Pertuzumab is a humanized recombinant monoclonal antibody that blocks ligand-dependent heterodimerization of human epidermal growth factor receptor-2 (HER2) and other epidermal growth factor receptors resulting in the inhibition of intracellular signaling pathways and eventually cell growth arrest and apoptosis. Pertuzumab also demonstrates antibody-dependent cell-mediated cytotoxicity. It was FDA-approved in 2012 for the first-line treatment of HER2-positive metastatic breast cancer in combination with trastuzumab and docetaxel based on a significant improvement in progression-free survival compared with placebo. Since then, the indication has been expanded to include neoadjuvant treatment of HER2-positive, locally advanced, inflammatory, or early stage breast cancer in combination with trastuzumab and docetaxel as part of a complete regimen for early breast cancer, as well as for the adjuvant treatment of HER2-positive early breast cancer at high risk of recurrence.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Hazardous Drugs Classification
-NIOSH 2016 List: Group 1
-NIOSH (Draft) 2020 List: No longer considered a hazardous drug by NIOSH.
-Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
-Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.
Emetic Risk
-Low
-Administer routine antiemetic prophylaxis prior to treatment.
Route-Specific Administration
Injectable Administration
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
-Do not administer pertuzumab without concomitant treatment with a trastuzumab product.
-When used in combination with trastuzumab and docetaxel, administer pertuzumab, trastuzumab, and docetaxel in sequential order.
-If a dose of pertuzumab is delayed or missed and it has been less than 6 weeks since the previous dose, give 420 mg IV as soon as possible. Do not wait until the next planned dose.
-If a dose of pertuzumab is delayed or missed and it has been 6 weeks or longer since the previous dose, re-administer the initial dose of 840 mg IV, then 3 weeks later, resume 420 mg IV every 3 weeks.
Dilution and Preparation:
-Withdraw the calculated dose of pertuzumab from the vial and add to 250 mL of 0.9% Sodium Chloride Injection in a PVC or non-PVC polyolefin infusion bag. Do not dilute with 5% Dextrose Injection.
-Mix the diluted solution by gentle inversion; do not shake.
-The diluted solution may be stored at 2 to 8 degrees Celsius for up to 24 hours.
Intravenous Infusion:
-Administer the diluted solution immediately if possible.
-Do not administer as an IV push or bolus.
-Give the first dose of 840 mg over 60 minutes and subsequent 420 mg doses over 30 to 60 minutes.
-Monitor for infusion-related reactions for 60 minutes following an 840 mg dose or for 30 minutes following a 420 mg dose.
-Slow or interrupt the infusion if an infusion-associated reaction occurs; discontinue immediately if a hypersensitivity reaction occurs.
Decreased left ventricular ejection fraction (LVEF) and congestive heart failure (CHF) have been reported with pertuzumab therapy. However, in the metastatic setting, pertuzumab did not increase the incidence of symptomatic left ventricular (LV) dysfunction or decreases in LVEF compared with placebo when given in combination with trastuzumab and docetaxel. Both LV dysfunction (4% vs. 8%) and symptomatic CHF (1% vs. 2%) occurred less often in the pertuzumab arm compared with placebo in this randomized, double-blind clinical trial (n = 804). In the neoadjuvant and adjuvant studies (n = 3,307), an LVEF decline of greater than 10% and a drop to less than 50% occurred in 0.6% to 16% of patients treated with pertuzumab. Left ventricular dysfunction occurred in 3% to 7% of pertuzumab-treated patients receiving neoadjuvant therapy (n = 943), while symptomatic CHF occurred in 4% of patients treated with neoadjuvant pertuzumab or less. Ejection fraction recovered to 50% or higher in all but one patient in 2 of the 4 neoadjuvant trials (n = 546). Asymptomatic or mildly symptomatic declines in LVEF (NYHA Class II) were reported with an equal incidence in the pertuzumab and placebo arms (3% vs. 3%), with recovery in 80% and 81% of these patients, respectively. Additionally, peripheral edema occurred in 0.9% to 12% (grade 3 or 4, 1% or less) of patients receiving neoadjuvant pertuzumab (n = 953), 17% of patients receiving adjuvant therapy (n = 2,364), and 23% (grade 3 or 4, 0.5%) of patients receiving pertuzumab for metastatic breast cancer (n = 407). Evaluate LVEF at baseline and at regular intervals during treatment. If the LVEF declines and has not improved, or has declined further at the subsequent assessment, discontinuation of PERJETA and trastuzumab should be strongly considered.
Generally mild dermatologic adverse reactions were reported across neoadjuvant, adjuvant, and metastatic clinical trials of pertuzumab administered in combination with trastuzumab and with or without various chemotherapy regimens. In one arm of a clinical trial where neoadjuvant pertuzumab was administered with trastuzumab (n = 108), mild (grade 1 or 2) alopecia was reported in 3% and rash in 11% of patients. In other arms of this trial, as well as several other clinical trials of neoadjuvant, adjuvant, and metastatic use of pertuzumab in combination with trastuzumab and various types of chemotherapy (e.g., docetaxel, paclitaxel, TCH, FEC, AC) (n = 3,199), alopecia (all grade, 49% to 67%; grade 3 or 4, 0.1% or less), rash (all grade, 11% to 34%; grade 3 or 4, 2% or less), nail disorder (all grade, 7% to 23%; grade 3 or 4, 1% or less), pruritus (all grade, 3% to 14%; grade 3 or 4, 0.1% or less), and xerosis (all grade, 6% to 14%; grade 3 or 4, 0.1% or less) were also reported. In patients with metastatic breast cancer treated with pertuzumab or placebo in combination with trastuzumab and docetaxel (n = 804), adverse reactions were reported less frequently after discontinuation of docetaxel treatment, including rash which occurred in 12% of patients after discontinuation of docetaxel. Paronychia was additionally reported in 7% or less of patients in 3 clinical trials of patients treated with pertuzumab plus trastuzumab and chemotherapy (n = 2,922) (e.g., docetaxel, carboplatin, 5-fluorouracil, epirubicin, doxorubicin, or cyclophosphamide), palmar-plantar erythrodysesthesia (hand and foot syndrome) in 6% to 11% (grade 3 or 4, 0.5% or less) of patients in 2 neoadjuvant clinical trials receiving pertuzumab plus trastuzumab and chemotherapy (n = 620), and nail discoloration in 2% to 15% of patients in one neoadjuvant clinical trial (n = 397).
