Fesgo

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Phesgo® (Phesgo®)

Composition:

Active substances: pertuzumab, trastuzumab;

1 vial contains pertuzumab 600 mg and trastuzumab 600 mg in 10 ml;

1 vial contains pertuzumab 1200 mg and trastuzumab 600 mg in 15 ml;

Excipients: recombinant human hyaluronidase (rHuPH20), L-histidine, L-histidine hydrochloride monohydrate, α,α-trehalose dihydrate, sucrose, polysorbate 20, L-methionine, water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: liquid, from clear to opalescent, from colorless to slightly brown.

Pharmacotherapeutic group. Antineoplastic and immunomodulating agents. Antineoplastic agents. Monoclonal antibodies and antibody-drug conjugates. Combined monoclonal antibodies and antibody-drug conjugates. Pertuzumab and trastuzumab.

ATC code L01FY01.

Pharmacological properties.

Pharmacodynamics.

The medicinal product Perjeta® contains pertuzumab and trastuzumab, which provide its therapeutic effect, and hyaluronidase alfa—a enzyme used to enhance dispersion and absorption of co-administered medicinal products upon subcutaneous administration.

Pertuzumab and trastuzumab are recombinant humanized monoclonal antibodies of the IgG1 class, targeting the human epidermal growth factor receptor 2 (HER2). Both active substances bind to different subdomains of HER2 without competitive interaction and have complementary mechanisms of disrupting HER2 signaling:

• Pertuzumab selectively interacts with the extracellular dimerization domain (subdomain II) of HER2, thereby blocking ligand-dependent heterodimerization of HER2 with other members of the HER family, including epidermal growth factor receptors (EGFR), HER3, and HER4. As a result, pertuzumab inhibits ligand-initiated intracellular signal transduction via two major pathways: mitogen-activated protein kinase (MAPK) and phosphoinositide-3-kinase (PI3K). Inhibition of these signaling pathways may lead to cell growth arrest and apoptosis, respectively.
• Trastuzumab binds to subdomain IV of the extracellular domain of the HER2 protein to suppress ligand-independent HER2-mediated signals promoting proliferation and survival of human tumor cells overexpressing HER2.

In addition, both active substances mediate antibody-dependent cellular cytotoxicity (ADCC). In vitro, ADCC of pertuzumab and trastuzumab is directed predominantly against tumor cells overexpressing HER2 compared to tumor cells without HER2 overexpression.

Pharmacokinetics.

Results of the PK study for the primary endpoint Cmin of pertuzumab in cycle 7 (i.e., prior to administration in cycle 8) demonstrated non-inferior efficacy of pertuzumab in Perjeta® (geometric mean 88.7 µg/mL) compared to intravenous pertuzumab (geometric mean 72.4 µg/mL), with a geometric mean ratio of 1.22 (90% CI: 1.14–1.31). The lower bound of the two-sided 90% confidence interval for the ratio of geometric means of pertuzumab in Perjeta® versus intravenous pertuzumab was 1.14, which is above the pre-specified limit of 0.8.

Results of the PK study for the secondary endpoint Cmin of trastuzumab in cycle 7 (i.e., prior to administration in cycle 8) demonstrated non-inferior efficacy of trastuzumab in Perjeta® (geometric mean 57.5 µg/mL) compared to intravenous trastuzumab (geometric mean 43.2 µg/mL), with a geometric mean ratio of 1.33 (90% CI: 1.24–1.43).

Absorption

The median maximum serum concentration (Cmax) of pertuzumab in Perjeta® and the time to reach maximum concentration (Tmax) were 157 µg/mL and 3.82 days, respectively. According to population PK analysis, the absolute bioavailability was 0.712 and the first-order absorption rate constant (Ka) was 0.348 (L/day).

The median Cmax of trastuzumab in Perjeta® and Tmax were 114 µg/mL and 3.84 days, respectively. According to population PK analysis, the absolute bioavailability was 0.771 and Ka was 0.404 (L/day).

Distribution

According to population PK analysis, the central compartment volume of distribution (Vc) for pertuzumab in Perjeta® in a typical patient was 2.77 liters.

According to population PK analysis, the Vc for trastuzumab after subcutaneous administration in a typical patient was 2.91 liters.

Metabolism

The metabolism of the medicinal product Perjeta® has not been directly studied. Antibody metabolism occurs primarily via catabolism.

Elimination

According to population PK analysis, the clearance of pertuzumab in Perjeta® was 0.163 L/day, and the elimination half-life (t1/2) was approximately 24.3 days.

According to population PK analysis, the clearance of trastuzumab in Perjeta® was 0.111 L/day. It is estimated that trastuzumab concentrations < 1 µg/mL (approximately 3% of the predicted population steady-state Cmin, or approximately 97% washout) are achieved in at least 95% of patients within 7 months after the last dose.

Special patient populations

Elderly patients

Pharmacokinetic studies of Perjeta® in elderly patients have not been conducted.

Population PK analysis of pertuzumab in Perjeta® and intravenous pertuzumab showed no clinically significant effect of age on pertuzumab PK.

Population PK analysis of subcutaneous or intravenous trastuzumab demonstrated that age does not affect trastuzumab distribution.

Renal impairment

Pharmacokinetic studies of Perjeta® in patients with renal impairment have not been conducted.

Based on population PK analysis of pertuzumab in Perjeta® and intravenous pertuzumab, renal impairment does not affect pertuzumab exposure; however, only limited data from patients with severe renal impairment were included in the population pharmacokinetic analysis.

Population PK analysis of subcutaneous or intravenous trastuzumab demonstrated that renal impairment does not affect trastuzumab distribution.

Hepatic impairment

Formal PK studies in patients with hepatic impairment have not been conducted. Based on population PK analysis of pertuzumab in Perjeta®, mild hepatic impairment does not affect pertuzumab exposure. However, only limited data from patients with mild hepatic impairment were included in the population PK analysis. IgG1 molecules such as pertuzumab and trastuzumab are catabolized by widely distributed proteolytic enzymes, not limited to liver tissue. Therefore, changes in liver function are unlikely to affect the elimination of pertuzumab and trastuzumab.

Clinical characteristics.

Indications.

Early breast cancer (EBC)

The medicinal product Fesgo® is indicated in combination with chemotherapy for:

• neoadjuvant treatment of adult patients with HER2-positive locally advanced, inflammatory, or early breast cancer with high risk of recurrence;
• adjuvant treatment of adult patients with HER2-positive early breast cancer with high risk of recurrence.

Metastatic breast cancer (MBC)

The medicinal product Fesgo® is indicated in combination with docetaxel for the treatment of adult patients with HER2-positive metastatic or locally recurrent unresectable breast cancer who have not previously received anti-HER2 therapy or chemotherapy for metastatic disease.

Contraindications.

Hypersensitivity to the active substances or to any of the excipients listed in the section "Composition".

Interaction with other medicinal products and other forms of interaction.

Studies on interaction with other medicinal products have not been conducted.

Pertuzumab

No pharmacokinetic interaction between pertuzumab and trastuzumab or between pertuzumab and docetaxel was observed in a sub-study involving 37 participants conducted within the randomized pivotal CLEOPATRA study in patients with metastatic breast cancer. Additionally, population pharmacokinetic analyses showed no evidence of interaction between pertuzumab and trastuzumab or between pertuzumab and docetaxel. This lack of interaction between these medicinal products was confirmed by pharmacokinetic data from the NEOSPHERE and APHINITY studies.

