Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: ADC Therapeutics (NL) B.V., Laarderhoogtweg 25, Amsterdam, Noord-Holland, 1101 EB, Netherlands
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
Serious effusion and oedema have been reported in patients treated with Zynlonta (see section 4.8).
Patients should be monitored for new or worsening oedema or effusions. Zynlonta should be withheld for Grade 2 or greater oedema or effusion until the toxicity resolves. Diagnostic imaging should be considered in patients who develop symptoms of pleural effusion or pericardial effusion, such as new or worsened dyspnoea, chest pain, and/or ascites such as swelling in the abdomen and bloating. Appropriate medical management for oedema or effusions should be instituted (see section 4.2).
Treatment with Zynlonta can cause serious or severe myelosuppression, including neutropenia, thrombocytopenia, and anaemia (see section 4.8).
Complete blood cell counts should be monitored prior to each dose of Zynlonta. Cytopenias may require more frequent lab monitoring and/or interruption, dose reduction, or discontinuation of Zynlonta. Prophylactic granulocyte colony-stimulating factor administration should be considered, as applicable (see section 4.2).
Fatal and serious infections, including opportunistic infections, have been reported in patients treated with Zynlonta (see section 4.8).
Patients should be monitored for any new or worsening signs or symptoms consistent with infection. For Grade 3 or 4 infection, Zynlonta should be withheld until infection has resolved (see section 4.2).
Serious cutaneous reactions have been reported in patients treated with Zynlonta. In clinical studies with Zynlonta oral and topical corticosteroids and anti-pruritic therapy were used to treat cutaneous reactions (see section 4.8).
Patients should be monitored for new or worsening cutaneous reactions, including photosensitivity reactions. Zynlonta should be withheld for severe (Grade 3) cutaneous reactions until resolution (see section 4.2). Patients should be advised to minimise or avoid exposure to direct natural or artificial sunlight including exposure through glass windows. Patients should be instructed to protect skin from exposure to sunlight by wearing sun-protective clothing and/or the use of sunscreen products. If a skin reaction or rash develops, dermatologic consultation should be considered (see section 5.3).
Zynlonta may cause embryo-foetal harm when administered to a pregnant woman because it contains a genotoxic compound (SG3199), which affects actively dividing cells.
Pregnant women should be advised of the potential risk to the foetus. Women of childbearing potential should be advised to use effective contraception during treatment with Zynlonta and for 10 months after the last dose. Men with partners of childbearing potential should be advised to use effective contraception during treatment with Zynlonta, and for 7 months after the last dose (see section 4.6).
In non-clinical studies, loncastuximab tesirine was associated with testicular toxicity so may impair male reproductive function and fertility (see section 5.3).
No interaction studies have been performed in humans for loncastuximab tesirine, free tesirine, SG3199 and related metabolites.
No clinically important PK interactions are expected (see section 5.2).
Women of childbearing potential should be advised to use effective contraception during treatment with loncastuximab tesirine and for at least 10 months after the last dose.
Because of the potential for genotoxicity, men with partners of childbearing potential should be advised to use effective contraception during treatment with loncastuximab tesirine and for at least 7 months after the last dose.
There are no data on the use of loncastuximab tesirine in pregnant women. No animal reproduction studies were conducted with loncastuximab tesirine. Zynlonta may cause embryo-foetal toxicity when administered to a pregnant woman, because it contains a genotoxic compound (SG3199) and affects actively dividing cells. Zynlonta is not recommended during pregnancy unless the potential benefit for the woman outweighs the potential risk to the foetus. Zynlonta is not recommended in women of childbearing potential not using contraception.
Pregnancy testing is advised prior to initiating Zynlonta.
There is no data on the presence of loncastuximab tesirine or SG3199 in human milk, the effects on the breastfed child, or milk production. A risk for breast-feeding children cannot be excluded. Breast-feeding should be discontinued during treatment with Zynlonta and for at least 3 months after the last dose.
Based on the results from animal studies, loncastuximab tesirine may impair male fertility (see section 5.3). Therefore, men being treated with this medicine should be advised to consider having sperm samples preserved and stored before initiating treatment.
Zynlonta has no or negligible influence on the ability to drive and use machines. However, fatigue has been reported in patients taking loncastuximab tesirine and this should be taken into account when driving or using machines.
The most frequent reported adverse reactions with loncastuximab tesirine were γ-glutamyltransferase increased (35.8%), neutropenia (34.9%), fatigue (30.2%), anaemia (28.8%), thrombocytopenia (28.4%), nausea (26.5%), peripheral oedema (23.3%), and rash (20.0%).The most frequent severe adverse reactions (≥ Grade 3) were neutropenia (24.2%), γ-glutamyltransferase increased (17.2%), thrombocytopenia (15.8%), anaemia (11.6%) and infections (9.8%).
The most frequent serious adverse reactions were febrile neutropenia (3.3%), abdominal pain, dyspnoea and pleural effusion (1.9% each). Lung infection was identified as an adverse reaction associated with fatal outcome (0.5%).
The most frequent adverse reactions leading to treatment withdrawal were γ-glutamyltransferase increased (8.8%), peripheral oedema (2.8%), thrombocytopenia (1.9%), pleural and pericardial effusion (1.4% each).
The frequency of dose modification or interruption due to adverse reactions was 47.4%. The most frequent adverse reaction leading to dose reduction was γ-glutamyltransferase increased (3.3%), and the most frequent adverse reactions leading to dose delay were γ-glutamyltransferase increased (17.7%), neutropenia (11.2%) and thrombocytopenia (7.9%).