The incidence of diarrhea associated with pertuzumab therapy varies among clinical trials and concomitant chemotherapy regimens. As adjuvant therapy for breast cancer, pertuzumab plus trastuzumab and chemotherapy (i.e., 5-fluorouracil/epirubicin/cyclophosphamide (FEC), 5-fluorouracil/doxorubicin/cyclophosphamide (FAC), doxorubicin/cyclophosphamide (AC), epirubicin/cyclophosphamide (EC), or docetaxel/carboplatin/trastuzumab (TCH)) (n = 2,364) was compared with placebo plus trastuzumab and chemotherapy (n = 2,405). In this trial, the addition of pertuzumab to trastuzumab and chemotherapy increase the incidence of diarrhea compared with placebo (all grade, 71% vs. 45%; grade 3 or 4, 10% vs. 4%). In patients receiving adjuvant therapy, diarrhea occurred in 67% receiving pertuzumab/trastuzumab/AC compared with 41% receiving placebo/trastuzumab/AC; it was reported in 85% of patients treated with pertuzumab/TCH compared with 62% receiving placebo/TCH. In another randomized clinical trial of patients with metastatic breast cancer, diarrhea occurred in 67% (grade 3 or 4, 8%) of patients treated with pertuzumab/trastuzumab/docetaxel (n = 407) compared with 46% (grade 3 or 4, 5%) of patients who received placebo/trastuzumab/docetaxel (n = 397). In a neoadjuvant breast cancer trial (n = 397), the incidence of diarrhea was also higher when chemotherapy was administered with pertuzumab (61% in the pertuzumab group vs. 34% in the placebo group), and was higher when administered with non-anthracycline based therapy (85% in the pertuzumab group vs. 62% in the placebo group) than with anthracycline-based therapy (67% in the pertuzumab group vs. 41% in the placebo group). The median duration of diarrhea for patients receiving pertuzumab in this trial was 8 days, although grade 3 or higher diarrhea lasted for a median of 20 days; hospitalization due to diarrhea was required in 2.4% of patients who received pertuzumab. Generally mild (grade 1 or 2) diarrhea occurred in 28% of patients treated with pertuzumab plus trastuzumab (n = 108) in one arm of a neoadjuvant breast cancer clinical trial. In three neoadjuvant clinical trials where treatment consisted of pertuzumab in combination with docetaxel, paclitaxel, FEC, or TCH (n = 943), diarrhea was reported in 46% to 72% (grade 3 or 4, 3% to 12%) of patients. In neoadjuvant, adjuvant, and metastatic clinical trials, the incidence of diarrhea with pertuzumab therapy after discontinuation of chemotherapy ranged from 18% to 19%.
Generally mild (grade 1 or 2) gastrointestinal (GI) adverse reactions occurred in patients treated with pertuzumab plus trastuzumab (n = 108) in one arm of a neoadjuvant breast cancer clinical trial, including mucosal inflammation (grade 1 or 2, 3%), diarrhea (grade 1 or 2, 28%), nausea (grade 1 or 2, 14%), stomatitis (grade 1 or 2, 5%), vomiting (grade 1 or 2, 5%), dysgeusia (grade 1 or 2, 5%), and anorexia (grade 1 or 2, 2%); grade 3 or 4 GI adverse reactions were not reported. As expected, the incidence is higher across several clinical trials where patients received pertuzumab in combination with trastuzumab and chemotherapy (e.g., docetaxel, paclitaxel, 5-fluorouracil/epirubicin/cyclophosphamide (FEC), trastuzumab/carboplatin/docetaxel (TCH), and doxorubicin/cyclophosphamide (AC)) (n = 3,606), including mucosal inflammation (all grade, 17% to 37%; grade 3 or 4, 4% or less), nausea (all grade, 36% to 71%; grade 3 or 4, 3% or less), stomatitis (all grade, 10% to 29%; grade 3 or 4, 5% or less), vomiting (all grade, 13% to 40%; grade 3 or 4, 5% or less), dysgeusia (all grade, 7% to 26%; grade 3 or 4, 0.5% or less), anorexia (all grade, 11% to 29%; grade 3 or 4, 2% or less), constipation (all grade, 15% to 38%; grade 3 or 4, 0.5% or less), dyspepsia (all grade, 25% or less; grade 3 or 4, 1% or less), upper abdominal pain (all grade, 13% or less; grade 3 or 4, 0.3% or less), generalized abdominal pain (grade 1 or 2, 12% or less), gastroesophageal reflux disease (grade 1 or 2, 12% or less), and oropharyngeal pain (all grade, 12% or less; grade 3 or 4, 0.5% or less).