The effect of pertuzumab on the pharmacokinetics of concomitantly administered cytotoxic agents—docetaxel, paclitaxel, gemcitabine, capecitabine, carboplatin, and erlotinib—was studied in five trials. There were no data indicating pharmacokinetic interactions between pertuzumab and any of these agents. Pertuzumab pharmacokinetics in these studies were comparable to those observed in monotherapy studies.

Trastuzumab

Appropriate interaction studies with other medicinal products have not been conducted. No clinically significant interactions were observed during concomitant administration of trastuzumab with medicinal products used in clinical trials.

Effect of trastuzumab on the pharmacokinetics of other antineoplastic agents

Pharmacokinetic data obtained from the BO15935 and M77004 studies in women with HER2-positive metastatic breast cancer indicated that exposure to paclitaxel and doxorubicin (and their major metabolites—6-α-hydroxypaclitaxel, POH, and doxorubicinol, DOL) was not altered in the presence of trastuzumab (loading dose 8 mg/kg or 4 mg/kg followed by 6 mg/kg every 3 weeks or 2 mg/kg weekly intravenously). However, trastuzumab may increase overall exposure to one metabolite of doxorubicin (7-deoxy-13-dihydro-doxorubicinone, D7D). The bioavailability of the D7D metabolite and the clinical significance of its increased exposure have not been established.

Data from the non-comparative JP16003 study of trastuzumab (4 mg/kg intravenous loading dose and 2 mg/kg intravenous weekly) and docetaxel (60 mg/m² intravenous) in Japanese women with HER2-positive metastatic breast cancer indicated that concomitant administration of trastuzumab did not affect the single-dose pharmacokinetics of docetaxel. The sub-study JP19959 of the BO18255 (ToGA) study, involving Japanese men and women with advanced gastric cancer, evaluated the pharmacokinetics of capecitabine and cisplatin when administered with or without trastuzumab. Results from this sub-study showed that exposure to biologically active metabolites (e.g., 5-FU) of capecitabine was not altered by concomitant administration of cisplatin or by concomitant administration of cisplatin and trastuzumab. However, higher concentrations and a longer elimination half-life of capecitabine were demonstrated when administered concomitantly with trastuzumab. Data also indicate that the pharmacokinetics of cisplatin were not affected by concomitant administration of capecitabine or by concomitant administration of capecitabine and trastuzumab.

Pharmacokinetic data obtained from the H4613g/GO01305 study in patients with metastatic or locally advanced unresectable HER2-positive cancer indicate that trastuzumab did not affect the pharmacokinetics of carboplatin.

Effect of antineoplastic agents on the pharmacokinetics of trastuzumab

Comparison of modeled serum trastuzumab concentrations after trastuzumab monotherapy (4 mg/kg loading dose; 2 mg/kg weekly intravenous) and observed serum concentrations in Japanese women with HER2-positive metastatic breast cancer (study JP16003) revealed no pharmacokinetic effect of concomitant docetaxel administration on trastuzumab pharmacokinetics. Comparison of trastuzumab pharmacokinetic results from two phase II studies (BO15935 and M77004) and one phase III study (H0648g), in which patients received combination therapy with trastuzumab and paclitaxel, and two phase II studies in which trastuzumab was administered as monotherapy (W016229 and MO16982), in women with HER2-positive metastatic breast cancer, showed variability in individual and mean trough serum concentrations of trastuzumab across studies, but no clear effect of concomitant paclitaxel administration on trastuzumab pharmacokinetics.

Comparison of trastuzumab pharmacokinetic data from study M77004, in which women with HER2-positive metastatic breast cancer received combination therapy with trastuzumab, paclitaxel, and doxorubicin, with trastuzumab pharmacokinetic data from studies where trastuzumab was administered as monotherapy (H0649g) or in combination with an anthracycline and cyclophosphamide or paclitaxel (study H0648g), showed no influence of doxorubicin and paclitaxel on trastuzumab pharmacokinetics.

Pharmacokinetic data from study H4613g/GO01305 indicate that carboplatin had no effect on the pharmacokinetics of trastuzumab.

Concomitant administration of anastrozole did not affect the pharmacokinetics of trastuzumab.

Special precautions for use.

Traceability

In order to enhance the traceability of biological medicinal products, it is necessary to clearly and legibly document the name and batch number of the medicinal product administered.

Left ventricular dysfunction (including congestive heart failure)

Decreases in left ventricular ejection fraction (LVEF) have been observed during treatment with agents that block HER2 activity, including pertuzumab and trastuzumab. The incidence of symptomatic left ventricular systolic dysfunction (congestive heart failure) was higher in patients receiving pertuzumab in combination with trastuzumab and chemotherapy compared to those receiving trastuzumab and chemotherapy. Most cases of symptomatic heart failure were observed in the adjuvant setting in patients who received anthracycline-based chemotherapy (see section "Side effects"). Based on results from studies of intravenous pertuzumab administered in combination with trastuzumab and chemotherapy in patients previously treated with anthracyclines or prior thoracic radiation therapy, the risk of LVEF decline may be higher.

Patients with severe cardiac disease or significant comorbidities in medical history, ventricular arrhythmias, or risk factors for ventricular arrhythmias were excluded from the pivotal clinical trial (neo-)adjuvant treatment of HER2-positive breast cancer with the medicinal product Fesgo® (FEDERICA study).

The use of Fesgo® has not been studied in patients with LVEF values prior to treatment < 55% (early breast cancer) or < 50% (metastatic breast cancer); with a history of congestive heart failure (CHF); with conditions that may impair left ventricular function (uncontrolled hypertension, recent myocardial infarction, serious cardiac rhythm disorders requiring treatment, or prior anthracycline therapy with a cumulative doxorubicin or equivalent dose > 360 mg/m²). Furthermore, the use of pertuzumab in combination with trastuzumab has not been studied in patients with LVEF reduction to < 50% during prior adjuvant trastuzumab therapy.

LVEF should be assessed before initiating treatment with Fesgo® and regularly during treatment (e.g., once during neoadjuvant treatment and every 12 weeks during adjuvant therapy or treatment of metastatic cancer) to ensure that LVEF values remain within normal limits. If LVEF declines, as specified in the section "Method of administration and dosage", and does not improve or further declines upon subsequent evaluation, careful consideration should be given to discontinuing Fesgo®, except when the benefit for an individual patient outweighs the risk.

The risk of cardiac complications should be carefully evaluated and balanced against the medical necessity for each patient prior to administering Fesgo® with anthracycline-containing regimens. Due to the pharmacological action of HER2-targeting agents and anthracyclines, the risk of cardiotoxicity may be higher when Fesgo® and anthracyclines are administered concurrently compared to sequential administration.

Sequential administration of Fesgo® (in combination with a taxane) was studied after doxorubicin as part of two anthracycline-based regimens in the FEDERICA study, while sequential administration of intravenous pertuzumab (in combination with trastuzumab and a taxane) was studied after epirubicin or doxorubicin as components of multiple anthracycline-based regimens in the APHINITY and BERENICE studies. However, only limited safety data are available regarding the concurrent use of intravenous pertuzumab in combination with trastuzumab and an anthracycline. In the TRYPHAENA study, intravenous pertuzumab in combination with trastuzumab was administered concurrently with epirubicin as part of the FEC regimen (5-fluorouracil, epirubicin, cyclophosphamide) (see section "Side effects"). Treatment was given only to patients who had not previously received chemotherapy, and they received a low cumulative dose of epirubicin (up to 300 mg/m²). In this study, cardiac safety was similar to that observed in patients receiving a comparable regimen where pertuzumab was administered sequentially (after FEC chemotherapy).

