Special Warning : אזהרת שימוש

5          WARNINGS AND PRECAUTIONS

5.1         Left Ventricular Dysfunction
Left ventricular cardiac dysfunction can occur with MARGENZA. In SOPHIA, left ventricular dysfunction occurred in 1.9% of patients treated with MARGENZA. MARGENZA has not been studied in patients with a pretreatment LVEF value of < 50%, a prior history of myocardial infarction or unstable angina within 6 months, or congestive heart failure NYHA class II-IV.

Withhold MARGENZA for ≥ 16% absolute decrease in LVEF from pretreatment values or LVEF value below institutional limits of normal (or 50% if no limits are available) and ≥ 10% absolute decrease in LVEF from pretreatment values. Permanently discontinue MARGENZA if LVEF decline persists for greater than 8 weeks, or if dosing is interrupted on greater than 3 occasions due to LVEF decline [see Dosage and Administration (2.2)].

Cardiac Monitoring

Conduct thorough cardiac assessment, including history, physical examination, and determination of LVEF by echocardiogram or MUGA scan. The following schedule is recommended:

•   Baseline LVEF measurement within 4 weeks prior to initiation of MARGENZA •   LVEF measurements (MUGA/echocardiogram) every 3 months during and upon completion of MARGENZA
•   Repeat LVEF measurement at 4-week intervals if MARGENZA is withheld for significant left ventricular cardiac dysfunction [see Dosage and Administration (2.2)].
5.2         Embryo-Fetal Toxicity

Based on findings in animals and mechanism of action, MARGENZA can cause fetal harm when administered to a pregnant woman. There are no available data on the use of MARGENZA in pregnant women to inform the drug-associated risk. In post-marketing reports, use of a HER2- directed antibody during pregnancy resulted in cases of oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities and neonatal death. In an animal reproduction study, intravenous administration of margetuximab-cmkb to pregnant cynomolgus monkeys once every 3 weeks starting at gestational day (GD) 20 until delivery resulted in oligohydramnios and delayed infant kidney development. Animal exposures were ≥ 3 times the human exposures at the recommended dose, based on Cmax.

Verify pregnancy status of females of reproductive potential prior to initiation of MARGENZA.
Advise pregnant women and females of reproductive potential that exposure to MARGENZA during pregnancy or within 4 months prior to conception can result in fetal harm. Advise females of reproductive potential to use effective contraception during treatment and for 4 months following the last dose of MARGENZA [see Use in Specific Populations (8.1, 8.3)].

5.3         Infusion-Related Reactions

MARGENZA can cause infusion-related reactions (IRRs) [see Adverse Reactions (6.1)].
Symptoms may include fever, chills, arthralgia, cough, dizziness, fatigue, nausea, vomiting, headache, diaphoresis, tachycardia, hypotension, pruritus, rash, urticaria, and dyspnea.

In SOPHIA, IRRs were reported by 13% of patients on MARGENZA plus chemotherapy. Most of the IRRs occur during Cycle 1. Grade 3 IRRs were reported in 1.5% of MARGENZA-treated patients. All IRRs resolved within 24 hours, irrespective of severity. In SOPHIA, IRRs leading to interruption of treatment occurred in 9% of patients treated with MARGENZA and chemotherapy. One patient (0.4%) on MARGENZA discontinued treatment due to IRR.

An infusion substudy in 88 patients in SOPHIA evaluated MARGENZA administered over 120 minutes for the initial dose, then 30 minutes from Cycle 2 forward. IRRs were ≤ Grade 2 and most occurred during the first (120 minutes) administration of MARGENZA. From Cycle 2 onward, one patient (1.1%) had an IRR (Grade 1).

Monitor patients for IRRs during MARGENZA administration and as clinically indicated after completion of infusion. Have medications and emergency equipment to treat IRRs available for immediate use. Monitor patients carefully until resolution of signs and symptoms.

In patients who experience mild or moderate IRRs, consider premedications, including antihistamines, corticosteroids, and antipyretics. Decrease the rate of infusion for mild or moderate IRRs. Interrupt MARGENZA infusion in patients experiencing dyspnea or clinically significant hypotension and intervene with medical therapy which may include epinephrine, corticosteroids, diphenhydramine, bronchodilators and oxygen. Patients should be evaluated and carefully monitored until complete resolution of signs and symptoms. Permanently discontinue MARGENZA in all patients with severe or life-threatening IRRs.

5.4         Effects on Ability to Drive and Use Machines

Margenza has a minor influence on the ability to drive or use machines. Dizziness and somnolence may occur during treatment with Margenza. Patients experiencing infusion-related symptoms should be advised not to drive and use machines until symptoms abate.

6         ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the SPC: •   Left Ventricular Dysfunction [see Warnings and Precautions (5.1)] •   Embryo-Fetal Toxicity [see Warnings and Precautions (5.2)]
•   Infusion-Related Reactions [see Warnings and Precautions (5.3)] Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important.
It allows continued monitoring of the benefit/risk balance of the medicinal product.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il/ and emailed to the Registration Holder’s Patient Safety Unit at: drugsafety@neopharmgroup.com


6.1          Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect rates observed in practice.

The safety of MARGENZA was evaluated in HER2-positive breast cancer patients who received two or more prior anti-HER2 regimens in SOPHIA [see Clinical Studies (14.1)].

Patients were randomized (1:1) to receive either MARGENZA 15 mg/kg every 3 weeks plus chemotherapy or trastuzumab plus chemotherapy. Among patients who received MARGENZA, 40% were exposed for 6 months or longer and 11% were exposed for greater than one year.