Hematologic adverse reactions associated with pertuzumab therapy vary according to its place in therapy and concomitant chemotherapy. The lowest incidence of hematologic toxicity is in breast cancer patients from one arm of a neoadjuvant breasts cancer clinical trial who received treatment with pertuzumab plus trastuzumab alone, without chemotherapy (n = 108); in these patients, only neutropenia (grade 3 or 4, 0.9%) and anemia (all grade, 5%) were reported. Two neoadjuvant trials included arms of patients where pertuzumab/trastuzumab/docetaxel was administered after 5-fluorouracil/epirubicin/cyclophosphamide (FEC) (n = 273) or pertuzumab/trastuzumab/paclitaxel was administered after dose dense AC (doxorubicin/cyclophosphamide) (n = 198); in these patients, neutropenia occurred in 16% to 47% (grade 3 or 4, 9% to 43%), leukopenia in 3% to 16% (grade 3 or 4, 2% to 12%), anemia in 9% to 30% (grade 3 or 4, 3% to 4%), grade 1 or 2 thrombocytopenia in 1% or less, and grade 3 or 4 febrile neutropenia in 7% to 17% of patients. Neutropenia (all grade, 50% to 65%; grade 3 or 4, 45% to 57%) and leukopenia (all grade, 9% to 22%; grade 3 or 4, 5% to 19%) occurred more frequently in patients receiving neoadjuvant pertuzumab/trastuzumab/docetaxel (n = 107), pertuzumab/docetaxel (n = 108), and pertuzumab/trastuzumab/FEC followed by pertuzumab/trastuzumab/docetaxel (n = 72) in separate clinical trials, although the incidence of anemia (all grade, 3% to 19%; grade 3 or 4, 1% or less), febrile neutropenia (7% to 18%), and thrombocytopenia (grade 1 or 2, 7% or less) were similar. Anemia (all grade, 38%; grade 3 or 4, 17%) and thrombocytopenia (all grade, 30%; grade 3 or 4, 12%) occurred more often in a small arm of a neoadjuvant study where patients received pertuzumab plus trastuzumab/carboplatin/docetaxel (TCH) (n = 72), although the frequency of neutropenia (all grade, 49%; grade 3 or 4, 46%), leukopenia (all grade, 17%; grade 3 or 4, 12%), and febrile neutropenia (grade 3 or 4, 17%) were consistent. As adjuvant therapy, various chemotherapy regimens (i.e., FEC, FAC, EC, AC, TCH) were administered with pertuzumab (n = 2,364) versus placebo (n = 2,405). The addition of pertuzumab did not greatly increase the incidence of hematologic adverse reactions associated with chemotherapy compared with the placebo arm, including neutropenia (all grade, 14% to 25% vs. 14% to 23%; grade 3 or 4, 10% to 16% vs. 10% to 16%), leukopenia (all grade, 9% vs. 9%), anemia (all grade, 28% vs. 23%; grade 3 or 4, 7% vs. 5%), and neutropenic fever (grade 3 or 4, 12% vs. 11%); neutropenic fever was reported in association with a fatal outcome. Hematologic toxicities occurred more frequently in patients with metastatic disease treated with pertuzumab/trastuzumab/docetaxel (n = 407) in a randomized clinical trial, but again not at a greatly increased incidence compared with placebo/trastuzumab/docetaxel (n = 397), including neutropenia (all grade, 53% vs. 50%; grade 3 or 4, 49% vs. 46%), leukopenia (all grade, 18% vs. 20%; grade 3 or 4, 12% vs. 15%), anemia (all grade, 23% vs. 19%; grade 3 or 4, 2% vs. 4%), and neutropenic fever (all grade, 14% vs. 8%; grade 3 or 4, 13% vs. 7%); neutropenic fever was reported in association with a fatal outcome. An increased incidence of neutropenic fever was observed for Asian patients in both treatment arms of this study compared with patients of other races and from other geographic regions; among Asian patients, the incidence of neutropenic fever was higher in the pertuzumab-treated group compared with the placebo-treated group (26% vs. 12%).
Dizziness (all grade, 3% to 16%; grade 3 or 4, 1% or less) and headache (all grade, 11% to 30%; grade 3 or 4, 1% or less) were reported in patients treated with pertuzumab in combination with trastuzumab and chemotherapy across neoadjuvant, adjuvant, and metastatic breast cancer clinical trials (n = 3,606). In a randomized clinical trial of patients with metastatic breast cancer treated with pertuzumab plus trastuzumab and docetaxel (n = 407), the incidence of headache occurred less frequently after discontinuation of docetaxel treatment compared (21% vs. 11%).
Pertuzumab has been associated with infusion-related reactions, including fatal events. Infusion-related reactions (e.g., hypersensitivity, anaphylactic/anaphylactoid reactions, acute infusion reaction, or cytokine release syndrome occurring during the infusion or on the same day) were reported in 13% (grade 3 or 4, less than 1%) of HER2-positive metastatic breast cancer patients who received pertuzumab compared with 10% who received placebo in a randomized, double-blind clinical trial; the remainder of chemotherapy for the first cycle (trastuzumab and docetaxel) was administered on day 2 to allow for reactions to pertuzumab. The most common infusion reactions (1% or more) were asthenia, chills, fatigue, fever, hypersensitivity, and vomiting. During the second cycle when all drugs were administered on the same day, the most common infusion reactions in the pertuzumab-treated group (1% or more) were fatigue, dysgeusia, hypersensitivity, myalgia, and vomiting. Infusion-related reactions were reported in 13% to 21% (grade 3 or 4, 1% or less) of patients treated with neoadjuvant pertuzumab plus trastuzumab and chemotherapy in clinical trials. Across neoadjuvant, adjuvant, and metastatic clinical trials, hypersensitivity was reported in 1% to 12% (grade 3 or 4, 9% or less) of patients who received pertuzumab in combination with chemotherapy. Overall, the incidence of hypersensitivity/anaphylaxis with neoadjuvant treatment was consistent with that observed in patients with metastatic disease. Anaphylaxis occurred in 4 patients with metastatic breast cancer treated with pertuzumab and in 2 patients receiving neoadjuvant pertuzumab plus docetaxel in separate studies. Angioedema has been described in postmarketing experience with pertuzumab, and fever occurred in 8% to 20% (grade 3 or 4, 1% or less) of patients treated with pertuzumab in combination with trastuzumab and chemotherapy across clinical trials. Monitor patients for 60 minutes after the first pertuzumab infusion and for 30 minutes with subsequent infusions. Slow or interrupt the infusion if a patient develops an infusion reaction, initiate appropriate therapy for hypersensitivity if necessary, and carefully observe the patient until all infusion-related symptoms resolve. Consider permanently discontinuing pertuzumab if a severe infusion reaction occurs; pertuzumab should be discontinued if a severe hypersensitivity reaction occurs.
As adjuvant therapy for breast cancer, pertuzumab plus trastuzumab and chemotherapy (i.e. 5-fluorouracil/epirubicin/cyclophosphamide (FEC), 5-fluorouracil/doxorubicin/cyclophosphamide (FAC), doxorubicin/cyclophosphamide (AC), epirubicin/cyclophosphamide (EC), or docetaxel/carboplatin/trastuzumab (TCH)) (n = 2,364) was compared with placebo plus trastuzumab and chemotherapy. In this trial, the incidence of infection, both upper respiratory infection (all grade, 8% vs. 7%) and naso-pharyngitis (all grade, 13% vs. 12%; grade 3 or 4, less than 0.1% vs. 0.1%), was similar between patients treated with pertuzumab plus trastuzumab and chemotherapy compared with placebo plus trastuzumab and chemotherapy. Also, in patients with metastatic breast cancer treated with either pertuzumab (n = 407) or placebo (n = 397) in combination with trastuzumab and docetaxel, the incidence of upper respiratory tract infection (all grade, 17% vs. 13%; grade 3 or 4, 0.7% vs. 0%) and nasopharyngitis (all grade, 12% vs. 13%; grade 3 or 4, 0% vs. 0.3%) were similar between treatment arms. In this trial, upper respiratory tract infection occurred less frequently (13%) after discontinuation of docetaxel in the pertuzumab arm. Three neoadjuvant breast cancer clinical trials were not placebo-controlled, and pertuzumab was administered in combination with trastuzumab and various types of chemotherapy (n = 953). In these trials, upper respiratory tract infections occurred in 2% to 8.3% of patients in pertuzumab arms, nasopharyngitis in 6.7% to 9% of pertuzumab-treated patients, urinary tract infections in 2% to 11% of pertuzumab-treated patients, and paronychia in 0.5% to 1% of pertuzumab-treated patients.