Injection-related reactions / Infusion reactions

The use of Fesgo® has been associated with injection-related reactions (see section "Side effects"). Injection-related reactions were defined as any systemic reaction with symptoms such as fever, chills, headache, likely due to cytokine release occurring within 24 hours after administration of Fesgo®. Close monitoring of patients is recommended during and for 30 minutes after administration of the loading dose, and during and for 15 minutes after administration of the maintenance dose of Fesgo®. In case of a severe injection-related reaction, the injection rate should be slowed or the injection stopped, and appropriate medical treatment should be administered. Patients should be evaluated and closely monitored until signs and symptoms have completely resolved. For patients experiencing severe injection-related reactions, permanent discontinuation of the medicinal product should be considered. Clinical evaluation should take into account the severity of the previous reaction and response to treatment of this adverse reaction (see section "Method of administration and dosage"). Although fatal outcomes due to injection-related reactions have not been observed with Fesgo®, caution should be exercised since infusion reactions leading to fatal outcomes have been associated with intravenous administration of pertuzumab in combination with intravenous trastuzumab and chemotherapy.

Hypersensitivity reactions / Anaphylaxis

Patients should be closely monitored for hypersensitivity reactions. Severe hypersensitivity reactions, including anaphylaxis and fatal cases, have been observed with pertuzumab in combination with trastuzumab and chemotherapy (see section "Side effects"). Most anaphylactic reactions occurred during the first 6–8 treatment cycles when pertuzumab and trastuzumab were administered in combination with chemotherapy. Medicinal products for the treatment of such reactions, as well as resuscitation and intensive care equipment, should be immediately available if needed. Fesgo® should be permanently discontinued in case of grade 4 hypersensitivity reactions (anaphylaxis) according to NCI-CTCAE, bronchospasm, or acute respiratory distress syndrome (see section "Method of administration and dosage"). Fesgo® is contraindicated in patients with known hypersensitivity to pertuzumab, trastuzumab, or any excipient of the product (see section "Contraindications").

Febrile neutropenia

Patients receiving treatment with Fesgo® in combination with a taxane have an increased risk of febrile neutropenia.

Patients receiving intravenous pertuzumab in combination with trastuzumab and docetaxel have an increased risk of febrile neutropenia compared to those receiving placebo, trastuzumab, and docetaxel, particularly during the first 3 treatment cycles (see section "Side effects"). In the CLEOPATRA study in patients with metastatic breast cancer, the minimum neutrophil count was similar in patients receiving pertuzumab and those receiving placebo. The higher incidence of febrile neutropenia in patients receiving pertuzumab was associated with a higher incidence of mucositis and diarrhea in these patients. Symptomatic treatment of mucositis and diarrhea should be considered. After discontinuation of docetaxel, no cases of febrile neutropenia were reported.

Diarrhea

Fesgo® may cause severe diarrhea. Diarrhea most commonly occurs during concomitant use with taxane therapy. The risk of diarrhea may be higher in elderly patients (≥ 65 years) compared to younger patients (< 65 years). Treatment of diarrhea should be conducted according to standard practice and guidelines. Early administration of loperamide, fluid and electrolyte replacement should be considered, especially in elderly patients and in cases of severe or prolonged diarrhea. If there is no improvement in the patient's condition, interruption of therapy with Fesgo® should be considered. After diarrhea is controlled, treatment with Fesgo® may be resumed.

Lung reactions

Severe pulmonary reactions have been observed during post-marketing use of trastuzumab. These events were sometimes fatal. Additionally, cases of interstitial lung disease have been reported, including pulmonary infiltrates, acute respiratory distress syndrome, pneumonia, pneumonitis, pleural effusion, respiratory distress, acute pulmonary edema, and respiratory failure. Risk factors for interstitial lung disease include prior or concomitant use of other antineoplastic agents capable of causing interstitial lung disease, such as taxanes, gemcitabine, vinorelbine, and radiation therapy. These events may occur as part of infusion reactions or may have a delayed onset. Patients with dyspnea at rest due to complications of advanced malignancy or comorbid conditions have an increased risk of pulmonary reactions. Therefore, such patients should not be treated with Fesgo®. Caution should be exercised regarding pneumonitis, especially in patients receiving concomitant taxane therapy.

Use during pregnancy or breastfeeding.

Women of reproductive potential / Contraception

Women of reproductive potential should use effective contraception during treatment with Fesgo® and for 7 months after the last dose.

Pregnancy

Reproductive toxicity of pertuzumab has been demonstrated in animal studies. Limited data are available on the use of pertuzumab in pregnant women.

In animal studies, it is unknown whether trastuzumab affects fertility. However, during post-marketing use of trastuzumab, cases of impaired fetal kidney development and/or function, associated with oligohydramnios, have been reported. Some cases were associated with fatal fetal lung hypoplasia when women received trastuzumab during pregnancy.

Given the above animal data and post-marketing experience, Fesgo® should be avoided during pregnancy unless the potential benefit to the mother outweighs the potential risk to the fetus. Women who become pregnant should be informed of the potential risk to the fetus. If a pregnant woman receives treatment with Fesgo® or if a patient becomes pregnant during treatment with Fesgo® or within 7 months after the last dose, close monitoring by a multidisciplinary team of specialists is recommended.

Breastfeeding

Since human IgG is secreted into human breast milk and the potential for absorption and harm to the infant is unknown, women should not breastfeed during treatment with Fesgo® and for 7 months after the last dose.

Fertility

Pertuzumab

Specific animal studies on the effect of pertuzumab on fertility have not been conducted. Data from repeat-dose toxicity studies of up to 6 months duration showed no adverse effects on reproductive organs in male and female cynomolgus monkeys.

Trastuzumab

Studies on the effect of trastuzumab on reproductive function in cynomolgus monkeys did not reveal any signs of impaired fertility in female cynomolgus monkeys.

Ability to affect reaction speed when driving or operating machinery.

Fesgo® has a minor influence on the ability to drive or operate machinery (see section "Side effects"). Patients who experience injection-related reactions or dizziness (see section "Special precautions for use") should be advised to refrain from driving or operating machinery until symptoms resolve.

Method of Administration and Dosage

Treatment with the medicinal product Fesgo® should be initiated under the supervision of a physician experienced in the use of anticancer medicinal products. Fesgo® must be administered only by a physician prepared to manage anaphylactic reactions, and the injection should be performed in departments equipped with full resuscitation equipment (see section "Special Precautions").

To avoid medication errors, it is essential to check the labeling of the vials to ensure that the medicinal product being prepared and administered is indeed Fesgo®.

Patients currently receiving intravenous pertuzumab and trastuzumab may be switched to treatment with Fesgo®. Switching treatment from intravenous pertuzumab and trastuzumab to Fesgo® (or vice versa) was studied in trial MO40628 (see section "Adverse Reactions").

Dosage

Tumors in patients receiving treatment with Fesgo® must be confirmed as HER2-positive, defined as an immunohistochemical (IHC) score of 3+ and/or an in situ hybridization (ISH) ratio of ≥ 2.0, determined by validated testing methods.

To ensure accuracy and reproducibility of test results, testing should be performed in a specialized laboratory capable of validating the testing methods. For detailed instructions on performing the test and interpreting results, refer to information regarding validated HER2 testing methods.

Recommended dosing regimens for Fesgo® in early and metastatic breast cancer are provided in Table 1.

