VYLOY Powder for concentrate for solution for infusion Ref.[112792] Active ingredients: Zolbetuximab

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Hypersensitivity reactions

Hypersensitivity reactions, including anaphylactic reaction and drug hypersensitivity, occurred in patients treated with zolbetuximab in combination with fluoropyrimidine and platinum-containing chemotherapy during clinical studies (see section 4.8). Patients should be monitored during and after infusion with zolbetuximab (at least 2 hours, or longer if clinically indicated) for hypersensitivity reactions with symptoms and signs that are highly suggestive of anaphylaxis (urticaria, repetitive cough, wheeze and throat tightness/change in voice).

Hypersensitivity reactions should be managed according to the dose modifications as recommended in Table 2.

Infusion-related reactions

Infusion-related reactions (IRRs) have occurred during clinical studies with zolbetuximab in combination with fluoropyrimidine and platinum-containing chemotherapy (see section 4.8).

Patients should be monitored for signs and symptoms of infusion-related reactions including nausea, vomiting, abdominal pain, salivary hypersecretion, pyrexia, chest discomfort, chills, back pain, cough, and hypertension. These signs and symptoms are usually reversible with the interruption of the infusion.

Infusion-related reactions should be managed according to the dose modifications as recommended in Table 2.

Nausea and vomiting

During clinical studies, nausea and vomiting were the most frequently observed gastrointestinal adverse reactions with zolbetuximab in combination with fluoropyrimidine and platinum-containing chemotherapy (see section 4.8).

To prevent nausea and vomiting, pre-treatment with a combination of antiemetics is recommended prior to each infusion of zolbetuximab (see section 4.2).

During and after infusion, patients should be monitored and managed using standard of care, including antiemetics or fluid replacement, as clinically indicated.

Nausea and vomiting should be managed according to the dose modifications as recommended in Table 2.

Mitigation measures before initiating treatment with zolbetuximab

Prior to treatment with zolbetuximab in combination with fluoropyrimidine- and platinum-containing chemotherapy, prescribers should evaluate the individual patient’s risk of gastrointestinal toxicities. It is important to proactively manage nausea and vomiting to mitigate the potential risk of reduced exposure to zolbetuximab and/or chemotherapy.

To prevent nausea and vomiting, pre-treatment with a combination of antiemetics is recommended prior to each infusion of zolbetuximab. During infusion, it is important to closely monitor patients and manage gastrointestinal toxicities by infusion interruption and/or infusion rate reduction to minimize the risk of severe adverse reactions or early treatment discontinuation. During and after infusion, patients should be monitored and managed using standard of care, including antiemetics or fluid replacement, as clinically indicated.

Patients excluded from clinical studies

Patients were excluded from clinical studies if they had a complete or partial gastric outlet syndrome, positive test for human immunodeficiency virus (HIV) infection or known active hepatitis B or C infection, significant cardiovascular disease (e.g., congestive heart failure per New York Heart Association Class III or IV, history of significant ventricular arrhythmias, QTc interval >450 msec for males; >470 msec for females) or history of central nervous system metastases.

Excipient information

This medicinal product contains 1.05 mg of polysorbate 80 in each 100 mg vial. Polysorbates may cause allergic reactions.

This medicinal product does not contain sodium, however, sodium chloride 9 mg/mL (0.9%) solution for infusion is used for the dilution of zolbetuximab prior to administration and this should be taken into consideration in the context of the daily sodium intake of the patient.

No formal pharmacokinetic drug interaction studies have been conducted with zolbetuximab. Since zolbetuximab is cleared from the circulation through catabolism, no metabolic drug-drug interactions are expected.

Women of childbearing potential

As a precautionary measure, women of childbearing potential should be advised to use effective contraception to prevent pregnancy during treatment.

Pregnancy

There are no data on the use of zolbetuximab in pregnant women. No adverse effects were observed in an animal reproductive and developmental study with intravenous administration of zolbetuximab to pregnant mice during organogenesis (see section 5.3). Zolbetuximab should only be given to a pregnant woman if the benefit outweighs the potential risk.

Breast-feeding

There are no data on the presence of zolbetuximab in human milk, the effects on the breast-fed child, or the effects on milk production. Since it is known that antibodies can be excreted in human milk, and because of the potential for serious adverse reactions in a breast-fed child, breast-feeding is not recommended during treatment with zolbetuximab.

Fertility

Studies to evaluate the effect of zolbetuximab on fertility have not been performed. Thus, the effect of zolbetuximab on male and female fertility is unknown.