Mildly increased lacrimation (grade 1 or 2) was reported in 4% to 18% of patients treated with pertuzumab in combination with trastuzumab and chemotherapy across neoadjuvant, adjuvant, and metastatic breast cancer clinical trials (n = 3,498). The incidence was lower (0.9%) in one arm of a neoadjuvant clinical trial in which patients were treated with only pertuzumab plus trastuzumab, without chemotherapy (n = 108).
Antibody formation may occur with therapeutic proteins such as pertuzumab. Antibodies to pertuzumab were reported in 13 patients (3%) who received pertuzumab plus trastuzumab and docetaxel (n = 389) compared with 25 patients (7%) who received placebo plus trastuzumab and docetaxel (n = 372) in a randomized, double-blind clinical trial in HER2-positive metastatic breast cancer patients. The assay used to evaluate pertuzumab-directed antibodies may have also detected trastuzumab antibodies. No patient who had detectable antibodies to pertuzumab experienced a treatment-related anaphylactic/hypersensitivity reaction. In a neoadjuvant breast cancer clinical trial, 1 patient of 383 who was treated with pertuzumab (0.3%) tested positive for anti-pertuzumab antibodies. This patient also did not experience any anaphylactic/hypersensitivity reactions.
The incidence of fatigue and asthenia associated with pertuzumab therapy varies among clinical trials and concomitant chemotherapy regimens. As adjuvant therapy for breast cancer, pertuzumab plus trastuzumab and chemotherapy (i.e., 5-fluorouracil/epirubicin/cyclophosphamide (FEC), 5-fluorouracil/doxorubicin/cyclophosphamide (FAC), doxorubicin/cyclophosphamide (AC), epirubicin/cyclophosphamide (EC), or docetaxel/carboplatin/trastuzumab (TCH)) (n = 2,364) was compared with placebo plus trastuzumab and chemotherapy (n = 2,405). In this trial, the incidence of fatigue (all grade, 49% vs. 44%; grade 3 or 4, 4% vs. 3%) and asthenia (all grade, 21% vs. 21%; grade 3 or 4, 1% vs. 2%) were similar between patients in the pertuzumab (n = 2,364) and placebo (n = 2,405) arms. In another randomized clinical trial of patients with metastatic breast cancer, fatigue occurred in 37% (grade 3 or 4, 2%) of patients treated with pertuzumab/trastuzumab/docetaxel (n = 407) compared with 37% (grade 3 or 4, 3%) of patients who received placebo/trastuzumab/docetaxel (n = 397); asthenia was reported in 26% versus 30% (grade 3 or 4, 2% vs. 2%), respectively. Generally mild (grade 1 or 2) fatigue (12%) and asthenia (3%) occurred patients treated with pertuzumab plus trastuzumab (n = 108) in one arm of a neoadjuvant breast cancer clinical trial. In three neoadjuvant clinical trials where treatment consisted of pertuzumab in combination with docetaxel, paclitaxel, FEC, or TCH (n = 943), fatigue was reported in 26% (grade 3 or 4, 0.9% to 1%) and asthenia in 16% to 21% (grade 3 or 4, 2%) of patients.
Dyspnea (all grade, 8% to 15%; grade 3 or 4, 0.4% to 3%), cough (all grade, 5% to 20%; grade 3 or 4, 0.5% or less), and epistaxis (all grade, 11% to 25%; grade 3 or 4, 1% or less) have been reported in clinical trials of patients treated with pertuzumab in combination with trastuzumab and various chemotherapy (n = 2,364). Pleural effusion was also reported in patients with metastatic breast cancer treated with pertuzumab, trastuzumab, and docetaxel (n = 407).
Insomnia was reported in 8% to 21% (grade 3 or 4, 0.3% or less) of patients treated with pertuzumab in combination with trastuzumab and chemotherapy across neoadjuvant, adjuvant, and metastatic breast cancer clinical trials (n = 3,498). The incidence was lower (4%) in one arm of a neoadjuvant clinical trial in which patients were treated with only pertuzumab plus trastuzumab, without chemotherapy (n = 108).
Elevated hepatic enzymes, and specifically grade 3 or 4 increases in ALT, occurred in greater than 2% of patients treated with neoadjuvant pertuzumab in combination with trastuzumab and chemotherapy in two neoadjuvant breast cancer clinical trials (n = 620). In one neoadjuvant clinical trial, increased ALT occurred in 11% (grade 3 or 4, 4%) of patients treated with pertuzumab plus trastuzumab/carboplatin/docetaxel (TCH) (n = 76), 7% of patients treated with pertuzumab/trastuzumab/5-fluorouracil, epirubicin, and cyclophosphamide (FEC) followed by pertuzumab/trastuzumab/docetaxel (n = 72), and 3% of patients who received FEC followed by pertuzumab/trastuzumab/docetaxel (n = 75).
Oligohydramnios resulting in teratogenesis (e.g., pulmonary hypoplasia and skeletal abnormalities) and neonatal death has been reported in another HER2/neu receptor antagonist. In animal reproduction studies, embryo-fetal death and fetal kidney development were reported following pertuzumab doses that resulted in 2.5- to 20-times the drug exposure in humans.