Table 1

Recommended doses and administration regimens of Fesgo®

a Patients should be monitored for reactions related to injection and hypersensitivity reactions.

b The observation period should begin after administration of the medicinal product Phesgo® and end before any further chemotherapy is administered.

For patients receiving a taxane, the medicinal product Phesgo® should be administered prior to the taxane.

The recommended initial dose of docetaxel when used in combination with the medicinal product Phesgo® is 75 mg/m², with subsequent escalation of docetaxel dose to 100 mg/m² depending on the chosen regimen and tolerability of the initial dose. A possible recommended initial dose of docetaxel of 100 mg/m² every 3 weeks may be considered depending on the chosen regimen. If a carboplatin-based regimen is used, the recommended dose of docetaxel is 75 mg/m² continuously (without dose escalation). When used in combination with the medicinal product Phesgo® in the adjuvant setting, the recommended dose of paclitaxel is 80 mg/m² once weekly for 12 weekly cycles.

For patients receiving anthracycline-based therapy, the medicinal product Phesgo® should be administered after completion of the full course of anthracycline therapy (see section "Special precautions for use").

Metastatic breast cancer

The medicinal product Phesgo® should be administered in combination with docetaxel. Treatment with Phesgo® may continue until disease progression or until the occurrence of unmanageable toxicity, even if docetaxel treatment has been discontinued (see section "Special precautions for use").

Early breast cancer

In the neoadjuvant treatment setting, the medicinal product Phesgo® should be administered for 3–6 cycles in combination with chemotherapy as part of a complete treatment regimen for early breast cancer.

In the adjuvant treatment setting, the medicinal product Phesgo® should be administered for a total of one year (up to 18 cycles or until disease recurrence or development of unmanageable toxicity, whichever occurs first) as part of a complete treatment regimen for early breast cancer and independent of the timing of surgery. Treatment should include standard anthracycline and/or taxane-based chemotherapy. Treatment with Phesgo® should begin on day 1 of the first taxane-based cycle and continue even after discontinuation of chemotherapy.

Delayed or missed doses

If the interval between two consecutive injections is:

• less than 6 weeks, the maintenance dose of 600 mg/600 mg of Phesgo® should be administered as soon as possible. Subsequently, continue administration every 3 weeks.
• 6 weeks or more, the loading dose of 1200 mg/600 mg of Phesgo® should be re-administered, followed by the maintenance dose of 600 mg/600 mg of Phesgo® every 3 weeks.

Dose adjustment

Dose reduction of Phesgo® is not recommended. Discontinuation of treatment with Phesgo® may be necessary at the physician’s discretion.

Treatment may continue during periods of reversible myelosuppression induced by chemotherapy; however, patients should be closely monitored for complications of neutropenia during this time.

For dose adjustments of docetaxel and other chemotherapy agents, refer to the respective product information.

Transition from intravenous pertuzumab and trastuzumab to Phesgo® treatment

• If less than 6 weeks have passed since the last intravenous dose of pertuzumab and trastuzumab, Phesgo® should be administered at the maintenance dose of 600 mg pertuzumab/600 mg trastuzumab every 3 weeks for subsequent administrations.
• If 6 or more weeks have passed since the last intravenous dose of pertuzumab and trastuzumab, Phesgo® should be administered at the loading dose of 1200 mg pertuzumab/600 mg trastuzumab, followed by the maintenance dose of 600 mg pertuzumab/600 mg trastuzumab every 3 weeks for subsequent administrations.

Left ventricular dysfunction

Administration of Phesgo® should be withheld for at least 3 weeks in the event of any signs or symptoms suggestive of congestive heart failure. Use of Phesgo® should be discontinued if symptomatic heart failure is confirmed (see detailed information in section "Special precautions for use").

Patients with metastatic breast cancer

The left ventricular ejection fraction (LVEF) prior to treatment should be ≥ 50%. Administration of Phesgo® should be withheld for at least 3 weeks in the following cases:

• decrease in LVEF to < 40%;
• LVEF of 40–45% with a decline of ≥ 10 percentage points compared to the pre-treatment value.

Resumption of treatment with Phesgo® may be considered when LVEF recovers to > 45% or to 40–45% with a difference of < 10 percentage points compared to pre-treatment values.

Patients with early breast cancer

The LVEF prior to treatment should be ≥ 55% (≥ 50% after completion of anthracycline-based chemotherapy component, if applicable).

Administration of Phesgo® should be withheld for at least 3 weeks in case of a decrease in LVEF to < 50%, associated with a decline of ≥ 10 percentage points compared to pre-treatment values.

Resumption of treatment with Phesgo® may be considered when LVEF recovers to ≥ 50% or to a difference of < 10 percentage points compared to pre-treatment values.

Special patient populations

Elderly patients

No overall differences in efficacy of Phesgo® were observed between patients aged ≥ 65 and those < 65 years. Dose adjustment in patients aged ≥ 65 years is not required. Data on use in patients aged > 75 years are limited.

For information on safety assessment in elderly patients, see section "Undesirable effects".

Renal impairment

Dose adjustment of Phesgo® is not required in patients with mild or moderate renal impairment. No recommendations can be made for patients with severe renal impairment due to limited pharmacokinetic (PK) data (see section "Pharmacokinetics").

Hepatic impairment

The safety and efficacy of Phesgo® in patients with hepatic impairment have not been studied. It is unlikely that dose adjustment of Phesgo® is required in patients with hepatic impairment. No specific dosing recommendations are available (see section "Pharmacokinetics").

Method of administration

Phesgo® should only be administered as a subcutaneous injection. Phesgo® is not intended for intravenous administration.

The subcutaneous injection site should be alternated only between the left and right thigh. New injections should be administered at least 2.5 cm away from the previous injection site on healthy skin and never into areas of skin with redness, bruising, pain, or induration. The dose should not be split between two syringes or two injection sites. During treatment with Phesgo®, other subcutaneously administered drugs should preferably be administered into different sites.

The loading and maintenance doses should be administered over 8 and 5 minutes, respectively.

To monitor for injection-related reactions, an observation period of 30 minutes after completion of the loading dose and 15 minutes after completion of the maintenance dose of Phesgo® is recommended (see sections "Special precautions for use" and "Undesirable effects").

Injection-related reactions

In the event of injection-related reactions, the injection may be slowed or stopped (see sections "Special precautions for use" and "Undesirable effects"). Treatment including oxygen, beta-agonists, antihistamines, rapid intravenous fluid administration, and antipyretics may also help alleviate systemic symptoms.

Hypersensitivity reactions/anaphylaxis

The injection should be immediately and permanently discontinued in the event of a Grade 4 reaction (anaphylaxis) according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), bronchospasm, or acute respiratory distress syndrome (see sections "Special precautions for use" and "Undesirable effects").

Special precautions for disposal and handling

Prior to administration, Phesgo® should be visually inspected for the presence of particulate matter and discoloration. If particulate matter is present or discoloration is observed, the vial should be discarded according to local disposal regulations.

Do not shake the vial.

A syringe, transfer needle, and injection needle are required to withdraw the solution from the vial and administer the subcutaneous injection. Subcutaneous injections of Phesgo® can be administered using 25G–27G injection needles with a length from 3/8" (10 mm) to 5/8" (16 mm). Phesgo® is compatible with stainless steel, polypropylene, polycarbonate, polyethylene, polyurethane, polyvinyl chloride, and fluorinated ethylene propylene.

