Phesgo

Pertuzumab, trastuzumab.

Phesgo is a clear to opalescent solution, colourless to slightly brownish solution supplied in sterile, preservative-free, non-pyrogenic single-dose vials.
Single dose vials contain: 1200 mg pertuzumab/600 mg trastuzumab/15 mL solution in a vial.
600 mg pertuzumab/600 mg trastuzumab/10 mL solution in a vial.
Excipients/Inactive Ingredients: Phesgo contains vorhyaluronidase alfa (recombinant human hyaluronidase; rHuPH20), an enzyme used to increase the dispersion and absorption of co-formulated drugs when administered subcutaneously.
All other excipients described as registered locally.

Pharmacology: Pharmacodynamics: Mechanism of action: Pertuzumab and trastuzumab are recombinant humanized immunoglobulin (Ig)G1κ monoclonal antibodies, which target the human epidermal growth factor receptor 2 (HER2, also known as c-erbB-2), a transmembrane glycoprotein with intrinsic tyrosine kinase activity. Pertuzumab and trastuzumab bind to distinct HER2 epitopes, subdomains II and IV, respectively, without competing and have complementary mechanisms for disrupting HER2 signaling. This results in augmented anti-proliferative activity in vitro and in vivo when pertuzumab and trastuzumab are given in combination.
Additionally, the Fc portion of both their IgG1 framework provides for potent activation of antibody-dependent cell-mediated cytotoxicity (ADCC). In vitro, both pertuzumab and trastuzumab ADCC are exerted preferentially on HER2-overexpressing cancer cells compared with cancer cells that do not overexpress HER2.
Clinical/efficacy studies: This section presents the clinical experience from Phesgo and intravenous pertuzumab in combination with trastuzumab patients with HER2-positive early and metastatic breast cancer. HER2 overexpression in all trials outlined as follows was determined at a central laboratory and defined as a score of 3+ by IHC or an ISH amplification ratio ≥2.0.
Early Breast Cancer: Fixed-dose combination of pertuzumab and trastuzumab Phesgo: FEDERICA WO40324: FEDERICA is an open-label, multicenter, randomized study conducted in 500 patients with HER2-positive early breast cancer that is operable or locally advanced (including inflammatory) breast cancer with a tumor size >2 cm or node-positive in the neoadjuvant and adjuvant setting. Patients were randomized to receive 8 cycles of neoadjuvant chemotherapy with concurrent administration of 4 cycles of either Phesgo or intravenous pertuzumab and trastuzumab during cycles 5-8. Investigators selected one of two of the following neoadjuvant chemotherapy regimens for individual patients: 4 cycles of doxorubicin (60 mg/m²) and cyclophosphamide (600 mg/m²) every 2 weeks followed by paclitaxel (80 mg/m²) weekly for 12 weeks; 4 cycles of doxorubicin (60 mg/m²) and cyclophosphamide (600 mg/m²) every 3 weeks followed by 4 cycles of docetaxel (75 mg/m² for the first cycle and then 100 mg/m² at subsequent cycles at the investigator's discretion) every 3 weeks.
Following surgery, patients continued therapy with Phesgo or intravenous pertuzumab and trastuzumab as treated prior to surgery, for an additional 14 cycles, to complete 18 cycles of HER2-targeted therapy. Patients also received adjuvant radiotherapy and endocrine therapy as per local practice. In the adjuvant setting, substitution of intravenous trastuzumab for subcutaneous trastuzumab SC was permitted at investigator discretion. HER2-targeted therapy was administered every 3 weeks according to Table 1 as follows: See Table 1.

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FEDERICA was designed to demonstrate non-inferiority of the pertuzumab Cycle 7 (i.e., pre-dose Cycle 8) serum C_trough of pertuzumab within Phesgo compared with intravenous pertuzumab (primary endpoint). Additional secondary endpoints included non-inferiority of the Cycle 7 serum trastuzumab C_trough of trastuzumab within Phesgo compared with intravenous trastuzumab, efficacy [total pathological complete response (tpCR)], and safety outcomes. Demographics were well balanced between the two treatment arms and the median age of patients treated in the study was 51 years. The majority of patients had hormone receptor-positive disease (61.2%), node-positive disease (57.6%), and were Caucasian (65.8%).
Non-inferiority of the pertuzumab and trastuzumab exposure from Phesgo was demonstrated (see Pharmacokinetics as follows). The analysis of secondary efficacy endpoint, tpCR, defined as an absence of invasive disease in the breast and axilla (ypT0/is, ypN0), is shown in Table 2. (See Table 2.)

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Intraveneous Pertuzumab and Trastuzumab: Neoadjuvant Treatment: NEOSPHERE (WO20697): NEOSPHERE is a multicenter, randomized Phase II clinical trial conducted in 417 patients with operable, locally advanced, or inflammatory HER2-positive breast cancer (T2-4d) who were scheduled for neoadjuvant therapy. Patients were randomized to receive one of four neoadjuvant regimens prior to surgery as follows: trastuzumab plus docetaxel, pertuzumab plus trastuzumab and docetaxel, pertuzumab plus trastuzumab, or pertuzumab plus docetaxel. Randomization was stratified by breast cancer type (operable, locally advanced, or inflammatory) and estrogen (ER) or progesterone (PgR) positivity.
Pertuzumab and trastuzumab were administered intravenously as outlined in Table 1 for 4 cycles. Following surgery all patients received three cycles of 5-Fluorouracil (600 mg/m²), epirubicin (90 mg/m²), cyclophosphamide (600 mg/m²) (FEC) given intravenously every three weeks and trastuzumab administered intravenously every three weeks to complete one year of therapy. Patients in the pertuzumab plus trastuzumab and docetaxel arm received docetaxel every three weeks for four cycles prior to FEC after surgery so that all patients received equivalent cumulative doses of the chemotherapeutic agents and trastuzumab.
The primary endpoint of the study was pathological complete response (pCR) rate in the breast (ypT0/is). Secondary efficacy endpoints were clinical response rate, breast conserving surgery rate (T2-3 only), disease-free survival (DFS), and PFS. Additional exploratory pCR rates included nodal status (ypT0/isN0 and ypT0N0).
Demographics were well balanced [median age was 49-50 years old, the majority were Caucasian (71%)] and all were female. Overall 7% of patients had inflammatory breast cancer, 32% had locally advanced breast cancer and 61% had operable breast cancer. Approximately half the patients in each treatment group had hormone receptor-positive disease (defined as ER positive and/or PgR positive).
The efficacy results are summarized in Table 3. A statistically significant and clinically meaningful improvement in pCR rate (ypT0/is) was observed in patients receiving pertuzumab plus trastuzumab and docetaxel compared to patients receiving trastuzumab and docetaxel (45.8% vs 29.0%, p value = 0.0141). A consistent pattern of results was observed regardless of pCR definition.
Pathological complete response (pCR) rates as well as the magnitude of improvement with pertuzumab were lower in the subgroup of patients with hormone receptor-positive tumors than in patients with hormone receptor-negative tumors (5.9% to 26.0% and 27.3% to 63.2%, respectively).
TRYPHAENA (BO22280): TRYPHAENA is a multicenter, randomized Phase II clinical study conducted in 225 patients with HER2-positive locally advanced, operable, or inflammatory (T2-4d) breast cancer. Patients were randomized to receive one of three neoadjuvant regimens prior to surgery as follows: 3 cycles of FEC followed by 3 cycles of docetaxel all in combination with pertuzumab and trastuzumab, 3 cycles of FEC alone followed by 3 cycles of docetaxel and trastuzumab in combination with pertuzumab, or 6 cycles of TCH in combination with pertuzumab. Randomization was stratified by breast cancer type (operable, locally advanced, or inflammatory) and ER and/or PgR positivity.
Pertuzumab and trastuzumab were administered intravenously as outlined in Table 1. 5-Fluorouracil (500 mg/m²), epirubicin (100 mg/m²), cyclophosphamide (600 mg/m²) were given intravenously every three weeks for 3 cycles. Docetaxel was given as an initial dose of 75 mg/m² IV infusion every three weeks with the option to escalate to 100 mg/m² at the investigator's discretion if the initial dose was well tolerated. However, in the pertuzumab in combination with TCH arm, docetaxel was given intravenously at 75 mg/m² and no escalation was permitted and carboplatin (AUC 6) was given intravenously every three weeks. Following surgery all patients received trastuzumab to complete one year of therapy, which was administered intravenously every 3 weeks.
The primary endpoint of this study was cardiac safety during the neoadjuvant treatment period of the study (see Adverse Reactions). Secondary efficacy endpoints were pCR rate in the breast (ypT0/is), DFS, PFS and OS.
Demographics were well balanced (median age was 49-50 years old, the majority were Caucasian (77%) and all were female. Overall 6% of patients had inflammatory breast cancer, 25% had locally advanced breast cancer and 69% had operable breast cancer, with approximately half the patients in each treatment group had ER-positive and/or PgR-positive disease.
High pCR rates were observed in all 3 treatment arms (see Table 3). A consistent pattern of results was observed regardless of pCR definition. pCR rates were lower in the subgroup of patients with hormone receptor-positive tumors than in patients with hormone receptor-negative tumors (46.2% to 50.0% and 65.0% to 83.8% respectively). (See Table 3.)