Serious adverse reactions occurred in 16% of patients who received MARGENZA. Serious adverse reactions in > 1% of patients included febrile neutropenia (1.5%), neutropenia/neutrophil count decrease (1.5%) and infusion related reactions (1.1%). Fatal adverse reactions occurred in 1.1% of patients who received MARGENZA, including viral pneumonia (0.8%) and aspiration pneumonia (0.4%).

Permanent discontinuation due to an adverse reaction occurred in 3% of patients who received MARGENZA. Adverse reactions which resulted in permanent discontinuation in > 1% of patients who received MARGENZA included left ventricular dysfunction and infusion-related reactions.

Dosage interruptions due to an adverse reaction occurred in 11% of patients who received MARGENZA. Adverse reactions which required dosage interruption in > 5% of patients who received MARGENZA included infusion-related reactions.

Table 1 summarizes the adverse reactions in SOPHIA.
Table 1                    Adverse Reactions (>10%) in Patients with Metastatic HER2-Positive Breast Cancer Who Received MARGENZA in SOPHIA
Adverse Reaction              MARGENZA + Chemotherapy                    Trastuzumab + Chemotherapy (n = 264)                                     (n = 266)
All Grades           Grade 3 or 4          All Grades          Grade 3 or 4 (%)                 (%)                    (%)                (%)
General disorders and administration site conditions
Fatigue/Asthenia                   57                    7                   47                   4.5 Pyrexia                            19                   0.4                  14                   0.4 Gastrointestinal disorders
Nausea                            33                    1.1                  32                   0.4 Diarrhea                          25                    2.3                  25                   2.3 Vomiting                          21                    0.8                  14                   1.5 Constipation                      19                    0.8                  17                   0.8 Abdominal paina                   17                    1.5                  21                   1.5 Skin and Subcutaneous tissue
Alopecia                          18                     0                   15                    0 Palmar-plantar                    13                     0                   15                    3 erythrodysesthesia
Nervous System Disorders
Headacheb                         19                     0                   16                    0 c
Peripheral neuropathy             16                    1.1                  15                   2.3 Respiratory, thoracic and mediastinal disorders
Cough                             14                    0.4                  12                    0 Dyspnea                           13                    1.1                  11                   2.3 Metabolism and nutrition disorders
Decreased appetite                14                    0.4                  14                   0.4 Musculoskeletal and connective tissue disorders
Arthralgia/Myalgia                14                    0.4                  12                   0.8 Extremity pain                    11                    0.8                  9                     0 Injury, poisoning and procedural complications
Infusion-related reaction         13                    1.5                   3                    0 a     Includes abdominal pain, abdominal discomfort, lower abdominal pain and upper abdominal pain b     Includes headache and migraine c     Includes peripheral neuropathy, peripheral sensory neuropathy, peripheral motor neuropathy, and neuropathy 

Clinically relevant adverse reactions in ≤10% of patients who received MARGENZA in combination with chemotherapy included: dizziness and stomatitis (10%) each, decreased weight, dysgeusia, rash, and insomnia (6%) each, hypertension (5%), and syncope (1.5%).

Table 2 summarizes the laboratory abnormalities in SOPHIA.
Table 2                     Select Laboratory Abnormalities (>20%) That Worsened from Baseline in Patients with Metastatic HER2-Positive Breast Cancer
Who Received MARGENZA in SOPHIA
Laboratory Abnormality              MARGENZA + Chemotherapy1                    Trastuzumab + Chemotherapy1 All Grades (%)       Grade 3 or 4 (%)       All Grades (%)       Grade 3 or 4 (%) 
Hematology
Decreased hemoglobin                     52                   3.2                    43                    2.4 
Decreased leukocytes                     40                    5                     36                    3.2 Decreased neutrophils                    34                    9                     28                    9 Increased aPTT                           32                   3.4                    34                    4.3 Decreased lymphocytes                    31                   4.4                    38                    4.4 Increased INR                            24                   1.2                    25                    0.4 Chemistry
Increased creatinine                     68                   0.4                    60                    0 Increased ALT                            32                    2                     30                    0.8 Increased lipase                         30                    6                     24                    3.2 Increased AST                            23                    2                     22                    0.8 Increased alkaline phosphatase           21                    0                     23                    0.8 1
The denominator used to calculate the rate varied from 229 to 253 based on the number of patients with a baseline value and at least one post-treatment value.
aPTT: activated partial thromboplastin time; INR: prothrombin international normalized ratio; ALT: alanine aminotransferase; AST: aspartate aminotransferase


6.2              Immunogenicity
As with all therapeutic proteins, there is potential for immunogenicity with MARGENZA. The detection of antibody formation is highly dependent on assay sensitivity and specificity.
Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to MARGENZA in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

In SOPHIA, samples were obtained from patients on MARGENZA for immunogenicity testing at baseline, every 2 cycles, and at end of study therapy. All patients enrolled in SOPHIA received trastuzumab previously, and treatment-emergent anti-margetuximab antibodies were observed in 4 patients (1.7%). Of these 4 patients, anti-margetuximab antibodies were detected prior to Cycle
7 of MARGENZA dosing in 1 patient, and more than 2 months after the last MARGENZA dose in 3 patients. In the infusion substudy, treatment-emergent anti-margetuximab antibodies were observed in 2 patients (3.8%). Of these 2 patients, anti-margetuximab antibodies were detected prior to Cycle 3 of MARGENZA dosing in 1 patient, and more than 6 months after the last MARGENZA dose in 1 patient. Due to the limited number of patients who developed anti- margetuximab antibodies during treatment with MARGENZA, the impact of anti-margetuximab antibodies on the PK, safety and efficacy of MARGENZA is unknown.

Effects on Driving