Since Phesgo® does not contain antimicrobial preservatives, the product should be used immediately from a microbiological standpoint. If not used immediately, preparation should be carried out under controlled and validated aseptic conditions. After drawing the solution into the syringe, it is recommended to replace the transfer needle with a syringe cap to prevent drying of the solution in the syringe and to maintain product quality. A peel-off sticker (the peelable part of the vial label) should be applied to the syringe. The subcutaneous injection needle should be attached to the syringe immediately before administration, with the volume adjusted to 15 mL when using Phesgo® 1200 mg/600 mg and to 10 mL when using Phesgo® 600 mg/600 mg.

Phesgo® is intended for single use only. Any unused medicinal product or waste should be disposed of in accordance with local requirements.

Children

The safety and efficacy of Phesgo® in children and adolescents (under 18 years of age) have not been established. There is insufficient experience with Phesgo® in children for the indication of breast cancer.

Overdose

The highest studied dose of Phesgo® was 1200 mg pertuzumab/600 mg trastuzumab. In case of overdose, patients should be closely monitored for signs and symptoms of adverse reactions, and appropriate symptomatic treatment should be administered.

Adverse Reactions

Summary of Safety Profile

The most common adverse reactions (≥ 30%) observed in patients treated with the medicinal product Phesgo® or intravenous pertuzumab in combination with trastuzumab and chemotherapy were alopecia, diarrhea, nausea, anemia, asthenia, and arthralgia.

The most common serious adverse reactions (≥ 1%) observed in patients treated with the medicinal product Phesgo® or intravenous pertuzumab in combination with trastuzumab were febrile neutropenia, heart failure, pyrexia, neutropenia, neutropenic sepsis, decreased neutrophil count, and pneumonia.

The safety profile of Phesgo® was generally consistent with the known safety profile of intravenous pertuzumab in combination with trastuzumab, with the additional adverse reaction of injection site reaction (15.3% vs. 0.4%).

In the pivotal study FEDERICA, the incidence of serious adverse events was similar in the group of patients receiving Phesgo® and in the group receiving intravenous pertuzumab in combination with trastuzumab. The adverse reactions listed below occurred at a higher frequency (≥ 5%) with Phesgo® compared to intravenous pertuzumab in combination with trastuzumab: alopecia – 79% vs. 73%, myalgia – 27.0% vs. 20.6%, and dyspnea – 12.1% vs. 6%.

The safety of pertuzumab in combination with trastuzumab was evaluated in 3,834 patients with HER2-positive breast cancer in the pivotal studies CLEOPATRA, NEOSPHERE, TRYPHAENA, APHINITY, and FEDERICA. Overall, the safety profile was consistent across these studies, although the frequency and most common adverse reactions varied depending on whether the pertuzumab-trastuzumab combination was administered concomitantly with other antineoplastic agents or not.

In Table 2, the first column lists adverse reactions reported in association with the use of pertuzumab in combination with trastuzumab and chemotherapy in the pivotal clinical studies described below (n = 3,834) and during post-marketing use. Because pertuzumab is used in combination with trastuzumab and chemotherapy, it is difficult to establish a causal relationship between a specific adverse reaction and a particular medicinal product. The last two columns provide information on adverse reactions observed in the group of patients who received Phesgo® in the FEDERICA study (n = 243), when Phesgo® was administered in combination with chemotherapy and as monotherapy.

• Study CLEOPATRA, in which pertuzumab was administered in combination with trastuzumab and docetaxel to patients with metastatic breast cancer (n = 453).
• Studies NEOSPHERE (n = 309) and TRYPHAENA (n = 218), in which pertuzumab was administered in the neoadjuvant setting in combination with trastuzumab and chemotherapy to patients with locally advanced, inflammatory, or early-stage breast cancer.
• Study APHINITY, in which pertuzumab was administered in the adjuvant setting in combination with trastuzumab and anthracycline-based or anthracycline-free taxane-containing chemotherapy regimens to patients with early-stage breast cancer (n = 2,364).
• Study FEDERICA, in which Phesgo® (n = 243) or intravenous pertuzumab and trastuzumab (n = 247) were initially administered in combination with chemotherapy (neoadjuvant phase), followed by monotherapy (adjuvant phase) to patients with early-stage breast cancer.

Adverse reactions are listed below by MedDRA System Organ Classes (SOC) and frequency categories:

• 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);
• Frequency not known (cannot be estimated from available data).

Within each frequency category and SOC, adverse reactions are listed in order of decreasing severity.

Table 2

Summary of adverse reactions in patients treated with pertuzumab and trastuzumab in pivotal clinical studies^, ^^ and during post-marketing use†

^ Combined data from the overall treatment period in the CLEOPATRA study (data cutoff date: 11 February 2014; median number of pertuzumab treatment cycles was 24) and the neoadjuvant phase in the NEOSPHERE study (median number of pertuzumab treatment cycles was 4 in all treatment groups) and in the TRYPHAENA study (median number of pertuzumab treatment cycles was 3–6 in treatment groups), the treatment period in the APHINITY study (median number of pertuzumab treatment cycles was 18), and the treatment period in the FEDERICA study (median number of treatment cycles with the medicinal product Phesgo® was 18).

^^ Data from the use of the medicinal product Phesgo® throughout the treatment period in the FEDERICA study (median number of treatment cycles with the medicinal product Phesgo® was 18).

* Adverse reactions reported including fatal outcomes.

** Data from the overall treatment period in 5 studies (CLEOPATRA, NEOSPHERE, TRYPHAENA, APHINITY, FEDERICA). Frequency of left ventricular dysfunction and congestive heart failure reported in individual studies, according to MedDRA preferred terms.

° MedDRA preferred terms, most commonly recorded as the medical concepts "Anaphylactic reaction" and "Infusion/injection reaction", further described in the section "Description of selected adverse reactions".

°° No cases of interstitial lung disease were observed in the FEDERICA study, but such cases have been reported with trastuzumab use.

°°° Observed only with the medicinal product Phesgo® (related to subcutaneous administration). The higher frequency observed during the adjuvant phase is associated with a longer treatment duration when Phesgo® was used as monotherapy.

† Adverse reactions reported during the post-marketing period.

Description of selected adverse reactions

Left ventricular dysfunction

Medicinal product Phesgo ®

In the pivotal FEDERICA study, the incidence of symptomatic heart failure (NYHA functional class II–IV) with a decrease in LVEF of at least 10 percentage points from baseline to < 50 % was 0.4 % in patients receiving treatment with the medicinal product Phesgo®, compared to 0 % in patients receiving intravenous pertuzumab in combination with trastuzumab during the neoadjuvant phase (concomitantly with chemotherapy). None of the patients receiving the medicinal product Phesgo® who developed symptomatic heart failure recovered by the data cutoff date, and one patient discontinued treatment with Phesgo® due to symptomatic heart failure. The incidence of symptomatic heart failure with a decrease in LVEF of at least 10 percentage points from baseline to < 50 % was similar during adjuvant therapy (when Phesgo® was used as monotherapy) and during subsequent follow-up. Asymptomatic or minimally symptomatic (NYHA functional class II) decrease in LVEF of at least 10 percentage points from baseline to < 50 % (confirmed by a second LVEF measurement) was not observed in patients receiving Phesgo® and was reported in 0.4 % of patients receiving intravenous pertuzumab and trastuzumab during neoadjuvant therapy (see sections "Dosage and administration" and "Special warnings and precautions for use"). No cases of asymptomatic or minimally symptomatic (NYHA functional class II) decrease in LVEF of at least 10 percentage points from baseline to < 50 % (confirmed by a second LVEF measurement) were observed in either group during adjuvant therapy. During subsequent follow-up, this cardiac adverse reaction was reported in 1.6 % of patients receiving Phesgo® and in 3.6 % of patients receiving intravenous pertuzumab in combination with trastuzumab.