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BERENICE (WO29217): BERENICE is a non-randomized, open-label, multicenter, multinational, Phase II trial conducted in 401 patients with HER2-positive locally advanced, inflammatory, or early-stage HER2-positive breast cancer.
The BERENICE study included two parallel groups of patients. Patients considered suitable for neoadjuvant treatment with trastuzumab plus anthracycline/taxane-based chemotherapy were allocated to receive one of the two following regimens prior to surgery as follows: Cohort A - 4 cycles of two-weekly doxorubicin and cyclophosphamide (dose dense AC) followed by 4 cycles of pertuzumab in combination with trastuzumab and paclitaxel.
Cohort B - 4 cycles of FEC followed by 4 cycles of pertuzumab in combination with trastuzumab and docetaxel.
Pertuzumab and trastuzumab were administered intravenously as outlined in Table 1. Doxorubicin 60 mg/m² IV and cyclophosphamide 600 mg/m² IV were administered every 2 weeks (ddAC) for four cycles (Cycles 1-4) with G-CSF (granulocyte colony stimulating factor) support at investigator discretion, followed by paclitaxel 80 mg/m² IV weekly for 12 weeks (Cycles 5-8), with pertuzumab and trastuzumab every 3 weeks during Cycles 5-8 (from the start of paclitaxel; four cycles of pertuzumab and trastuzumab in total during the neoadjuvant period). 5-Fluorouracil (500 mg/m²), epirubicin (100 mg/m²), cyclophosphamide (600 mg/m²) were given intravenously every three weeks for 4 cycles. Docetaxel was given at an initial dose of 75 mg/m² IV infusion every three weeks with the option to escalate to 100 mg/m² at the investigator's discretion if the initial dose was well tolerated. Following surgery all patients received pertuzumab and trastuzumab which were administered intravenously every 3 weeks, to complete one year of therapy.
The primary endpoint of this study was cardiac safety during the neoadjuvant treatment period of the study (see Precautions). Key secondary endpoints at the time of primary analysis were neoadjuvant safety and pCR rate in the breast and nodes (i.e. ypT0/is ypN0). Long-term clinical and safety outcomes will also be assessed (IDFS, EFS and OS, not yet available).
Demographics of the patients were well balanced between the groups. The median age of the patients was 49 years, the majority of patients were Caucasian (83%) and all but one patient was female. Approximately two-thirds of patients (64.3% [n = 128] in Cohort A and 61.7% [n = 124] in Cohort B) had hormone receptor-positive disease.
High pCR rates were observed in both treatment arms, with pCR (ypT0/is ypN0) rates of 61.8% in Cohort A and 60.7% in Cohort B. A consistent pattern of results was observed regardless of pCR definition. pCR rates were lower in the subgroup of patients with hormone receptor-positive tumors than in patients with hormone receptor-negative tumors in both Cohorts (51.6% to 81.5% and 57.3% to 68.0% respectively).
Adjuvant Treatment: APHINITY (BO25126): APHINITY is a multicenter, randomized, double-blind, placebo-controlled Phase III trial conducted in 4804 patients with HER2-positive early breast cancer who had their primary tumor excised prior to randomization. Patients were then randomized to receive pertuzumab or placebo, in combination with adjuvant trastuzumab and chemotherapy. Investigators selected one of the following anthracycline-based or non-anthracycline-based chemotherapy regimens for individual patients: 3 or 4 cycles of FEC or 5-fluorouracil, doxorubicin and cyclophosphamide (FAC), followed by 3 or 4 cycles of docetaxel or 12 cycles of weekly paclitaxel; 4 cycles of AC or EC, followed by 3 or 4 cycles of docetaxel or 12 cycles of weekly paclitaxel; 6 cycles of docetaxel in combination with carboplatin.
Pertuzumab and trastuzumab were administered intravenously as outlined in Table 1 starting on Day 1 of the first taxane-containing cycle, for a total of 52 weeks (maximum 18 cycles) or until recurrence, withdrawal of consent or unmanageable toxicity. Standard doses of 5-fluorouracil, epirubicin, doxorubicin, cyclophosphamide, docetaxel, paclitaxel and carboplatin were administered. After completion of chemotherapy, patients received radiotherapy and/or hormone therapy as per local clinical standard.
The primary endpoint of the study was invasive disease-free survival (IDFS), defined as the time from randomization to first occurrence of ipsilateral local or regional invasive breast cancer recurrence, distant recurrence, contralateral invasive breast cancer, or death from any cause.
Demographics were well balanced between the two treatment arms. The median age was 51 years, and over 99% of patients were female. The majority of patients had node-positive (63%) and/or hormone receptor-positive disease (64%), and were Caucasian (71%).
After a median follow-up to 45.4 months, the APHINITY study demonstrated 19% (hazard ratio [HR] = 0.81) reduction in risk of recurrence or death in patients randomized to receive pertuzumab compared with patients randomized to receive placebo.
The efficacy results from the APHINITY trial are summarized in Table 4 and in Figures 1 and 2. (See Table 4 and Figure 1.)