The incidence of peripheral neuropathy associated with pertuzumab therapy varies among clinical trials and concomitant chemotherapy regimens. As adjuvant therapy for breast cancer, pertuzumab plus trastuzumab and chemotherapy (i.e., 5-fluorouracil/epirubicin/cyclophosphamide (FEC), 5-fluorouracil/doxorubicin/cyclophosphamide (FAC), doxorubicin/cyclophosphamide (AC), epirubicin/cyclophosphamide (EC), or docetaxel/carboplatin/trastuzumab (TCH)) (n = 2,364) was compared with placebo plus trastuzumab and chemotherapy. In this trial, the addition of pertuzumab to trastuzumab and chemotherapy did not greatly increase the incidence of peripheral neuropathy (all grade, 33% vs. 32%; grade 3 or 4, 1% vs. 1%) or paresthesias (all grade, 12% vs. 10%; grade 3 or 4, 0.5% vs. 0.2%) compared with placebo. In another randomized clinical trial of patients with metastatic breast cancer, peripheral neuropathy occurred in 32% (grade 3 or 4, 3%) of patients treated with pertuzumab/trastuzumab/docetaxel (n = 407) compared with 34% (grade 3 or 4, 2%) of patients who received placebo/trastuzumab/docetaxel (n = 397). In one neoadjuvant breast cancer study, patients treated with trastuzumab/docetaxel (n = 107), pertuzumab/trastuzumab/docetaxel (n = 107), and pertuzumab/docetaxel (n = 108) experienced more peripheral neuropathy than patients who received pertuzumab/trastuzumab without chemotherapy (n = 108) (all grade, 12% vs. 8% vs. 11% vs. 2%; grade 3 or 4, 0.9% vs. 0.9% vs. 0% vs. 0%). In another neoadjuvant clinical trial, the incidence of grade 1 or 2 peripheral neuropathy ranged from 1% in patients receiving pertuzumab/trastuzumab/docetaxel following completion of 5-fluorouracil/epirubicin/cyclophosphamide (FEC) (n = 75), to 6% in patients who received pertuzumab/trastuzumab/FEC followed by pertuzumab/trastuzumab/docetaxel (n = 72), to 11% in those treated with pertuzumab/trastuzumab/carboplatin/docetaxel (n = 76). The incidence was higher in another neoadjuvant trial in patients who received pertuzumab/trastuzumab/docetaxel following FEC (n = 198) (all grade, 26%; grade 3 or 4, 0.5%); grade 1 or 2 paresthesias were additionally reported in 9% of patients treated with this regimen. In the same trial, 42% of patients treated with neoadjuvant pertuzumab/trastuzumab/docetaxel following completion of dose-dense AC (doxorubicin/cyclophosphamide) (n = 199) reported peripheral neuropathy (grade 3 or 4, 3%) and 15% reported grade 1 or 2 paresthesias.
Arthralgia was reported in 5% to 29% (grade 3 or 4, 1% or less) and myalgia in 9% to 33% (grade 3 or 4, 1% or less) of patients treated with pertuzumab in combination with trastuzumab and chemotherapy across neoadjuvant, adjuvant, and metastatic breast cancer clinical trials (n = 3,606). In patients receiving adjuvant therapy with pertuzumab, trastuzumab, and chemotherapy (n = 2,364), arthralgia occurred at a lower frequency in the pertuzumab arm after discontinuation of chemotherapy (all grade, 29% vs. 15%). Additionally, bone pain (all grade, 12% or less; grade 3 or 4, 0.5% or less), extremity pain (all grade, 10% or less; grade 3 or 4, 0.2% or less), and back pain (grade 1 or 2, 10% or less) have been reported in clinical trials.
As adjuvant therapy for breast cancer, pertuzumab plus trastuzumab and chemotherapy (i.e. 5-fluorouracil/epirubicin/cyclophosphamide (FEC), 5-fluorouracil/doxorubicin/cyclophosphamide (FAC), doxorubicin/cyclophosphamide (AC), epirubicin/cyclophosphamide (EC), or docetaxel/carboplatin/trastuzumab (TCH)) (n = 2,364) was compared with placebo plus trastuzumab and chemotherapy (n = 2,405). In this trial, the addition of pertuzumab to trastuzumab and chemotherapy resulted in a similar incidence of hot flashes compared with placebo plus trastuzumab and chemotherapy (all grade, 20% vs. 21%; grade 3 or 4, 0.2% vs. 0.4%). In this study, the incidence of hot flashes decreased to 12% after chemotherapy was discontinued, in the targeted treatment alone phase of the trial. The incidence of hot flashes was similar (grade 1 or 2, 13% to 19%) in a neoadjuvant breast cancer study of patients treated with pertuzumab in combination with trastuzumab and either paclitaxel or docetaxel (n= 397).
As adjuvant therapy for breast cancer, pertuzumab plus trastuzumab and chemotherapy (i.e. 5-fluorouracil/epirubicin/cyclophosphamide (FEC), 5-fluorouracil/doxorubicin/cyclophosphamide (FAC), doxorubicin/cyclophosphamide (AC), epirubicin/cyclophosphamide (EC), or docetaxel/carboplatin/trastuzumab (TCH)) (n = 2,364) was compared with placebo plus trastuzumab and chemotherapy (n = 2,405). In this trial, the addition of pertuzumab to trastuzumab and chemotherapy slightly increased the incidence of a radiation recall reaction compared with placebo (all grade, 13% vs. 11%; grade 3 or 4, 0.3% vs. 0.3%). The incidence of radiation skin injury in patients treated with pertuzumab decreased slightly in the targeted treatment alone phase (12%), after discontinuation of chemotherapy.
Cases of tumor lysis syndrome (TLS) have been reported in patients treated with pertuzumab. Patients with significant tumor burden (e.g., bulky metastases) may be at higher risk. Patients could present with hyperuricemia, hyperphosphatemia, and acute renal failure (unspecified); consider additional monitoring and/or treatment as clinically indicated.
Grade 3 or 4 hypokalemia was reported in greater than 2% of breast cancer patients treated with neoadjuvant pertuzumab in combination with trastuzumab and chemotherapy in one randomized clinical trial (n = 223).
Use pertuzumab with caution in patients with a history of cardiac disease or heart failure. Decreases in left ventricular ejection fraction (LVEF) and left ventricular dysfunction have been reported with drugs that block HER2 activity, including pertuzumab; pertuzumab has not been studied in patients with a pretreatment LVEF less than 50%, a prior history of congestive heart failure (CHF), patients who had LVEF decreases to less than or equal to 50% during prior trastuzumab therapy, or conditions that could impair left ventricular function such as uncontrolled hypertension, recent myocardial infarction, serious cardiac arrhythmias requiring treatment, or a cumulative prior anthracycline exposure to greater than 360 mg/m2 of doxorubicin (or equivalent). Patients treated with prior anthracyclines or who have received prior radiation therapy to the chest may be at an increased risk. Assess LVEF prior to starting treatment with pertuzumab and every 12 weeks during treatment (once during neoadjuvant therapy). For patients with early breast cancer, the LVEF should be 55% or higher prior to starting pertuzumab therapy, and 50% or higher in patients who received prior anthracycline therapy. For patients with metastatic breast cancer, the LVEF should be 50% or higher before starting treatment with pertuzumab. If the LVEF decreases during therapy, an interruption or discontinuation of therapy may be necessary. Discontinue pertuzumab treatment for a confirmed clinically significant decrease in left ventricular function.