Pertuzumab for intravenous infusion in combination with trastuzumab and chemotherapy

In the pivotal CLEOPATRA study, the incidence of left ventricular dysfunction during the study treatment was higher in the placebo group than in the pertuzumab group (8.6 % and 6.6 %, respectively). The incidence of symptomatic left ventricular dysfunction was also lower in the pertuzumab group (1.8 % in the placebo group compared to 1.5 % in the pertuzumab group) (see section "Special warnings and precautions for use").

In the neoadjuvant NEOSPHERE study, in which patients received four cycles of pertuzumab as neoadjuvant treatment, the incidence of left ventricular dysfunction (during the overall treatment period) was higher in the pertuzumab, trastuzumab, and docetaxel treatment group (7.5 %) compared to the trastuzumab and docetaxel group (1.9 %). One case of symptomatic left ventricular dysfunction occurred in the trastuzumab and docetaxel group.

In the neoadjuvant TRYPHAENA study, the incidence of left ventricular dysfunction (during the overall treatment period) was 8.3 % in the pertuzumab plus trastuzumab and FEC (5-fluorouracil, epirubicin, cyclophosphamide) group followed by pertuzumab plus trastuzumab and docetaxel; 9.3 % in the pertuzumab plus trastuzumab and docetaxel group after FEC; and 6.6 % in the pertuzumab in combination with TCH (docetaxel, carboplatin, trastuzumab) group. The incidence of symptomatic left ventricular dysfunction (congestive heart failure) was 1.3 % in the pertuzumab plus trastuzumab and docetaxel group after FEC (excluding one patient who experienced symptomatic left ventricular dysfunction during FEC treatment before pertuzumab plus trastuzumab and docetaxel), and also 1.3 % in the pertuzumab in combination with TCH group. No patient in the pertuzumab plus trastuzumab and FEC group followed by pertuzumab plus trastuzumab and docetaxel experienced symptomatic left ventricular dysfunction.

In the neoadjuvant phase of the BERENICE study, the incidence of symptomatic left ventricular dysfunction (NYHA functional class III/IV) (congestive heart failure according to NCI-CTCAE version 4) was 1.5 % in the doxorubicin and cyclophosphamide (AC) group with dose-dense administration followed by pertuzumab plus trastuzumab and paclitaxel, and 0 % in the FEC group followed by pertuzumab in combination with trastuzumab and docetaxel. The incidence of asymptomatic left ventricular dysfunction (decreased ejection fraction according to NCI-CTCAE version 4) was 7 % in the AC dose-dense group followed by pertuzumab plus trastuzumab and paclitaxel and 3.5 % in the FEC group followed by pertuzumab in combination with trastuzumab and docetaxel.

In the APHINITY study, the incidence of symptomatic left ventricular dysfunction (NYHA functional class III or IV) with a decrease in LVEF of at least 10 percentage points from baseline to < 50 % was < 1 % (0.6 % of patients receiving pertuzumab compared to 0.3 % of patients receiving placebo). Among patients who developed symptomatic heart failure, recovery occurred in 46.7 % of patients receiving pertuzumab and in 57.1 % of patients receiving placebo (defined as LVEF > 50 % on two consecutive measurements) by the data cutoff date. Most events occurred in patients receiving anthracycline treatment. Asymptomatic or minimally symptomatic decrease in LVEF (NYHA functional class II) of at least 10 percentage points from baseline to < 50 % was reported in 2.7 % of patients receiving pertuzumab and in 2.8 % of patients receiving placebo, with recovery in 79.7 % of patients in the pertuzumab group and 80.6 % in the placebo group by the data cutoff date.

Infusion/injection-related reactions

Medicinal product Phesgo ®

In the pivotal FEDERICA study, infusion/injection-related reactions were defined as any systemic reaction reported within 24 hours after administration of the medicinal product Phesgo® or intravenous pertuzumab in combination with trastuzumab (see sections "Dosage and administration" and "Special warnings and precautions for use").

Injection-related reactions were reported in 0.4 % of patients receiving treatment with the medicinal product Phesgo®, while infusion-related reactions were reported in 10.7 % of patients receiving intravenous pertuzumab and trastuzumab during neoadjuvant therapy. During adjuvant therapy, no injection-related reactions were reported in patients receiving Phesgo®, while infusion-related reactions were reported in 1.6 % of patients receiving intravenous pertuzumab and trastuzumab. In most cases, the infusion/injection-related reactions observed with Phesgo® or intravenous pertuzumab in combination with trastuzumab were chills, nausea, or vomiting.

Injection site reactions, defined as any local reaction reported within 24 hours after administration of the medicinal product Phesgo®, were reported in 6.9 % and 12.9 % of patients receiving Phesgo® during neoadjuvant and adjuvant therapy, respectively; these cases were of grade 1 or 2 severity. In most cases, the local reactions observed with Phesgo® were injection site pain or erythema.

Pertuzumab for intravenous infusion in combination with trastuzumab and chemotherapy

Infusion-related reactions were defined in the pivotal studies as any hypersensitivity, anaphylactic reaction, acute infusion reaction, or cytokine release syndrome occurring during or on the day of infusion. In the pivotal CLEOPATRA study, the initial dose of pertuzumab was administered one day before trastuzumab and docetaxel to monitor for reactions associated with pertuzumab administration. On the first day, when only pertuzumab was administered, the overall incidence of infusion-related reactions was 9.8 % in the placebo group and 13.2 % in the pertuzumab group, with most reactions being mild or moderate in severity. The most common infusion-related reactions (≥ 1.0 %) in the pertuzumab group were fever, chills, fatigue, headache, asthenia, hypersensitivity, and vomiting.

During the second cycle, when all medicinal products were administered on the same day, the most common infusion-related reactions (≥ 1.0 %) in the pertuzumab group were fatigue, drug hypersensitivity, taste alteration, hypersensitivity, myalgia, and vomiting (see section "Special warnings and precautions for use").

In the neoadjuvant and adjuvant studies, pertuzumab was administered on the same day as other study treatments. 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 the CLEOPATRA study, with most reactions being mild or moderate in severity.

Hypersensitivity/anaphylaxis reactions

Medicinal product Phesgo ®

In the pivotal FEDERICA study, the overall incidence of hypersensitivity/anaphylaxis events related to anti-HER2 therapy was 1.2 % in patients receiving treatment with the medicinal product Phesgo®, compared to 0.8 % in patients receiving intravenous pertuzumab in combination with trastuzumab, with none of the events being grade 3–4 according to NCI-CTCAE (version 4.0) (see section "Special warnings and precautions for use"). One patient experienced a hypersensitivity/anaphylaxis event during or immediately after administration of Phesgo® during the first cycle, leading to premature discontinuation of therapy (see sections "Dosage and administration" and "Special warnings and precautions for use").

During neoadjuvant therapy, drug hypersensitivity was reported in 0.4 % of patients receiving Phesgo® and in 0.4 % of patients receiving intravenous pertuzumab in combination with trastuzumab. During adjuvant therapy, drug hypersensitivity was reported in 0.4 % of patients receiving Phesgo®, and no cases were reported in patients receiving intravenous pertuzumab in combination with trastuzumab.