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The estimate of IDFS at 4-years was 92.3% in the pertuzumab-treated group versus 90.6% in the placebo-treated group. At the time of the estimate the median follow-up was 45.4 months.
Results of Subgroup Analysis: Consistent results were observed across the majority of pre-specified patient subgroups. The benefits of pertuzumab were more apparent for patients in certain high risk groups, notably patients with node-positive or hormone receptor-negative disease (see Figure 2 as follows).

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Estimates of IDFS rates in the node positive subgroup were 92.0% versus 90.2% at 3 years and 89.9% vs. 86.7% at 4 years in pertuzumab-treated patients versus the placebo-treated patients, respectively. In the node negative subgroup estimates of IDFS rates were 97.5% versus 98.4% at 3 years and 96.2% versus 96.7% at 4 years in pertuzumab-treated patients versus placebo-treated patients, respectively.
In the hormone receptor-positive subgroup estimates of IDFS were 94.8% versus 94.4% at 3 years and 93.0% versus 91.6% at 4 years in pertuzumab-treated patients versus placebo-treated patients, respectively. In the hormone receptor-negative subgroup estimates of IDFS rates were 92.8% versus 91.2% at 3 years and 91.0% versus 88.7% at 4 years in pertuzumab-treated patients versus placebo-treated patients, respectively.
Patient Reported Outcomes (PRO): Secondary endpoints included the assessment of patient-reported global health status, role and physical function, and treatment symptoms using the EORTC QLQ-C30 and EORTC QLQ-BR23 questionnaires. In the analyses of patient-reported outcomes, a 10-point difference was considered clinically meaningful.
Patients' physical function, global health status and diarrhea scores showed a clinically meaningful change during chemotherapy in both treatment arms. The mean decrease from baseline at that time for physical function was -10.7 (95% CI-11.4, -10.0) in the pertuzumab-arm and -10.6 (95% -11.4, -9.9) in the placebo arm; global health status was -11.2 (95% CI -12.2, -10.2) in the pertuzumab-arm and -10.2 (95% CI -11.1, -9.2) in the placebo arm. Change in diarrhea symptoms increased to +22.3 (95% CI 21.0, 23.6) in the pertuzumab-arm versus +9.2 (95% CI 8.2, 10.2) in the placebo arm.
Thereafter in both arms, physical function and global health status scores returned to baseline levels during targeted treatment. Diarrhea symptoms returned to baseline after HER2 therapy in the pertuzumab-arm. The addition of pertuzumab to trastuzumab plus chemotherapy did not affect patients' overall role function over the course of the study.
Metastatic Breast Cancer: CLEOPATRA (WO20698): CLEOPATRA is a multicenter, randomized, double-blind, placebo-controlled Phase III clinical trial conducted in 808 patients with HER2-positive metastatic or locally recurrent unresectable breast cancer who have not received previous anti-HER2 therapy or chemotherapy for their metastatic disease. Patients were randomized 1:1 to receive placebo plus trastuzumab and docetaxel (placebo-treated) or pertuzumab plus trastuzumab and docetaxel (pertuzumab-treated). Randomization was stratified by prior treatment status (de novo or prior adjuvant / neoadjuvant therapy) and geographic region (Europe, North America, South America and Asia). Patients with prior adjuvant or neoadjuvant therapy were required to have a disease free interval of at least 12 months before enrolment into the trial.
Pertuzumab and trastuzumab were administered intravenously as outlined in Table 1. Patients were treated with pertuzumab and trastuzumab until disease progression, withdrawal of consent or unmanageable toxicity. Docetaxel was given as an initial dose of 75 mg/m² IV infusion every 3 weeks for at least 6 cycles. The dose of docetaxel could be escalated to 100 mg/m² at the investigator's discretion if the initial dose was well tolerated. At the time of the primary analysis, the mean number of cycles of study treatment received was 16.2 in the placebo treatment group and 19.9 in the pertuzumab-treated group.
The primary endpoint of the study was progression-free survival (PFS) as assessed by an independent review facility (IRF) and defined as the time from the date of randomization to the date of disease progression or death (from any cause) if the death occurred within 18 weeks of the last tumor assessment. Secondary efficacy endpoints were overall survival (OS), PFS (investigator-assessed), objective response rate (ORR), duration of response, and time to symptom progression according to the FACT B QoL questionnaire.
Demographics were well balanced (median age was 54 years old, the majority were Caucasian (59%) and all were female with the exception of 2 patients). Approximately half the patients in each treatment group had hormone receptor-positive disease (defined as estrogen receptor [ER] positive and/or progesterone receptor [PgR] positive) and approximately half of the patients in each treatment group had received prior adjuvant or neo-adjuvant therapy (192 patients [47.3%] in the placebo-treated group vs 184 patients [45.8%] pertuzumab-treated group). At the time of the primary progression-free survival analysis, a total of 242 patients (59%) in the placebo-treated group and 191 patients (47.5%) in the pertuzumab-treated group had IRF-confirmed progressive disease or had died within 18 weeks of their last tumor assessment.
At the time of the primary analysis the CLEOPATRA study demonstrated a statistically significant improvement in IRF-assessed PFS (hazard ratio [HR] = 0.62, 95% CI = 0.51, 0.75, p<0.0001) in the pertuzumab-treated group compared with the placebo-treated group, and an increase in median PFS of 6.1 months (median PFS of 12.4 months in the placebo-treated group vs 18.5 months in the pertuzumab-treated group) (see Figure 3). The results for investigator-assessed PFS were comparable to those observed for IRF-assessed PFS (median PFS was 12.4 months for placebo vs 18.5 months for pertuzumab) (see Table 5). Consistent results were observed across pre-specified patient subgroups including the subgroups based on stratification factors of geographic region and prior adjuvant /neoadjuvant therapy or de novo metastatic breast cancer (see Figure 4).
The efficacy results from the CLEOPATRA trial are summarized in Table 5 as follows. (See Table 5 and Figures 3 and 4.)

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At the primary analysis of efficacy, an interim analysis of OS showed a strong trend suggestive of a survival benefit in favor of the Perjeta-treated group.
An interim analysis of OS performed one year after the primary analysis of efficacy, demonstrated a statistically significant OS benefit in favor of the pertuzumab-treated group (HR 0.66, p = 0.0008 log-rank test). The median time to death was 37.6 months in the placebo-treated group but had not yet been reached in the pertuzumab-treated group.
The final analysis of OS was performed when 389 patients had died (221 in the placebo-treated group and 168 in the pertuzumab-treated group). The statistically significant OS benefit in favor of the pertuzumab-treated group was maintained (HR 0.68, p = 0.0002 log-rank test). The median time to death was 40.8 months in the placebo-treated group and 56.5 months in the pertuzumab-treated group (see Table 5, Figure 5). (See Figure 5.)

