Phesgo 600 mg Subcutaneous Injection

Early Breast Cancer (EBC) Phesgo is indicated in combination with chemotherapy for the:

• neoadjuvant treatment of 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
• adjuvant treatment of patients with HER2-positive early breast cancer at high risk of recurrence.

Metastatic Breast Cancer (MBC) Phesgo is indicated in combination with docetaxel for 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.

Method of Administration 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. Patients currently receiving intravenous pertuzumab and trastuzumab can switch to Phesgo. Switching treatment from intravenous pertuzumab and trastuzumab to Phesgo (or vice versa) was investigated in study MO40628 (see 4.8 Undesirable Effects and Clinical / Efficacy Studies) 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 1

Table 1: Phesgo recommended dosing and administration

a Patients should be observed for injection-related and hypersensitivity reactions b Observation period should start following administration of Phesgo and be completed prior to any subsequent administration of chemotherapy

In patients receiving intravenous pertuzumab and trastuzumab with < 6 weeks since their last dose, Phesgo should be administered as a maintenance dose of 600 mg pertuzumab/600 mg trastuzumab and every 3 weeks for subsequent administrations. In patients receiving intravenous pertuzumab and trastuzumab with u2265 6 weeks since their last dose, Phesgo should be administered as a loading dose of 1200 mg pertuzumab/600 mg trastuzumab, followed by a maintenance dose of 600 mg pertuzumab/600 mg trastuzumab every 3 weeks for subsequent administrations. 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 Clinical/ Efficacy Studies). 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 Clinical/Efficacy Studies). 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-adminstered 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 4.4 Special warnings and Precautions).

Hypersensitivity/anaphylaxis The injection should be discontinued immediately and permanently if the patient experiences a serious hypersensitivity reaction (e.g. anaphylaxis) (see 4.4 Special warnings and Precautions).

Left ventricular dysfunction See 4.4 Special warnings and 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 u226565 years of age (see Geriatric Use and Pharmacokinetics in Special populations). 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 u226565 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

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 Pharmacokinetics in special populations).

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 Pharmacokinetics in Special populations).

Phesgo is contraindicated in patients with a known hypersensitivity to pertuzumab, trastuzumab or any of the excipients. (see section 6.1)

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 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.

Sugar Phesgo contains sucrose. Patients with the rare hereditary conditions of sucrose intolerance e.g. galactosaemia, Lapp lactase deficiency, glucose-galactose malabsorption or fructose intolerance should not take Phesgo. Phesgo contains sucrose which may have an effect on the glycaemic control of patients with diabetes mellitus.

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 4.8 Undesirable effects). 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 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 2 below). If the LVEF declines as indicated in Table 2 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.

Table 2: Dose recommendations for left ventricular dysfunction

Early Breast Cancer u2265 55%b ~12 weeks (once during neoadjuvant therapy) <50% with a fall of u226510%-points below pre-treatment value Either u2265 50% < 10%- points below pretreatment value

a based on intravenous pertuzumab data (CLEOPATRA study) b for patients receiving anthracycline-based chemotherapy, a LVEF of u2265 50% is required after completion of anthracyclines, before starting Phesgo.

febrile/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 2.2 Dosage and 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 4.8 Undesirable effects). 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 4.3 Contraindications).

No formal drug-drug interaction studies have been performed.

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 coadministered 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-u03b1 hydroxylpaclitaxel, 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.

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. 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.

Breastfeeding 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.

Fertility No specific fertility studies in animals have been performed to evaluate the effects of Phesgo.

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.

Labour and Delivery The safe use of Phesgo during labor and delivery has not been established.

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 4.4 Special warnings and Precautions and 4.8 Undesirable effects).

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 (u22655%) adverse drug reactions (ADRs) reported in patients treated with Phesgo or intravenous pertuzumab in combination with trastuzumab were, injection site reaction, infusion-related reactions, asthenia, fatigue, rash, ejection fraction decreased, and anemia. The most common (u22651%) 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 (u22655%) with Phesgo compared to intravenous pertuzumab in combination with trastuzumab [64]: 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 3 presents ADRs that have been reported in association with the use of pertuzumab, trastuzumab and chemotherapy in the pivotal clinical trials and in the postmarketing 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 (u22651/10), common (u22651/100 to <1/10), uncommon (u22651/1,000 to <1/100), rare (u22651/10,000 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.