Pertuzumab has been associated with infusion-related reactions, including fatal events, and carries a risk of serious hypersensitivity reactions/anaphylaxis. Pertuzumab is contraindicated in patients with known hypersensitivity to pertuzumab or any of its excipients. Monitor patients closely for infusion-related reactions (e.g., anaphylactoid reaction, acute infusion reaction, cytokine release syndrome) for 60 minutes after the first infusion and for 30 minutes after subsequent infusions of pertuzumab. If a significant infusion-associated reaction occurs, slow or interrupt the infusion and administer appropriate medical therapies. Monitor patients carefully until complete resolution of signs and symptoms of the infusion-related reaction. Consider permanent discontinuation in patients with severe infusion reactions. Patients should also be observed closely for hypersensitivity reactions. Severe hypersensitivity, including anaphylaxis, has been observed in clinical trials. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use.
Cases of tumor lysis syndrome (TLS) have been reported in patients treated with pertuzumab. Patients with significant tumor burden (e.g., bulky metastases) may be at higher risk. Patients could present with hyperuricemia, hyperphosphatemia, and acute renal failure (unspecified); consider additional monitoring and/or treatment as clinically indicated.
Based on its mechanism of action, fetal harm including intrauterine fetal death and birth defects may occur when pertuzumab is administered during pregnancy; monitoring for oligohydramnios is recommended if a patient is exposed during pregnancy or within 7 months of conception. If oligohydramnios occurs, fetal testing should be done that is appropriate for gestational age and is consistent with community standards of care. Pregnancy should be avoided by females during pertuzumab therapy and for 7 months after the last dose of pertuzumab in combination with trastuzumab; women who become pregnant during this time frame should be apprised of the potential hazard to the fetus. Healthcare professionals and patients should report any pregnancy during therapy or within 7 months of completion of therapy to the pregnancy pharmacovigilance program at Genentech (1-888-835-2555). Postmarketing, oligohydramnios and oligohydramnios sequence (manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death) occurred in pregnant women who received another HER2/neu receptor antagonist (trastuzumab) during pregnancy. In an animal study, oligohydramnios, delayed fetal kidney development, and embryo-fetal death occurred in pregnant cynomolgus monkeys who had a pertuzumab maximal exposure (Cmax) of 2.5 to 20 times greater than the recommended human dose.
Counsel patients about the reproductive risk and contraception requirements during pertuzumab treatment. Pertuzumab can be teratogenic if taken by the mother during pregnancy or within 7 months of conception. Females should avoid pregnancy and use effective contraception during pertuzumab treatment and for at least 7 months after treatment with pertuzumab in combination with trastuzumab. Verify the pregnancy status of a female patient prior to initiating pertuzumab therapy; females of reproductive potential should undergo pregnancy testing prior to initiation of pertuzumab. Women who become pregnant while receiving pertuzumab should be apprised of the potential hazard to the fetus and encouraged to enroll in the MotHER Pregnancy Registry (1-800-690-6720 or www.motherpregnancyregistry.com); additionally, healthcare providers and patients should report pertuzumab exposure to the pregnancy pharmacovigilance program at Genentech (1-888-835-2555).
It is not known whether pertuzumab is excreted into human milk. Published data suggest human IgG is present in human milk, but does not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in a nursing infant, advise women to discontinue breast-feeding during treatment with pertuzumab (in combination with trastuzumab) and for 7 months after the last dose.
For the treatment of HER2-positive breast cancer:
NOTE: Patients should be selected based on the presence of HER2 protein over expression or HER2 gene amplification in tumor specimens. Information on FDA-approved tests for the detection of HER2 protein over expression and HER2 gene amplification is available at www.fda.gov/CompanionDiagnostics.
-for the neoadjuvant treatment of HER2-positive, locally advanced, inflammatory, or early-stage breast cancer (greater than 2 cm diameter or node-positive) in combination with trastuzumab and chemotherapy:
Intravenous dosage:
Adults: 840 mg IV over 60 minutes on day 1, plus trastuzumab (8 mg/kg IV over 90 minutes on day 1). Three weeks later, give pertuzumab 420 mg IV over 30 to 60 minutes and trastuzumab (6 mg/kg IV over 30 to 90 minutes) every 3 weeks for a total of 3 to 6 cycles as part of one of the following treatment regimens: Four preoperative cycles of pertuzumab in combination with trastuzumab and docetaxel with 3 postoperative cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC); Three or four preopoerative cycles of FEC alone followed by 3 or 4 preoperative cycles of pertuzumab in combination with docetaxel and trastuzumab; Six preoperative cycles of pertuzumab in combination with docetaxel, carboplatin, and trastuzumab (TCH); Four preoperative cycles of dose-dense doxorubicin and cyclophosphamide (ddAC) alone followed by 4 preoperative doses of pertuzumab in combination with paclitaxel and trastuzumab. After surgery, give IV pertuzumab and trastuzumab every 3 weeks to complete 1 year of therapy (up to 18 cycles). Pertuzumab and trastuzumab can be given in any order; however, both agents should be given PRIOR to the taxane infusion in patients receiving a taxane-containing regimen. In patients receiving an anthracycline-containing regimen, pertuzumab and trastuzumab should be given following completion of the anthracycline. Observe closely for infusion-related reactions for 60 minutes after the first pertuzumab infusion and for 30 minutes after subsequent infusions; do not start other infusions until after this observation period. Do not administer pertuzumab without trastuzumab; withhold or discontinue pertuzumab therapy if trastuzumab is withheld or discontinued.