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There was no statistically significant difference between treatment groups in Health Related Quality of Life as assessed by time to symptom progression on the FACTB TOI-PFB subscale, defined as a 5 point reduction in subscale score (HR =0.97, 95% CI =0.81; 1.16). In an exploratory analysis, patients treated with pertuzumab in combination with trastuzumab and docetaxel experienced a lower risk of symptom progression on the FACT-B breast cancer subscale (defined as a 2 point reduction in subscale score) compared to those treated with trastuzumab and docetaxel alone (HR =0.78, 95% CI =0.65; 0.94).
Immunogenicity: As with all therapeutic proteins, there is the potential for immune response in patients treated with Phesgo. Immunogenicity assay results are highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of incidence of treatment-emergent antibodies to Phesgo with the incidence of antibodies to other products may be misleading.
In the FEDERICA study, the incidence of treatment-emergent anti-pertuzumab and anti-trastuzumab antibodies was 3% (7/237) and 0.4% (1/237), respectively, in patients treated with intravenous pertuzumab and trastuzumab.
The incidence of treatment-emergent anti-pertuzumab, anti-trastuzumab, and anti- vorhyaluronidase alfa antibodies was 4.8% (11/231), 0.9% (2/232), and 0.9% (2/225), respectively, in patients treated with Phesgo. The clinical relevance of the development of anti-pertuzumab, anti-trastuzumab or anti-vorhyaluronidase alfa antibodies after treatment with Phesgo is unknown.
Pharmacokinetics: Pertuzumab and trastuzumab exposure following subcutaneous administration of Phesgo (1200 mg pertuzumab/600 mg trastuzumab loading dose followed by 600 mg pertuzumab/600 mg trastuzumab every 3 weeks) in the FEDERICA study is shown in Table 1. The pharmacokinetic (PK) results for the primary endpoint of pertuzumab Cycle 7 C_trough (i.e., pre-dose cycle 8), showed non-inferiority of pertuzumab within Phesgo (geometric mean 88.7 mcg/mL) compared to intravenous pertuzumab (geometric mean 72.4 mcg/mL) with a geometric mean ratio of 1.22 (90% CI: 1.14–1.31). The lower boundary of the two-sided 90% confidence interval for the geometric mean ratio of pertuzumab within Phesgo and intravenous pertuzumab was 1.14, i.e., greater than the predefined margin of 0.8.
The PK results for the secondary endpoint, trastuzumab Cycle 7 C_trough (i.e., predose Cycle 8), showed non-inferiority of trastuzumab within Phesgo (geometric mean 58.7 mcg/mL) compared to intravenous trastuzumab (geometric mean 44.1 mcg/mL) with a geometric mean ratio of 1.33 (90% CI: 1.24-1.43).
A population PK model of pertuzumab with linear elimination from the central compartment was constructed using pooled pertuzumab within Phesgo and intravenous pertuzumab PK data from FEDERICA to describe the observed pertuzumab PK concentrations following subcutaneous Phesgo administration and intravenous pertuzumab administration.
A population PK model with parallel linear and nonlinear elimination from the central compartment was constructed using pooled trastuzumab PK data from the phase III study BO22227 (Hannah) of subcutaneous trastuzumab vs. intravenous trastuzumab, to describe the observed PK concentrations following intravenous trastuzumab or subcutaneous trastuzumab administration in HER2 positive EBC patients. The PK analysis using the HANNAH population PK model demonstrated that there was no impact on the PK of trastuzumab within Phesgo from pertuzumab within Phesgo as consistent PK were observed between trastuzumab within Phesgo and subcutaneous trastuzumab.
The population PK predicted pertuzumab and trastuzumab exposures are summarized in Table 6 as follows. (See Table 6.)

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Absorption: The median maximum serum concentration (C_max) of pertuzumab within Phesgo and time to maximal concentration (T_max) were 157 ug/mL and 3.82 days, respectively. Based on population PK analysis, the absolute bioavailability was 0.712 and the first-order absorption rate (K_a) is 0.348 (1/day).
The median maximum serum concentration (C_max) of trastuzumab within Phesgo and time to maximal concentration (T_max) were 117 ug/mL and 3.85 days, respectively. Based on population PK analysis, the absolute bioavailability was 0.771 and the first-order absorption rate (K_a) is 0.404 (1/day).
Distribution: Based on population PK analysis, the volume of distribution of the central (Vc) compartment of pertuzumab within Phesgo in the typical patient, was 2.77 L.
Based on population PK analysis, the volume of distribution of the central (Vc) compartment of subcutaneous trastuzumab in the typical patient, was 2.91 L.
Metabolism: The metabolism of Phesgo has not been directly studied. Antibodies are cleared principally by catabolism.
Elimination: Based on population pharmacokinetic (PK) analysis, the clearance of pertuzumab within Phesgo was 0.163 L/day and the elimination half-life (t_½) was approximately 24.3 days.
Based on population pharmacokinetic (PK) analysis, the linear clearance of subcutaneous trastuzumab was 0.111 L/day. Trastuzumab is estimated to reach concentrations that are <1 μg/mL (approximately 3% of the population predicted C_min,ss, or about 97% washout) in at least 95% patients 7 months after the last dose.
Pharmacokinetics in Special Populations: Pediatric Population: No studies have been conducted to investigate the pharmacokinetics of Phesgo in the pediatric population.
Geriatric Population: No studies have been conducted to investigate the pharmacokinetics of Phesgo in geriatric patients.
In population PK analyses of pertuzumab within Phesgo and intravenous pertuzumab, age was not found to significantly affect PK of pertuzumab.
In population PK analyses of subcutaneous or intravenous trastuzumab, age has been shown to have no effect on the disposition of trastuzumab.
Renal impairment: No formal PK study of Phesgo has been conducted in patients with renal impairment.
Based on population PK analyses of pertuzumab within Phesgo and intravenous pertuzumab, renal impairment was shown not to affect pertuzumab exposure; however, only limited data from patients with severe renal impairment were included in population PK analyses.
In a population pharmacokinetic analysis of subcutaneous and intravenous trastuzumab, renal impairment was shown not to affect trastuzumab disposition.
Hepatic impairment: No formal pharmacokinetic study of Phesgo has been conducted in patients with hepatic impairment.
Toxicology: Preclinical Safety Data: No dedicated studies were conducted with the combination of subcutaneous pertuzumab, trastuzumab, and vorhyaluronidase alfa.
Subcutaneous and Intravenous Pertuzumab and Trastuzumab: Subcutaneous pertuzumab (250 mg/kg/week for 4 weeks) and intravenous pertuzumab (up to 150 mg/kg weekly for up to 26 weeks) was well tolerated in cynomolgus monkeys (binding species), except for the development of diarrhea. With intravenous pertuzumab doses of 15 mg/kg and higher, intermittent mild treatment-associated diarrhea was noted. In a subset of monkeys, chronic dosing (26 weekly doses) resulted in episodes of diarrhea-related dehydration which were managed with intravenous fluid replacement therapy. Trastuzumab was well tolerated in mice (non-binding species), rabbits (non-binding species) and Macaque (rhesus and cynomolgus) monkeys (binding species) in single-dose (IV) and repeat-dose toxicity (SC and IV) studies of up to 13 weeks (25 mg/kg twice weekly) or 26 weeks (25 mg/kg weekly) duration, respectively. No evidence of acute or chronic toxicity was identified.
Intravenous trastuzumab: Lactation: A study conducted in cynomolgus monkeys that had received trastuzumab at doses 25 times that of the weekly human maintenance dose of 2 mg/kg intravenous trastuzumab from days 120 to 150 of pregnancy, demonstrated that trastuzumab is secreted in the milk postpartum. The exposure to trastuzumab in utero and the presence of trastuzumab in the serum of these infant monkeys was not associated with any adverse effects on their growth or development from birth to 1 month of age.
Carcinogenicity: No carcinogenicity studies have been performed to establish the carcinogenic potential of pertuzumab or trastuzumab within Phesgo.
Genotoxicity: No studies have not been performed to evaluate the mutagenic potential of pertuzumab or trastuzumab within Phesgo.
Impairment of Fertility: Intravenous Pertuzumab: No specific fertility studies in animals have been performed to evaluate the effect of pertuzumab. No adverse effects on male and female reproductive organs were observed in repeat-dose toxicity studies of up to six month duration in cynomolgus monkeys.
Intravenous Trastuzumab: Reproduction studies of female fertility have been conducted in cynomolgus monkeys at doses up to 25 times that of the weekly human maintenance dose of 2 mg/kg intravenous trastuzumab and have revealed no evidence of impaired fertility. Additionally, no adverse effects on male and female reproductive organs were observed in repeat-dose toxicity studies of up to six month duration in cynomolgus monkeys.
Reproductive toxicity: Intravenous Pertuzumab: Reproductive toxicology studies have been conducted in cynomolgus monkeys at loading doses of 30 to 150 mg/kg and maintenance doses of 10 to 100 mg/kg achieving clinically relevant exposures. Intravenous administration of pertuzumab from Gestation Day (GD) 19 through 50 (period of organogenesis) has been shown to be embryotoxic with a dose dependent increase in embryo-fetal deaths between GD 25 to 70. Delayed renal development and oligohydramnios were identified at GD100.
Intravenous Trastuzumab: Reproduction studies have been conducted in cynomolgus monkeys at doses up to 25 times that of the weekly human maintenance dose of 2 mg/kg intravenous trastuzumab and have revealed no evidence of harm to the fetus. Placental transfer of trastuzumab during the early (days 20 - 50 of gestation) and late (days 120 - 150 of gestation) fetal development period was observed.
Other: Subcutaneous trastuzumab: Subcutaneous trastuzumab with vorhyaluronidase alfa was well tolerated in a rabbit local tolerance study (non-binding species) and in a 13-week repeat dose toxicity study in cynomolgus monkeys (binding species).