Table 3: Summary of adverse drug reactions reported from the pertuzumab, trastuzumab pivotal trials and in and in the post-marketing setting a

ADR (MedDRA Preferred Term) System Organ Class Pertuzumab + trastuzumab + chemotherapy b Frequency rate % Frequency category All Grades % Grades 3-4 % Blood and lymphatic system disorders Neutropenia 31.4 24.2 Very common Anemia 24.8 5.7 Very common Febrile neutropenia d 11.9 11.8 Very common Leukopenia 10.8 6.1 Very common Cardiac disorders Left ventricular dysfunction e 1.4 0.3 Common Cardiac failure congestive e 0.1 <0.1 Uncommon Eye disorders Lacrimation increased 12.1 - Very common Gastrointestinal disorders Diarrhea 67.9 8.9 Very common Nausea 60.8 1.9 Very common Vomiting 30.0 1.7 Very common Stomatitis 24.9 1.6 Very common Constipation 24.5 0.4 Very common Dyspepsia 13.2 <0.1 Very common Abdominal pain 11.7 0.4 Very common General disorders and administration site conditions Fatigue 44.3 3.3 Very common Mucosal inflammation 23.2 1.5 Very common Asthenia 20.9 1.5 Very common Pyrexia 18.9 0.6 Very common Edema peripheral 16.2 <0.1 Very common Injection site reactions f 12.9 0 Very common Immune system disorders Hypersensitivity 3.3 0.4 Common Drug hypersensitivity 2.5 0.4 Common Infections and infestations Nasopharyngitis 12.8 <0.1 Very common Upper respiratory tract infection 9.5 0.3 Common Paronychia 3.9 <0.1 Common Metabolism and nutrition disorders Decreased appetite 23.1 0.8 Very common Tumor lysis syndrome g Unknown Musculoskeletal and connective tissue disorders Arthralgia 24.6 0.7 Very common Myalgia 24.3 0.8 Very common Pain in extremity 10.0 0.2 Very common Nervous system disorders Dysgeusia 22.7 <0.1 Very common Headache 21.8 0.4 Very common Peripheral sensory neuropathy 15.7 0.5 Very common Neuropathy peripheral 14.7 0.7 Very common Dizziness 11.2 0.1 Very common Paraesthesia 10.2 0.4 Very common Psychiatric disorders Insomnia 15.9 0.2 Very common Respiratory, thoracic and mediastinal disorders Epistaxis 15.6 <0.1 Very common Cough 15.5 <0.1 Very common Dyspnea 11.5 0.5 Very common Pleural effusion 0.9 <0.1 Uncommon Skin and subcutaneous tissue disorders Alopecia 63.1 <0.1 Very common Rash 26.4 0.5 Very common Nail disorder 12.9 0.3 Very common Pruritus 12.9 <0.1 Very common Dry skin 11.7 <0.1 Very common Vascular disorders Hot flush 15.7 0.1 Very common

a Table 3 shows pooled data from the overall treatment period in CLEOPATRA; from the neoadjuvant treatment period in NEOSPHERE and TRYPHAENA; and from the treatment period of APHINITY). Additionally, Table 3 shows an ADR specific to the Phesgo route of administration that has been reported in FEDERICA.

b In NEOSPHERE, 108 patients received pertuzumab + trastuzumab alone without docetaxel and 94 patients received pertuzumab + docetaxel without trastuzumab.

c In this table this denotes an adverse reaction that has been reported in association with a fatal outcome.

d The incidence of left ventricular dysfunction and cardiac failure congestive reflect the MedDRA preferred terms reported in the individual studies.

e observed with Phesgo only.

f identified in the postmarketing setting.

Description of selected adverse drug reactions from clinical trials 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 4.4 Special warnings & 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.

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