-for the neoadjuvant treatment of HER2-positive, locally advanced, inflammatory, or early-stage breast cancer (greater than 2 cm diameter or node-positive) in combination with trastuzumab; HYALURONIDASE and chemotherapy:
Intravenous dosage:
Adults: 840 mg IV over 60 minutes on day 1, plus trastuzumab; hyaluronidase (600 mg trastuzumab and 10,000 units hyaluronidase (5 mL) subcutaneously over approximately 2 to 5 minutes). Three weeks later, give pertuzumab 420 mg IV over 30 to 60 minutes and trastuzumab; hyaluronidase (600 mg trastuzumab and 10,000 units hyaluronidase (5 mL) subcutaneously over approximately 2 to 5 minutes) every 3 weeks for a total of 3 to 6 cycles as part of one of the following treatment regimens: Four preoperative cycles of pertuzumab in combination with trastuzumab; hyaluronidase and docetaxel with 3 postoperative cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC); Three or four preopoerative cycles of FEC alone followed by 3 or 4 preoperative cycles of pertuzumab in combination with docetaxel and trastuzumab; hyaluronidase; Six preoperative cycles of pertuzumab in combination with docetaxel, carboplatin, and trastuzumab; hyaluronidase (TCH); Four preoperative cycles of dose-dense doxorubicin and cyclophosphamide (ddAC) alone followed by 4 preoperative doses of pertuzumab in combination with paclitaxel and trastuzumab; hyaluronidase. After surgery, give IV pertuzumab and trastuzumab; hyaluronidase every 3 weeks to complete 1 year of therapy (up to 18 cycles). Pertuzumab and trastuzumab; hyaluronidase can be given in any order; however, both agents should be given PRIOR to the taxane infusion in patients receiving a taxane-containing regimen. In patients receiving an anthracycline-containing regimen, pertuzumab and trastuzumab; hyaluronidase should be given following completion of the anthracycline. Observe closely for infusion-related reactions for 60 minutes after the first pertuzumab infusion and for 30 minutes after subsequent infusions; do not start other infusions until after this observation period. Do not administer pertuzumab without trastuzumab; hyaluronidase; withhold or discontinue pertuzumab therapy if trastuzumab; hyaluronidase is withheld or discontinued.
-for the adjuvant treatment of early breast cancer in patients at high risk of recurrence, in combination with trastuzumab and standard anthracycline- and/or taxane-based chemotherapy:
Intravenous dosage:
Adults: 840 mg IV over 60 minutes on day 1, plus trastuzumab (8 mg/kg IV over 90 minutes on day 1). Three weeks later, give pertuzumab 420 mg IV over 30 to 60 minutes and trastuzumab (6 mg/kg IV over 30 to 90 minutes) every 3 weeks for a total of 1 year (up to 18 cycles) or until disease recurrence or unmanageable toxicity. Give with standard anthracycline- and/or taxane-based chemotherapy for early breast cancer. Pertuzumab and trastuzumab can be given in any order; however, both agents should be given before the taxane in taxane-containing regimens. Give pertuzumab and trastuzumab after the completion of the anthracycline dose in anthracycline-containing regimens. Observe closely for infusion-related reactions after the first pertuzumab infusion for 60 minutes and for 30 minutes after subsequent infusions; do not start other therapy until after this observation period. Do not administer pertuzumab without trastuzumab; withhold or discontinue pertuzumab therapy if trastuzumab is withheld or discontinued. Patients with HER2-positive early breast cancer were randomized to adjuvant treatment with either pertuzumab or placebo in combination with trastuzumab and standard chemotherapy (i.e., FEC or FAC followed by docetaxel or paclitaxel; AC followed by docetaxel or paclitaxel; or docetaxel in combination with carboplatin) in a multicenter, randomized, double-blind clinical trial (APHINITY; n = 4,804); after completion of chemotherapy, patients received radiotherapy and/or hormone therapy per investigator's discretion. After a median of 74 months of follow-up, the 6-year rate of invasive disease-free survival (IDFS) significantly improved in patients who received pertuzumab compared with placebo in the intent-to-treat population (91% vs. 88%). In patients with node-positive disease, the 6-year IDFS rate was also significantly improved (88% vs. 83%); 6-year IDFS was 95% versus 94.9%, respectively, in patients with node-negative disease. Overall survival at 6-years was 95% in the pertuzumab arm compared with 94% in the placebo arm.
-for the adjuvant treatment of early breast cancer in patients at high risk of recurrence, in combination with trastuzumab; HYALURONIDASE and standard anthracycline- and/or taxane-based chemotherapy:
Intravenous dosage:
Adults: 840 mg IV over 60 minutes on day 1, plus trastuzumab; hyaluronidase (600 mg trastuzumab and 10,000 units hyaluronidase (5 mL) subcutaneously over approximately 2 to 5 minutes). Three weeks later, give pertuzumab 420 mg IV over 30 to 60 minutes and trastuzumab; hyaluronidase (600 mg trastuzumab and 10,000 units hyaluronidase (5 mL) subcutaneously over approximately 2 to 5 minutes) every 3 weeks for a total of 1 year (up to 18 cycles) or until disease recurrence or unmanageable toxicity. Give with standard anthracycline- and/or taxane-based chemotherapy for early breast cancer. Pertuzumab and trastuzumab; hyaluronidase can be given in any order; however, both agents should be given before the taxane in taxane-containing regimens. Give pertuzumab and trastuzumab; hyaluronidase after the completion of the anthracycline dose in anthracycline-containing regimens. Observe closely for infusion-related reactions after the first pertuzumab infusion for 60 minutes and for 30 minutes after subsequent infusions; do not start other therapy until after this observation period. Do not administer pertuzumab without trastuzumab; hyaluronidase; withhold or discontinue pertuzumab therapy if trastuzumab; hyaluronidase is withheld or discontinued.
-for the treatment of HER2-positive metastatic breast cancer in patients who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease, in combination with trastuzumab and docetaxel:
Intravenous dosage:
Adults: 840 mg IV over 60 minutes, plus trastuzumab (8 mg/kg IV over 90 minutes) and docetaxel (75 mg/m2 IV) on day 1 of cycle 1. Beginning 3 weeks later with cycle 2, give pertuzumab 420 mg IV over 30 to 60 minutes IV, plus trastuzumab (6 mg/kg IV) and docetaxel (75 mg/m2 IV, or escalated to 100 mg/m2 IV if first dose was well tolerated) on day 1, every 3 weeks; in the clinical trial, docetaxel was continued for at least a total of 6 cycles and pertuzumab/trastuzumab were administered until disease progression or unacceptable toxicity. Pertuzumab and trastuzumab can be given in any order; however, both agents should be given PRIOR TO the docetaxel infusion. Observe closely for infusion-related reactions for 60 minutes after the first pertuzumab infusion and for 30 minutes after subsequent infusions; do not start other infusions until after this observation period. Do not administer pertuzumab without trastuzumab; withhold or discontinue pertuzumab therapy if trastuzumab is withheld or discontinued. In a multicenter, double-blind, placebo-controlled trial of patients with HER2-positive metastatic breast cancer (CLEOPATRA), treatment with pertuzumab, trastuzumab, and docetaxel significantly improved progression-free survival (18.5 months vs. 12.4 months) compared with trastuzumab and docetaxel alone. Overall survival was also significantly improved in the pertuzumab arm (56.5 months vs. 40.8 months).