Early Breast Cancer (EBC): Phesgo is indicated in combination with chemotherapy for the: neoadjuvant treatment of adult patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either >2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer (see Pharmacology: Pharmacodynamics: Clinical/efficacy studies under Actions); adjuvant treatment of adult patients with HER2-positive early breast cancer at high risk of recurrence (see Pharmacology: Pharmacodynamics: Clinical/efficacy studies under Actions).
Metastatic Breast Cancer (MBC): Phesgo is indicated in combination with docetaxel for adult patients with HER2-positive metastatic or locally recurrent unresectable breast cancer, who have not received previous anti-HER2 therapy or chemotherapy for their metastatic disease.

Patient Selection: Patients treated with Phesgo should have HER2-positive tumor status, defined as a score of 3+ by immunohistochemistry (IHC) or a ratio of ≥ 2.0 by in situ hybridization (ISH), assessed by a validated test.
To ensure accurate and reproducible results, the testing must be performed in a specialized laboratory, which can ensure validation of the testing procedures.
For full instructions on assay performance and interpretation, please refer to the package inserts of validated HER2 testing assays.
Administration of Phesgo: Phesgo therapy should only be administered under the supervision of a healthcare professional experienced in the treatment of cancer patients.
Substitution by any other biological medicinal product requires the consent of the prescribing physician.
In order to prevent medication errors, it is important to check the vial labels to ensure that the drug being prepared and administered is Phesgo.
Phesgo is for subcutaneous (SC) use in the thigh only. Do not administer intravenously.
Metastatic and Early Breast Cancer: For Phesgo dose recommendations in early and metastatic breast cancer refer to Table 7. (See Table 7.)

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The injection site should be alternated between the left and right thigh only. New injections should be given at least 1 inch/2.5 cm from the previous site on healthy skin and never into areas where the skin is red, bruised, tender, or hard. Do not split the dose between two syringes or between two sites of administration. During the treatment course with Phesgo, other medications for SC administration should preferably be injected at different sites.
In patients receiving a taxane, Phesgo should be administered prior to the taxane. When administered with Phesgo, the recommended initial dose of docetaxel is 75 mg/m2.
In patients receiving an anthracycline-based regimen, Phesgo should be administered following completion of the entire anthracycline regimen.
Early Breast Cancer (EBC): In the neoadjuvant setting (before surgery), it is recommended that patients are treated with Phesgo for three to six cycles depending on the regimen chosen in combination with chemotherapy (see Pharmacology: Pharmacodynamics: Clinical/efficacy studies under Actions).
In the adjuvant setting (after surgery), Phesgo should be administered for a total of one year (maximum 18 cycles or until disease recurrence, or unmanageable toxicity, whichever occurs first), as part of a complete regimen for early breast cancer, including standard anthracycline- and/or taxane-based chemotherapy. Phesgo treatment should start on Day 1 of the first taxane-containing cycle and should continue even if chemotherapy is discontinued (see Pharmacology: Pharmacodynamics: Clinical/efficacy studies under Actions).
Patients who start Phesgo in the neoadjuvant setting should continue to receive adjuvant Phesgo to complete 1 year of treatment (maximum 18 cycles).
Metastatic Breast Cancer (MBC): Phesgo should be administered in combination with docetaxel until disease progression or unmanageable toxicity. Treatment with Phesgo may continue even if treatment with docetaxel is discontinued.
Delayed or Missed Doses: If the time between two sequential doses is less than 6 weeks, the 600 mg pertuzumab/600 mg trastuzumab maintenance dose of Phesgo should be administered as soon as possible. Do not wait until the next planned dose.
If the time between two sequential injections is 6 weeks or more, the loading dose of 1200 mg pertuzumab/600 mg trastuzumab should be re-administered followed by the maintenance dose of 600 mg pertuzumab/600 mg trastuzumab every 3 weeks thereafter.
Dose Modifications: No dose reductions of Phesgo are recommended.
For chemotherapy dose modifications, see relevant prescribing information.
Injection-related reactions: The injection should be slowed or paused if the patient experiences injection-related symptoms (see Precautions).
Hypersensitivity/anaphylaxis: The injection should be discontinued immediately and permanently if the patient experiences a serious hypersensitivity reaction (e.g. anaphylaxis) (see Precautions).
Left ventricular dysfunction: See Precautions for information on dose recommendations in the event of left ventricular dysfunction.
SPECIAL DOSAGE INSTRUCTIONS: Pediatric use: The safety and efficacy of Phesgo in children and adolescents (<18 years) has not been established.
Geriatric use: No dose adjustment of Phesgo is required in patients ≥65 years of age (see Use in the Elderly under Precautions and Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations: Geriatric Population under Actions).
Renal Impairment: Dose adjustments of Phesgo 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 Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions).
Hepatic Impairment: The safety and efficacy of Phesgo have not been studied in patients with hepatic impairment. No dose recommendation can be made for Phesgo (see Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions).