Pertuzumab for intravenous infusion in combination with trastuzumab and chemotherapy

In the pivotal CLEOPATRA study in metastatic breast cancer, the overall investigator-reported incidence of hypersensitivity/anaphylaxis events during the entire treatment period was 9.3 % in the placebo group and 11.3 % in the pertuzumab group, of which 2.5 % and 2.0 % were grade 3–4 according to NCI-CTCAE, respectively. Overall, two patients in the placebo group and four patients in the pertuzumab group experienced events described by investigators as anaphylaxis (see section "Special warnings and precautions for use").

Most hypersensitivity reactions were mild or moderate in severity and resolved with treatment. Most reactions were considered secondary to docetaxel infusions based on treatment modifications.

In the neoadjuvant and adjuvant studies, hypersensitivity/anaphylaxis events were consistent with those observed in the CLEOPATRA study. In the NEOSPHERE study, anaphylaxis occurred in two patients in the pertuzumab and docetaxel treatment group. In both TRYPHAENA and APHINITY studies, the overall incidence of hypersensitivity/anaphylaxis was highest in the pertuzumab and TCH group (13.2 % and 7.6 %, respectively), of which 2.6 % and 1.3 % of events were grade 3–4 according to NCI-CTCAE.

Febrile neutropenia

Medicinal product Phesgo ®

In the pivotal FEDERICA study, febrile neutropenia (grade 3 or 4) occurred in 6.6 % of patients receiving treatment with the medicinal product Phesgo® and in 5.6 % of patients receiving intravenous pertuzumab in combination with trastuzumab during neoadjuvant therapy. No cases of febrile neutropenia (grade 3 or 4) were reported during adjuvant therapy.

As in the pivotal intravenous pertuzumab and trastuzumab studies, a higher incidence of febrile neutropenia (grade 3 or 4) was observed in Asian patients receiving intravenous pertuzumab and trastuzumab (13.0 %); similarly, the incidence of febrile neutropenia in Asian patients receiving Phesgo® was also highest (13.7 %) during neoadjuvant therapy. During adjuvant therapy, no cases of febrile neutropenia (grade 3 or 4) were reported in any patient group.

Pertuzumab for intravenous infusion in combination with trastuzumab and chemotherapy

In the pivotal CLEOPATRA study, most patients in both treatment groups experienced at least one event of leukopenia (63.0 % in the pertuzumab group and 58.3 % in the placebo group), with neutropenia being the most common (see section "Special warnings and precautions for use"). Febrile neutropenia occurred in 13.7 % of patients in the pertuzumab group and in 7.6 % of patients in the placebo group. In both treatment groups, the proportion of patients experiencing febrile neutropenia was highest during the first treatment cycle and decreased steadily thereafter. Increased incidence of febrile neutropenia was observed in Asian patients in both treatment groups compared to patients of other races and from other geographic regions. Among Asian patients, the incidence of febrile neutropenia was higher in those receiving pertuzumab (25.8 %) compared to the placebo group (11.3 %).

In the NEOSPHERE study, febrile neutropenia occurred in 8.4 % of patients receiving neoadjuvant pertuzumab, trastuzumab, and docetaxel, compared to 7.5 % of patients receiving trastuzumab and docetaxel. In the TRYPHAENA study, febrile neutropenia occurred in 17.1 % of patients receiving neoadjuvant pertuzumab + TCH and in 9.3 % of patients receiving neoadjuvant pertuzumab, trastuzumab, and docetaxel after FEC. In the TRYPHAENA study, the incidence of febrile neutropenia was higher in patients who received six cycles of pertuzumab compared to those who received three cycles, regardless of chemotherapy use. As in the CLEOPATRA study, higher incidences of neutropenia and febrile neutropenia were observed in Asian patients compared to other patients in both neoadjuvant studies. In the NEOSPHERE study, febrile neutropenia occurred in 8.3 % of Asian patients receiving neoadjuvant pertuzumab, trastuzumab, and docetaxel, compared to 4.0 % of Asian patients receiving neoadjuvant trastuzumab and docetaxel.

In the APHINITY study, febrile neutropenia occurred in 12.1 % of patients receiving pertuzumab and in 11.1 % of patients receiving placebo. As in the CLEOPATRA, TRYPHAENA, and NEOSPHERE studies, a higher incidence of febrile neutropenia was observed in Asian patients receiving pertuzumab compared to patients of other races in the APHINITY study (15.9 % of patients receiving pertuzumab and 9.9 % of placebo group patients).

Diarrhea

Medicinal product Phesgo ®

In the pivotal FEDERICA study, during neoadjuvant therapy, diarrhea occurred in 60.5 % of patients receiving treatment with the medicinal product Phesgo® and in 54.8 % of patients receiving intravenous pertuzumab in combination with trastuzumab. Diarrhea ≥ grade 3 was reported in 6.6 % of patients in the Phesgo® treatment group compared to 4.0 % of patients receiving intravenous pertuzumab in combination with trastuzumab (see section "Special warnings and precautions for use").

During adjuvant therapy, diarrhea occurred in 17.7 % of patients receiving Phesgo® and in 20.6 % of patients receiving intravenous pertuzumab in combination with trastuzumab. Diarrhea ≥ grade 3 was reported in 0 % of patients receiving Phesgo® compared to 1.2 % of patients receiving intravenous pertuzumab in combination with trastuzumab.

Pertuzumab for intravenous infusion in combination with trastuzumab and chemotherapy

In the pivotal CLEOPATRA study in metastatic breast cancer, diarrhea occurred in 68.4 % of patients receiving pertuzumab and in 48.7 % of patients receiving placebo (see section "Special warnings and precautions for use"). Most events were mild or moderate in severity and occurred during the first few treatment cycles. The incidence of grade 3–4 diarrhea according to NCI-CTCAE was 9.3 % in patients receiving pertuzumab compared to 5.1 % in the placebo group. The median duration of the longest episode was 18 days in patients receiving pertuzumab and 8 days in the placebo group. Diarrhea responded well to proactive treatment with antidiarrheal medicinal products.

In the NEOSPHERE study, diarrhea occurred in 45.8 % of patients receiving neoadjuvant pertuzumab, trastuzumab, and docetaxel, compared to 33.6 % of patients receiving trastuzumab and docetaxel. In the TRYPHAENA study, diarrhea occurred in 72.3 % of patients receiving neoadjuvant pertuzumab + TCH and in 61.4 % of patients receiving neoadjuvant pertuzumab, trastuzumab, and docetaxel after FEC. In both studies, most events were mild or moderate in severity.

In the APHINITY study, a higher incidence of diarrhea was reported in the pertuzumab group (71.2 %) compared to the placebo group (45.2 %). Diarrhea ≥ grade 3 was reported in 9.8 % of patients in the pertuzumab group compared to 3.7 % in the placebo group. Most reported events were grade 1 or 2. The highest incidence of diarrhea (all grades) was observed during targeted therapy + taxane chemotherapy (61.4 % of patients in the pertuzumab group compared to 33.8 % in the placebo group). The incidence of diarrhea was much lower after chemotherapy discontinuation, at 18.1 % in the pertuzumab group compared to 9.2 % in the placebo group during post-chemotherapy targeted therapy.