The frequencies of adverse reactions are based on 215 patients with relapsed or refractory DLBCL, who received Zynlonta alone as an intravenous infusion at the recommended initial dose (0.15 mg/kg) in two monotherapy studies, of whom 145 patients participated in the Phase 2 pivotal study ADCT-402-201 (LOTIS-2) and 70 patients participated in the Phase 1 study (ADCT-402-101). These patients were exposed to Zynlonta during a median of 45 days (range 1 to 569 days).
Unless otherwise stated, the frequencies of adverse reactions are based on all-cause adverse event frequencies in the clinical studies, where a proportion of the events for an adverse reaction may have other causes than the medicinal product, such as the disease, other medicinal products or unrelated causes.
Adverse reactions are presented according to the MedDRA system organ class (SOC) and classified, by frequency, as 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) and very rare (<1/10 000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented by seriousness from highest to lowest.
Table 2. Adverse reactions reported for Zynlonta in adult patients with relapsed or refractory DLBCL:
| MedDRA SOC | Very common | Common | Uncommon |
|---|---|---|---|
| Infections and infestations | Pneumoniaa (includes lung infection) Upper respiratory tract infection Lower respiratory tract infection | ||
| Blood and lymphatic system disorders | Anaemia Neutropenia Thrombocytopenia | Febrile neutropenia | |
| Metabolism and nutrition disorders | Decreased appetite | Fluid retention | Fluid overload |
| Nervous system disorders | Lethargy | ||
| Cardiac disorders | Pericardial effusion | Pericarditis | |
| Respiratory, thoracic and mediastinal disorders | Pleural effusion Dyspnoeab | ||
| Gastrointestinal disorders | Abdominal painc Diarrhoea Nausea Vomiting Constipation | Ascites | |
| Skin and subcutaneous tissue disorders | Rash Pruritus Erythema | Photosensitivity reaction Maculopapular rash Skin hyperpigmentation Pruritic rash Swelling face Bullous dermatitis | Pustular rash |
| Musculoskeletal and connective tissue disorders | Neck pain Pain in extremity Back pain Musculoskeletal pain Myalgia Musculoskeletal chest pain | Musculoskeletal discomfort Limb discomfort | |
| General disorders and administration site conditions | Oedema peripheral Fatigue | Face oedema Asthenia Peripheral swelling Swelling Non-cardiac chest pain | Generalised oedema |
| Investigations | γ-glutamyltransferase increased Aspartate aminotransferase increased Alanine aminotransferase increased Blood alkaline phosphatase increased |
Serious effusion and oedema occurred in patients treated with Zynlonta. Grade ≥3 oedema and effusion occurred in 5.6% of patients. Grade 3 or 4 pericardial effusion occurred in 1.4% of patients. Grade 3 pleural effusion occurred in 2.8%, Grade 3 peripheral oedema and ascites in 1.4% each, and Grade 3 peripheral swelling in 0.5% of patients (see section 4.4). Effusion and oedema led to discontinuation of treatment in 5.1% of patients. There were no fatal events of effusion or oedema. Median time to onset for Grade ≥3 effusion and oedema was 115 days and 101 days, respectively (see section 4.4).
Treatment with Zynlonta can cause severe myelosuppression. Grade 3 or 4 neutropenia occurred in 24.2%, Grade 3 or 4 thrombocytopenia in 15.8%, and Grade 3 or 4 anaemia in 11.6% of patients. Febrile neutropenia occurred in 3.3% of patients (see section 4.4). Thrombocytopenia and neutropenia led to discontinuation of treatment in 1.9% and 0.5% of patients, respectively. No patients discontinued treatment due to anaemia (see section 4.4). Median time to onset for Grade 3 or 4 neutropenia, thrombocytopenia and anaemia was 36.0 days, 28.5 days, and 22.0 days, respectively (see section 4.4).
Fatal and serious infections, including opportunistic infections, occurred in patients treated with Zynlonta. Grade ≥3 infections occurred in 9.8% of patients with an associated fatal infection in 0.5% of patients (see section 4.4). Infections led to discontinuation of treatment in 0.9% of patients.
Severe cutaneous reactions occurred in patients treated with Zynlonta. Grade 3 cutaneous reactions occurred in 3.7% and included photosensitivity reaction (1.4%), rash (0.9%), rash pustular (0.5%), rash maculo-papular (0.5%), and erythema (0.5%) (see section 4.4). There were no Grade 4 or Grade 5 cutaneous reactions. Three (3) patients (1.4%) discontinued Zynlonta due to Grade 1-2 cutaneous reactions, and no patients discontinued Zynlonta due to a severe cutaneous reaction. Median time to onset for Grade 3 photosensitivity reactions was 32.0 days and for Grade 3 non-photosensitivity cutaneous reactions was 56.0 days (see section 4.4).
Serious cutaneous reactions have been reported in patients treated with Zynlonta. In clinical studies with Zynlonta oral and topical corticosteroids and anti-pruritic therapy were used to treat cutaneous reactions (see section 4.4).
Abnormal liver function tests of severity Grade ≥3 occurred in 19.5% of patients, with Grade 3 or 4 γ-glutamyltransferase (GGT) increased in 17.2% of patients. GGT increase resulted in dose delay, dose reduction, and treatment withdrawal in 17.7%, 3.3%, and 8.8% of patients, respectively. Grade 3 alanine aminotransferase increased occurred in 2.8%, blood alkaline phosphatase increased in 1.4%, and aspartate aminotransferase increased in 0.9% of patients. Increased blood bilirubin was noted in 2.8% of patients, with Grade 3 occuring in 1.4% of patients.
The following adverse drug reactions have been identified from the post-marketing reports for Zynlonta. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Skin and Subcutaneous Tissue Disorders: telangiectasia, blister, rash vesicular (frequency unknown).
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.
This medicinal product must not be mixed with or administered as an infusion with other medicinal products except those mentioned in section 6.6.
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