRA the overall frequency of hypersensitivity/anaphylaxis reported events was 9.1% in the placebo-treated patients and 11.0% in the Pertuzumab-treated patients, of which 2.5% and 2.0% were NCI-CTCAE (version 3) grade 3-4, respectively. Overall, 2 patients in placebo-treated group and 4 patients in the Pertuzumab-treated group experienced anaphylaxis.

Overall, the majority of hypersensitivity reactions was mild or moderate in severity and resolved upon treatment. Based on modifications made to study treatment, most reactions were assessed as secondary to docetaxel infusions.

In NEOSPHERE and TRYPHAENA, hypersensitivity/anaphylaxis events were consistent with those observed in CLEOPATRA. In NEOSPHERE, one patient in the Pertuzumab and docetaxel treated group experienced anaphylaxis. In TRYPHAENA, the overall frequency of hypersensitivity/anaphylaxis was highest in the Pertuzumab and TCH treated group (13.2%), of which 2.6% were NCI-CTCAE (version 3) grade 3-4.

Laboratory Abnormalities: The incidence of NCI-CTCAE (version 3) grade 3-4 decreases in neutrophil counts were balanced in the 2 treated groups.

Post-Marketing: No data.

Laboratory Abnormalities: Not applicable.