-for the treatment of HER2-positive metastatic breast cancer in patients who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease, in combination with trastuzumab; HYALURONIDASE and docetaxel:
Intravenous dosage:
Adults: 840 mg IV over 60 minutes, plus trastuzumab; hyaluronidase (600 mg trastuzumab and 10,000 units hyaluronidase (5 mL) subcutaneously over approximately 2 to 5 minutes) and docetaxel (75 mg/m2 IV) on day 1 of cycle 1. Beginning 3 weeks later with cycle 2, give pertuzumab 420 mg IV over 30 to 60 minutes IV, plus trastuzumab; hyaluronidase (600 mg trastuzumab and 10,000 units hyaluronidase (5 mL) subcutaneously over approximately 2 to 5 minutes) and docetaxel (75 mg/m2 IV, or escalated to 100 mg/m2 IV if first dose was well tolerated) on day 1, every 3 weeks; in the clinical trial, docetaxel was continued for at least a total of 6 cycles and pertuzumab/trastuzumab were administered until disease progression or unacceptable toxicity. Pertuzumab and trastuzumab; hyaluronidase can be given in any order; however, both agents should be given PRIOR TO the docetaxel infusion. Observe closely for infusion-related reactions for 60 minutes after the first pertuzumab infusion and for 30 minutes after subsequent infusions; do not start other infusions until after this observation period. Do not administer pertuzumab without trastuzumab; hyaluronidase; withhold or discontinue pertuzumab therapy if trastuzumab; hyaluronidase is withheld or discontinued. In a multicenter, double-blind, placebo-controlled trial of patients with HER2-positive metastatic breast cancer (CLEOPATRA), treatment with pertuzumab, trastuzumab, and docetaxel significantly improved progression-free survival (18.5 months vs. 12.4 months) compared with trastuzumab and docetaxel alone. Overall survival was also significantly improved in the pertuzumab arm (56.5 months vs. 40.8 months).
Therapeutic Drug Monitoring:
Decreased Left Ventricular Ejection Fraction (LVEF)
-Early breast cancer, LVEF less than 50% with a decreaseof 10% or more from pretreatment value: Hold pertuzumab and trastuzumab therapy for at least 3 weeks. Treatment may be resumed after 3 weeks if the LVEF is greater than or equal to 50% or if the LVEF is less than 10% below the pretreatment value. Dose reductions are not recommended for pertuzumab. Pertuzumab should be discontinued if trastuzumab treatment is discontinued. Discontinue pertuzumab treatment for a confirmed clinically significant decrease in left ventricular function.
-Metastatic breast cancer, LVEF less than 40%, or LVEF between 40% to 45% with a 10% or greater decrease from pretreatment value: Hold pertuzumab and trastuzumab therapy for at least 3 weeks. Treatment may be resumed after 3 weeks if the LVEF is greater than 45% or if the LVEF is 40% to 45% and less than a 10% below the pretreatment value. Dose reductions are not recommended for pertuzumab. Pertuzumab should be discontinued if trastuzumab treatment is discontinued. Discontinue pertuzumab treatment for a confirmed clinically significant decrease in left ventricular function.
Maximum Dosage Limits:
-Adults
840 mg IV initially, then 420 mg IV every 3 weeks.
-Geriatric
840 mg IV initially, then 420 mg IV every 3 weeks.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available.
Patients with Renal Impairment Dosing
-CrCL 30 mL/min or higher: No dosage adjustment needed.
-CrCL less than 30 mL/min: Limited pharmacokinetic data; recommendations for dosage adjustment are not available.
*non-FDA-approved indication
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
Pertuzumab is a humanized recombinant IgG1 monoclonal antibody that binds to the extracellular dimerization domain (Subdomain II) of the human epidermal growth factor receptor-2 (HER2) protein. It blocks ligand-dependent heterodimerization of HER2 and other epidermal growth factor receptors including HER3 and HER4. Two intracellular signaling pathways, mitogen-activated protein (MAP) kinase and phosphoinositide 3-kinase (PI3K), are inhibited resulting in cell growth arrest and apoptosis. Pertuzumab also demonstrates antibody-dependent cell-mediated cytotoxicity. Pertuzumab differs from trastuzumab in where it binds to HER2; pertuzumab binds to the dimerization domain and trastuzumab binds in the juxtamembrane region. Combining pertuzumab with trastuzumab has demonstrated enhanced antitumor activity in HER2-amplified breast cancer in xenograft models. Additionally, combination therapy may reduce trastuzumab resistance.
Pertuzumab is administered as an intravenous infusion. At doses of 2 to 25 mg/kg, pertuzumab has linear pharmocokinetics.The median pertuzumab clearance was 0.24 L/day and the median half-life was 18 days in a pharmacokinetic analysis of 481 patients.
-Route-Specific Pharmacokinetics
Intravenous Route
In a pharmacokinetic analysis of 481 patients who received pertuzumab 840 mg IV followed 3 weeks later by pertuzumab maintenance with 420 mg IV every 3 weeks, the steady-state concentration was reached following the first maintenance dose.
-Special Populations
Hepatic Impairment
The effect of hepatic impairment on the pharmacokinetics of pertuzumab has not been evaluated.
Renal Impairment
The effect of renal impairment on the pharmacokinetics of pertuzumab has not been evaluated in clinical trials. However, pertuzumab exposure was similar in patients with mild (CrCL 60 to 90 mL/min; n = 200) or moderate (CrCL 30 to 60 mL/min; n = 71) renal impairment compared with patients with normal renal function (CrCL greater than 90 mL/min; n = 200) in a population pharmacokinetic analysis. There was no correlation between pertuzumab exposure and CrCL in the observed CrCL range of 27 to 244 mL/min.
Geriatric
Age did not affect the pharmacokinetic parameters of pertuzumab in a population pharmacokinetic analysis.
Gender Differences
Gender did not affect the pharmacokinetic parameters of pertuzumab in a population pharmacokinetic analysis.
Ethnic Differences
Ethnicity (e.g., Japanese vs. non-Japanese) did not affect the pharmacokinetic parameters of pertuzumab in a population pharmacokinetic analysis.
Obesity
Lean body weight and baseline serum albumin level had a minor impact on the pharmacokinetic parameters of pertuzumab in a population pharmacokinetic analysis; therefore, no pertuzumab dosage adjustments based on weight or baseline albumin level are needed.
Other
Disease status (i.e., neoadjuvant or adjuvant vs. metastatic setting) did not affect the pharmacokinetics of pertuzumab in a pharmacokinetic analysis.