There is no experience with overdose of Phesgo in human clinical trials. The highest Phesgo dose tested is 1200 mg pertuzumab/600 mg trastuzumab.

Phesgo is contraindicated in patients with a known hypersensitivity to pertuzumab, trastuzumab, hyaluronidase or any of the excipients.

General: In order to improve traceability of biological medicinal products, the trade name and the batch number of the administered product should be clearly recorded (or stated) in the patient file.
Left ventricular dysfunction: Decreases in LVEF have been reported with drugs that block HER2 activity, including pertzumab and trastuzumab. The incidence of symptomatic left ventricular systolic dysfunction (LVD [congestive heart failure]) was higher in patients treated with pertuzumab in combination with trastuzumab and chemotherapy compared to trastuzumb and chemotherapy. In the adjuvant setting, the majority of cases of symptomatic heart failure reported were in patients who received anthracycline-based chemotherapy (see Adverse Reactions). Patients who have received prior anthracyclines or prior radiotherapy to the chest area may be at higher risk of LVEF decreases based on studies with intravenous pertuzumab in combination with trastuzumab and chemotherapy.
Phesgo and/or intravenous pertuzumab and trastuzumab have not been studied in patients with: a pretreatment LVEF value of <55% (EBC) or <50% (MBC); a prior history of congestive heart failure (CHF); conditions that could impair left ventricular function such as uncontrolled hypertension, recent myocardial infarction, serious cardiac arrhythmia requiring treatment or a cumulative prior anthracycline exposure to >360 mg/m2 of doxorubicin or its equivalent. Intravenous pertuzumab in combination with trastuzumab and chemotherapy has not been studied in patients with decreases in LVEF <50% during prior trastuzumab adjuvant therapy.
Assess LVEF prior to initiation of Phesgo and at regular intervals during treatment to ensure that LVEF is within normal limits (see Table 8 as follows). If the LVEF declines as indicated in Table 8 and has not improved, or has declined further at the subsequent assessment, discontinuation of Phesgo should be strongly considered, unless the benefits for the individual patient are deemed to outweigh the risks. (See Table 8.)

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Injection/infusion-related reactions (IRRs): Phesgo has been associated with injection-related reactions. Injection-related reactions were defined as any systemic reaction with symptoms such as fever, chills, headache, likely due to a release of cytokines occurring within 24 hours of administration of Phesgo. Close observation of the patient during and for 30 minutes after administration of the loading dose and during and for 15 minutes following the administration of the maintenance dose of Phesgo is recommended. If a significant injection-related reaction occurs, the injection should be slowed down or paused and appropriate medical therapies should be administered. Patients should be evaluated and carefully monitored until complete resolution of signs and symptoms. Permanent discontinuation should be considered in patients with severe injection-related reactions. This clinical assessment should be based on the severity of the preceding reaction and response to administered treatment for the adverse reaction (see Dosage & Administration). Although fatal outcomes resulting from injection-related reactions have not been observed with Phesgo, caution should be exercised as fatal infusion related-reactions have been associated with intravenous pertuzumab in combination with intravenous trastuzumab and chemotherapy.
Hypersensitivity reactions/anaphylaxis: Patients should be observed closely for hypersensitivity reactions. Although severe hypersensitivity reactions, including anaphylaxis and events with fatal outcomes, have not been observed in patients treated with Phesgo, caution should be exercised as these have been associated with intravenous pertuzumab in combination with trastuzumab and chemotherapy (see Adverse Reactions). Medications to treat such reactions, as well as emergency equipment, should be available for immediate use. Phesgo is contraindicated in patients with known hypersensitivity to pertuzumab, trastuzumab, or to any of its excipients (see Contraindications).
Drug Abuse and Dependence: There is no evidence that Phesgo has the potential for drug abuse and dependence.
Renal impairment: See Special Dosage Instructions under Dosage & Administration and Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions.
Hepatic impairment: The safety and efficacy of Phesgo in patients with hepatic impairment has not been studied.
Effects on ability to drive and use machine: Phesgo has a minor influence on the ability to drive and use machines. Injection-related reactions and dizziness may occur during treatment with Phesgo (see as previously mentioned and Adverse Reactions).
Use in Children: The safety and efficacy of Phesgo in pediatric patients below 18 years of age have not been established.
Use in the Elderly: No overall differences in efficacy and safety of Phesgo was observed in patients ≥65 (n=26) and <65 years of age (n=222).
However, with intravenous pertuzumab in combination with trastuzumab, the incidence of the following all grade adverse events were at least 5% higher in patients patients ≥65 years of age (n=418) compared to patients <65 years of age (n=2926): decreased appetite, anemia, weight decreased, asthenia, dysgeusia, neuropathy peripheral, hypomagnesemia and diarrhea.

Females and Males of Reproductive Potential: Fertility: No specific fertility studies in animals have been performed to evaluate the effects of pertuzumab or trastuzumab within Phesgo.
No specific fertility studies in animals have been performed to evaluate the effect of pertuzumab. No adverse effects on male and female reproductive organs were observed in repeat-dose toxicity studies of pertzumab for up to six month duration in cynomolgus monkeys (see Pharmacology: Toxicology: Preclinical Safety Data: Impairment of Fertility under Actions).
Reproduction studies conducted in cynomologus monkeys with trastuzumab revealed no evidence of impaired fertility in female cynomologus monkeys (see Pharmacology: Toxicology: Preclinical Safety Data: Impairment of Fertility under Actions).
Contraception: Women of childbearing potential including those who are partners of male patients should use effective contraception during treatment with Phesgo and for 7 months following the last dose of Phesgo.
Pregnancy: Phesgo should be avoided during pregnancy unless the potential benefit for the mother outweighs the potential risk to the fetus.
No clinical studies of Phesgo in pregnant women have been performed. Pertuzumab administered intraveneously to cynomolgus monkeys during organogenesis led to oligohydramnios, delayed renal development and embryo fetal death (see Pharmacology: Toxicology: Preclinical Safety Data: Reproductive Toxicity under Actions). In the post-marketing setting for trastuzumab, cases of fetal renal growth and/or function impairment in association with oligohydramnios, some of which resulted in fatal pulmonary hypoplasia of the fetus, have been reported in pregnant women.
Based on the aforementioned animal studies and post-marketing data, Phesgo has the potential to cause fetal harm when administered to a pregnant woman. Women who become pregnant should be advised of the possibility of harm to the fetus. If a pregnant woman is treated with Phesgo, or if a patient becomes pregnant while receiving Phesgo or within 7 months following the last dose of Phesgo, close monitoring by a multidisciplinary team is desirable.
Labor and Delivery: The safe use of Phesgo during labor and delivery has not been established.
Lactation: As human IgG is excreted in human milk, and the potential for absorption and harm to the infant is unknown, women should be advised to discontinue nursing during Phesgo therapy and for 7 months after the last dose of Phesgo.