Zolbetuximab has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

The most common adverse reactions with zolbetuximab were nausea (77.2%), vomiting (66.9%), decreased appetite (42%), neutropenia (30.7%), neutrophil count decreased (28.4%), weight decreased (21.9%), pyrexia (17.4%), hypoalbuminaemia (17.1%), oedema peripheral (13.9%), hypertension (9%), dyspepsia (7.8%), chills (5.2%), salivary hypersecretion (3.8%), infusion related reaction (3.2%) and drug hypersensitivity (1.6%).

Serious adverse reactions occurred in 45% of patients treated with zolbetuximab. The most common serious adverse reactions were vomiting (6.8%), nausea (4.9%), and decreased appetite (1.9%).

Twenty percent of patients permanently discontinued zolbetuximab for adverse reactions; the most common adverse reactions leading to dose discontinuation were vomiting (3.8%) and nausea (3.3%).

Adverse reactions leading to dose interruption of zolbetuximab occurred in 60.9% of patients; the most common adverse reactions leading to dose interruption were vomiting (26.6%), nausea (25.5%), neutropenia (9.8%), neutrophil count decreased (5.9%), hypertension (3.2%), chills (2.2%), infusion related reaction (1.6%), decreased appetite (1.6%) and dyspepsia (1.1%).

Tabulated list of adverse reactions

The frequencies of adverse reactions are based on two phase 2 studies and two phase 3 studies in 631 patients who received at least one dose of zolbetuximab 800 mg/m² as a loading dose followed by 600 mg/m² maintenance doses every 3 weeks in combination with fluoropyrimidine- and platinum-containing chemotherapy. Patients were exposed to zolbetuximab for a median duration of 174 days (range: 1 to 1791 days).

Adverse reactions observed during clinical studies are listed in this section by frequency category. Frequency categories are defined as follows: 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); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 4. Adverse reactions:

Description of selected adverse reactions

Hypersensitivity reactions

In the integrated safety analysis, all grade anaphylactic reaction and drug hypersensitivity occurred with zolbetuximab in combination with fluoropyrimidine and platinum-containing chemotherapy at a frequency of 0.5% and 1.6%, respectively.

Severe (Grade 3) anaphylactic reaction and drug hypersensitivity occurred with zolbetuximab in combination with fluoropyrimidine and platinum-containing chemotherapy at a frequency of 0.5% and 0.2%.

Anaphylactic reaction led to permanent discontinuation of zolbetuximab in 0.3% of patients. Dose interruption of zolbetuximab was experienced due to drug hypersensitivity in 0.3% of patients. The infusion rate was reduced for zolbetuximab or fluoropyrimidine and platinum-containing chemotherapy in 0.2% of patients due to drug hypersensitivity.

Infusion related reaction

In the integrated safety analysis, all grade IRR occurred with zolbetuximab in combination with fluoropyrimidine and platinum-containing chemotherapy at a frequency of 3.2%.

Severe (Grade 3) IRR occurred in 0.5% of patients treated with zolbetuximab in combination with fluoropyrimidine and platinum-containing chemotherapy.

An IRR led to permanent discontinuation of zolbetuximab in 0.5% of patients, and dose interruption in 1.6% of patients. The infusion rate was reduced for zolbetuximab or fluoropyrimidine and platinum- containing chemotherapy in 0.3% of patients due to an IRR.

Nausea and vomiting

In the integrated safety analysis, all grade nausea and vomiting occurred with zolbetuximab in combination with fluoropyrimidine and platinum-containing chemotherapy at a frequency of 77.2% and 66.9%, respectively. Nausea and vomiting occurred more often during the first cycle of treatment but decreased in incidence with subsequent cycles of treatment. The median time to onset of nausea and vomiting was 1 day each with zolbetuximab in combination with fluoropyrimidine and platinum-containing chemotherapy. The median duration of nausea and vomiting was 3 days and 1 day, respectively, with zolbetuximab in combination with fluoropyrimidine and platinum-containing chemotherapy.

Severe (Grade 3) nausea and vomiting occurred with zolbetuximab in combination with fluoropyrimidine and platinum-containing chemotherapy at a frequency of 11.6% and 13.6%.

Nausea led to permanent discontinuation of zolbetuximab in 3.3% of patients, and dose interruption in 25.5% of patients. Vomiting led to permanent discontinuation of zolbetuximab in 3.8% of patients, and dose interruption in 26.6% of patients. The infusion rate was reduced for zolbetuximab or fluoropyrimidine and platinum-containing chemotherapy in 9.7% of patients due to nausea and in 7.8% of patients due to vomiting.

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. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.