Rash

Medicinal product Phesgo ®

In the pivotal FEDERICA study, rash occurred in 10.7 % of patients receiving treatment with the medicinal product Phesgo® and in 15.5 % of patients receiving intravenous pertuzumab in combination with trastuzumab during neoadjuvant therapy. During adjuvant therapy, rash was reported in 8.2 % of patients receiving Phesgo® and in 8.7 % of patients receiving intravenous pertuzumab in combination with trastuzumab. In most cases, rashes were grade 1 or 2 in severity.

Pertuzumab for intravenous infusion in combination with trastuzumab and chemotherapy

In the pivotal CLEOPATRA study in metastatic breast cancer, rash occurred in 51.7 % of patients receiving pertuzumab compared to 38.9 % in the placebo group. Most events were grade 1 or 2 in severity, occurred during the first two cycles, and responded to standard therapy, including topical or oral acne treatment.

In the NEOSPHERE study, rash occurred in 40.2 % of patients receiving neoadjuvant pertuzumab, trastuzumab, and docetaxel, compared to 29.0 % of patients receiving trastuzumab and docetaxel. In the TRYPHAENA study, rash occurred in 36.8 % of patients receiving neoadjuvant pertuzumab + TCH and in 20.0 % of patients receiving neoadjuvant pertuzumab, trastuzumab, and docetaxel after FEC. The incidence of rash was higher in patients who received six cycles of pertuzumab compared to those who received three cycles, regardless of chemotherapy use.

In the APHINITY study, rash as an adverse reaction occurred in 25.8 % of patients in the pertuzumab group compared to 20.3 % in the placebo group. In most cases, rashes were grade 1 or 2 in severity.

Laboratory abnormalities

Medicinal product Phesgo ®

In the pivotal FEDERICA study, the incidence of grade 3–4 neutropenia according to NCI-CTCAE version 4 was comparable between the two treatment groups (13.6 % in patients receiving Phesgo® and 13.9 % in patients receiving intravenous pertuzumab in combination with trastuzumab) during neoadjuvant therapy and significantly lower during adjuvant therapy (0.8 % of patients receiving Phesgo® and 0 % of patients receiving intravenous pertuzumab in combination with trastuzumab).

Pertuzumab for intravenous infusion in combination with trastuzumab and chemotherapy

In the pivotal CLEOPATRA study in metastatic breast cancer, the incidence of grade 3–4 neutropenia according to NCI-CTCAE version 3 was comparable between the two treatment groups (86.3 % in the pertuzumab group and 86.6 % in the placebo group, including 60.7 % and 64.8 % of grade 4 neutropenia cases, respectively).

In the NEOSPHERE study, the incidence of grade 3–4 neutropenia according to NCI-CTCAE version 3 was 74.5 % in patients receiving neoadjuvant pertuzumab, trastuzumab, and docetaxel compared to 84.5 % in patients receiving trastuzumab and docetaxel, including 50.9 % and 60.2 % of grade 4 neutropenia cases, respectively. In the TRYPHAENA study, the incidence of grade 3–4 neutropenia according to NCI-CTCAE version 3 was 85.3 % in patients receiving neoadjuvant pertuzumab + TCH and 77.0 % in patients receiving neoadjuvant pertuzumab, trastuzumab, and docetaxel after FEC, including 66.7 % and 59.5 % of grade 4 neutropenia cases, respectively.

In the APHINITY study, the incidence of grade 3–4 neutropenia according to NCI-CTCAE version 4 was 40.6 % in patients receiving pertuzumab, trastuzumab, and chemotherapy compared to 39.1 % in patients receiving placebo, trastuzumab, and chemotherapy, including 28.3 % and 26.5 % of grade 4 neutropenia cases, respectively.

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity to pertuzumab and trastuzumab in patients receiving treatment with the medicinal product Phesgo®.

In the FEDERICA study, the incidence of treatment-emergent antibodies to pertuzumab and trastuzumab was 10.6 % (26/245) and 0.4 % (1/245), respectively, in patients receiving intravenous pertuzumab and trastuzumab. Neutralizing antibodies to pertuzumab were detected in three of the patients with antibodies to pertuzumab.

The incidence of treatment-emergent antibodies to pertuzumab, trastuzumab, and hyaluronidase alfa was 12.9 % (31/241), 2.1 % (5/241), and 6.3 % (15/238), respectively, in patients receiving treatment with the medicinal product Phesgo®. Among these patients, neutralizing antibodies to pertuzumab were detected in two and neutralizing antibodies to trastuzumab in one.

The clinical significance of antibody formation to pertuzumab, trastuzumab, or hyaluronidase alfa after treatment with Phesgo® is unknown.

Switching from intravenous pertuzumab and trastuzumab to Phesgo® (or vice versa)

The safety of switching from intravenous pertuzumab and trastuzumab to subcutaneous Phesgo® (Group A) and vice versa (Group B) was evaluated in study MO40628. The primary objective of this study was to assess patient preference for Phesgo®.

In Group A patients, the incidence of adverse events during cycles 1–3 (intravenous treatment) was 77.5 % (62/80 patients) compared to 72.5 % (58/80 patients) during cycles 4–6 (subcutaneous treatment). In Group B patients, the incidence of AEs during cycles 1–3 (subcutaneous treatment) was 77.5 % (62/80 patients) compared to 63.8 % (51/80 patients) during cycles 4–6 (intravenous treatment), primarily due to a higher incidence of injection site reactions (all grade 1 or 2) during Phesgo® administration. The incidence of serious adverse events, grade 3 adverse events, and discontinuation due to adverse events before switching to Phesgo® (cycles 1–3) was low (< 6 %) and similar after switching (cycles 4–6).

No adverse events of grade 4 or 5 severity were reported.

Patients of advanced age

In the FEDERICA study, overall, no differences in safety of the medicinal product Phesgo® were observed between patients aged ≥ 65 and < 65 years.

However, in the pivotal clinical studies of intravenous pertuzumab in combination with trastuzumab, decreased appetite, anemia, weight loss, asthenia, taste alteration, peripheral neuropathy, hypomagnesemia, and diarrhea occurred at a frequency ≥ 5 % higher in patients aged ≥ 65 years (n = 418) compared to patients aged < 65 years (n = 2926).

There are limited clinical trial data in patients aged > 75 years receiving the medicinal product Phesgo® or intravenous pertuzumab in combination with trastuzumab. Post-marketing data showed no difference in safety of pertuzumab in combination with trastuzumab between patients aged ≥ 65 and < 65 years.

Reporting of suspected adverse reactions after medicinal product authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua

Incompatibility.

The medicinal product Phesgo® is a ready-to-use solution and should not be mixed or diluted with other medicinal products.

Shelf life.

18 months.

Storage conditions.

Store at 2 to 8 °C in the original packaging to protect from light. Do not freeze. Do not shake. Keep out of reach of children.

Packaging.

Pertuzumab 600 mg and trastuzumab 600 mg in 10 mL: a 15 mL vial made of colorless glass (borosilicate glass, class I), stoppered with a butyl rubber stopper (laminated with fluororubber film) and sealed with an aluminum cap with an orange "flip-off" plastic disc. One vial per cardboard box.

Pertuzumab 1200 mg and trastuzumab 600 mg in 15 mL: a 20 mL vial made of colorless glass (borosilicate glass, class I), stoppered with a butyl rubber stopper (laminated with fluororubber film) and sealed with an aluminum cap with a cold green "flip-off" plastic disc. One vial per cardboard box.

Prescription category.

Prescription only.

Manufacturer.

F. Hoffmann-La Roche Ltd

Manufacturer's address and location of operations.

Wurmisweg, 4303 Kaiseraugst, Switzerland