Clinical Trials: Summary of the safety profile: The safety profile of Phesgo is based on data from the Phase III FEDERICA study in which HER2-positive early breast cancer patients were treated with either Phesgo (n=248) or intravenous pertuzumab and trastuzumab (n=252), in combination with chemotherapy.
The most common (≥5%) adverse drug reactions (ADRs) reported in patients treated with Phesgo or intravenous pertuzumab in combination with trastuzumab were diarrhea, injection site reaction, infusion-related reactions, asthenia, fatigue, rash, ejection fraction decreased, and anemia.
The most common (≥1%) serious adverse events (SAEs) reported in patients treated with Phesgo or intravenous pertuzumab in combination with trastuzumab were febrile neutropenia, pyrexia, neutropenia, neutropenic sepsis, infusion-related reaction and neutrophil count decreased. SAEs were equally distributed between the Phesgo treatment arm and the intravenous pertuzumab in combination with trastuzumab treatment arm. The following adverse drug reactions were reported with a higher frequency (≥5%) with Phesgo compared to intravenous pertuzumab in combination with trastuzumab: Alopecia 77% vs 70.2%, Dyspnea 10.1% vs 4.4%, and Fatigue 27.8% vs 22.6%.
Tabulated list of adverse drug reactions: The safety profile of Phesgo was overall consistent to the known safety profile of intravenous pertuzumab in combination with trastuzumab and chemotherapy as seen in the pertuzumab and trastuzumab-treated arms of the following pivotal studies (n=3344): CLEOPATRA, in which pertuzumab was given in combination with trastuzumab and docetaxel to patients with MBC (n=453); NEOSPHERE (n=309) and TRYPHAENA (n=218), in which neoadjuvant pertuzumab was given in combination with trastuzumab and chemotherapy to patients with locally advanced, inflammatory or EBC; APHINITY, in which adjuvant pertuzumab was given in combination with trastuzumab and anthracycline-based or non-anthracycline-based, taxane-containing chemotherapy to patients with EBC (n=2364).
Table 9 presents ADRs that have been reported in association with the use of pertuzumab, trastuzumab and chemotherapy in the pivotal clinical trials and in the post-marketing setting.
As pertuzumab and trastuzumab is used in combination with chemotherapy, it is difficult to ascertain the causal relationship of an adverse reaction to a particular drug.
In this section, 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 <1/1,000), very rare (<1/10,000), and unknown (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. (See Table 9.)

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Description of selected adverse drug reactions from clinical trials: Phesgo: Left ventricular dysfunction: In FEDERICA, the incidence of symptomatic heart failure (NYHA class III or IV) with a LVEF decline of at least 10%-points from baseline and to <50% was 0.4% of Phesgo treated patients vs 0% of intravenous pertuzumab and trastuzumab-treated patients. Of the patients who experienced symptomatic heart failure, all Phesgo-treated patients had recovered (defined as 2 consecutive LVEF measurements above 50%) at the data cutoff. Asymptomatic or mildly symptomatic (NYHA class II) declines in LVEF of at least 10%-points from baseline and to <50% (confirmed by secondary LVEF) were reported in 0.4% of Phesgo-treated patients and 0.8% of intravenous pertuzumab and trastuzumab-treated patients, of whom none of the Phesgo-treated patients or intravenous pertuzumab and trastuzumab-treated patients had recovered at the data cutoff.
Injection/infusion-related Reactions: In FEDERICA, an injection/infusion-related reaction was defined as any systemic reaction reported within 24hrs of Phesgo or intravenous pertuzumab in combination with trastuzumab administration. Injection-related reactions were reported in 1.2% of Phesgo-treated patients and infusion-related reactions were reported in 10.3% of intravenous pertuzumab and trastuzumab-treated patients.
Injection site reactions (defined as any local reaction reported within 24 hours of Phesgo) were reported in 12.9% of Phesgo treated patients and were all grade 1 or 2 events.
Hypersensitivity reactions/anaphylaxis: In FEDERICA, the overall frequency of hypersensitivity/anaphylaxis reported events related to HER2- targeted therapy was 1.6% in both the Phesgo-treated patients and intravenous pertuzumab and trastuzumab-treated patients, of which none were NCI-CTCAE (version 4) Grade 3-4 (see Precautions).
Laboratory Abnormalities: In FEDERICA, the incidence of NCI-CTCAE Grade 3-4 decreases in neutrophil counts were balanced in the Phesgo and intravenous pertuzumab and trastuzumab groups.
Intravenous Pertuzumab and Trastuzumab: Left ventricular dysfunction: In CLEOPATRA, the incidence of LVD during study treatment was higher in the placebo-treated group than the pertuzumab-treated group (8.6% and 6.6%, respectively). The incidence of symptomatic LVD was also lower in the pertuzumab-treated group (1.8% in the placebo-treated group vs. 1.5% in the pertuzumab-treated group) (see Precautions).
In NEOSPHERE, in which patients received four cycles of pertuzumab as neoadjuvant treatment, the incidence of LVD (during the overall treatment period) was higher in the pertuzumab, trastuzumab and docetaxel-treated group (7.5%) compared to the trastuzumab and docetaxel-treated group (1.9%). There was one case of symptomatic LVD in the pertuzumab and trastuzumab-treated group.
In TRYPHAENA, the incidence of LVD (during the overall treatment period) was 8.3% in the group treated with pertuzumab plus trastuzumab and 5-fluorouracil, epirubicin and cyclophosphamide (FEC) followed by pertuzumab plus trastuzumab and docetaxel; 9.3% in the group treated with pertuzumab plus trastuzumab and docetaxel following FEC; and 6.6% in the group treated with pertuzumab in combination with TCH. The incidence of symptomatic LVD (congestive heart failure) was 1.3% in the group treated with pertuzumab plus trastuzumab and docetaxel following FEC (this excludes a patient that experienced symptomatic LVD during FEC treatment prior to receiving pertuzumab plus trastuzumab and docetaxel) and also 1.3% in the group treated with pertuzumab in combination with TCH. No patients in the group treated with pertuzumab plus trastuzumab and FEC followed by pertuzumab plus trastuzumab and docetaxel experienced symptomatic LVD.
In the neoadjuvant period of the BERENICE trial, the incidence of NYHA Class III/IV symptomatic LVD (congestive heart failure according to NCI-CTCAE v.4) was 1.5% in the group treated with dose dense AC followed by pertuzumab plus trastuzumab and paclitaxel and none of the patients (0%) experienced symptomatic LVD in the group treated with FEC followed by pertuzumab in combination with trastuzumab and docetaxel. The incidence of asymptomatic LVD (PT ejection fraction decrease according to NCICTCAE v.4) was 7% in the group treated with dose dense AC followed by pertuzumab plus trastuzumab and paclitaxel and 3.5% in the group treated with FEC followed by pertuzumab plus trastuzumab and docetaxel.
In APHINITY, the incidence of symptomatic heart failure (NYHA class III or IV) with a LVEF decline of at least 10%-points from baseline and to <50% was <1% (0.6% of pertuzumab-treated patients vs 0.2% of placebo-treated patients). Of the patients who experienced symptomatic heart failure, 46.7% of pertuzumab-treated patients and 66.7% of placebo-treated patients had recovered (defined as 2 consecutive LVEF measurements above 50%) at the data cutoff. The majority of the events were reported in anthracycline-treated patients. Asymptomatic or mildly symptomatic (NYHA class II) declines in LVEF of at least 10%- points from baseline and to <50% were reported in 2.7% of pertuzumab-treated patients and 2.8% of placebo-treated patients, of whom 79.7% of pertuzumab-treated patients and 80.6% of placebo-treated patients had recovered at the data cutoff.
Infusion-related reaction: An infusion-related reaction was defined in the pivotal trials 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 CLEOPATRA, the initial dose of pertuzumab was given the day before 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 13.2% 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 (see Precautions).
In neoadjuvant and adjuvant trials, pertuzumab was administered on the same day as the other study treatment drugs. Infusion-related reactions occurred in 18.6% -25.0% of patients on the first day of pertuzumab administration (in combination with trastuzumab and chemotherapy). The type and severity of events were consistent with those observed in CLEOPATRA, with a majority of reactions being mild or moderate.
Hypersensitivity/anaphylaxis: In CLEOPATRA, the overall frequency of hypersensitivity/anaphylaxis reported events was 9.3% in the placebo-treated patients and 11.3% 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 (see Precautions).
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 neoadjuvant and adjuvant trials, hypersensitivity/anaphylaxis events were consistent with those observed in CLEOPATRA. In NEOSPHERE, two patients in the pertuzumab and docetaxel-treated group experienced anaphylaxis. In both TRYPHAENA and APHINITY, the overall frequency of hypersensitivity/anaphylaxis was highest in the pertuzumab and TCH treated group (13.2% and 7.6% respectively), of which 2.6% and 1.3% of events, respectively were NCI-CTCAE Grade 3-4.
Laboratory Abnormalities: In the pivotal trials CLEOPATRA, NEOSPHERE, and APHINITY the incidence of NCI-CTCAE Grade 3-4 decreases in neutrophil counts were balanced in the pertuzumab-treated and control groups.
Post marketing experience: Not applicable.

No formal drug-drug interaction studies have been performed.
Phesgo: Based on the population pharmacokinetics analysis of FEDERICA study, there was no evidence of drug-drug interaction between pertuzumab and trastuzumb within Phesgo.
Intravenous Pertuzumab: A sub-study in 37 patients in the pivotal trial CLEOPATRA showed no evidence of drug-drug interaction between pertuzumab and trastuzumab and between pertuzumab and docetaxel. In addition, no clinically relevant pharmacokinetic interaction of co-administered docetaxel or 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 and APHINITY studies.
Five studies evaluated the effects of pertuzumab on the pharmacokinetics of coadministered cytotoxic agents, docetaxel, paclitaxel, gemcitabine, capecitabine, carboplatin, and erlotinib. There was no evidence of any pharmacokinetics interaction between pertuzumab and any of these agents. The pharmacokinetics of pertuzumab in these studies was comparable to those observed in single-agent studies.
Intravenous trastuzumab: There have been no formal drug interaction studies performed with trastuzumab in humans. Clinically significant interactions between trastuzumab and the concomitant medications used in clinical trials have not been observed.
In studies where trastuzumab was administered in combination with docetaxel, carboplatin, or anastrozole, the pharmacokinetics of these medications was not altered nor was the pharmacokinetics of trastuzumab altered.
Concentrations of paclitaxel and doxorubicin (and their major metabolites 6-α hydroxyl-paclitaxel, POH, and doxorubicinol, DOL) were not altered in the presence of trastuzumab. However, trastuzumab may elevate the overall exposure of one doxorubicin metabolite, (7-deoxy-13 dihydro- doxorubicinone, D7D). The bioactivity of D7D and the clinical impact of the elevation of this metabolite is unclear. No changes were observed in trastuzumab concentrations in the presence of paclitaxel and doxorubicin.
The results of a drug interaction substudy evaluating the pharmacokinetics of capecitabine and cisplatin when used with or without trastuzumab suggested that the exposure to the bioactive metabolites (e.g. 5-FU) of capecitabine was not affected by concurrent use of cisplatin or by concurrent use of cisplatin plus trastuzumab. However, capecitabine itself showed higher concentrations and a longer half-life when combined with trastuzumab. The data also suggested that the pharmacokinetics of cisplatin were not affected by concurrent use of capecitabine or by concurrent use of capecitabine plus trastuzumab.

INCOMPATIBILITIES: No incompatibilities between Phesgo and polypropylene, polycarbonate, polyurethane, polyethylene, polyvinyl chloride and fluorinated ethylene polypropylene have been observed.
SPECIAL INSTRUCTIONS FOR USE, HANDLING AND DISPOSAL: The 1200 mg pertuzumab/600 mg trastuzumab and 600 mg pertuzumab/600 mg trastuzumab solution are ready to use solutions for injection which does not need to be mixed with other drugs or diluted.
Phesgo should be inspected visually to ensure there is no particulate matter or discolouration prior to administration. Do not shake.
Phesgo solution for injection is for single use only and should be prepared by a healthcare professional using aseptic technique.
From a microbiological point of view, the medicine should be used immediately once transferred from the vial to the syringe since the medicine does not contain any antimicrobial-preservative. If not used immediately, preparation should take place in controlled and validated aseptic conditions. Once transferred from the vial to the syringe, the medicinal product is physically and chemically stable for 28 days at 2°C - 8°C or 24 hours at 9°C - 30°C.
After transfer of the solution to the syringe, it is recommended to replace the transfer needle by a syringe closing cap to avoid drying of the solution in the needle and not compromise the quality of the medicinal product. Label the syringe with the peel-off sticker. The hypodermic injection needle must be attached to the syringe immediately prior to administration followed by volume adjustment to 10 mL (600 mg pertuzumab/600 mg trastuzumab) or 15 mL (1200 mg pertuzumab/600 mg trastuzumab).
No incompatibilities between Phesgo and polypropylene, polycarbonate, polyurethane, polyethylene, polyvinyl chloride and fluorinated ethylene polypropylene have been observed.
Disposal of unused/expired medicines: The release of pharmaceuticals in the environment should be minimized. Medicines should not be disposed of via wastewater and disposal through household waste should be avoided.
The following points should be strictly adhered to regarding the use and disposal of syringes and other medicinal sharps: Needles and syringes should never be reused.
Place all used needles and syringes into a sharps container (puncture-proof disposable container).
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Vials: Store at 2°C-8°C.
Keep vial in the outer carton in order to protect from light.
Do not freeze.

Targeted Cancer Therapy

L01FY01 - pertuzumab and trastuzumab ; Belongs to the class of combinations of monoclonal antibodies and antibody drug conjugates. Used in the treatment of cancer.

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