4.1. Therapeutic indications

Zynlonta as monotherapy is indicated for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and high-grade B-cell lymphoma (HGBL), after two or more lines of systemic therapy.

4.2. Posology and method of administration

Zynlonta must only be administered under the supervision of a healthcare professional experienced in the diagnosis and treatment of cancer patients.

Posology

The recommended dose of Zynlonta is 0.15 mg/kg every 21 days for 2 cycles, followed by 0.075 mg/kg every 21 days for subsequent cycles until disease progression or unacceptable toxicity.

Premedication with dexamethasone

Unless contraindicated, dexamethasone 4 mg is to be administered orally or intravenously twice daily for 3 days, beginning the day before administering Zynlonta to mitigate pyrrolobenzodiazepine (PBD)-related toxicities. If dexamethasone administration does not begin the day before Zynlonta, oral or intravenous dexamethasone should begin at least 2 hours prior to administration of Zynlonta.

Delayed or missed doses

If a planned dose of Zynlonta is missed, it should be administered as soon as possible, and the schedule of administration should be adjusted to maintain a 21‑day interval between doses.

Dose modification

For dose modification for haematologic and non-haematologic adverse reactions (see section 4.8), see Table 1 below.

Table 1: Zynlonta dose modification for haematologic and non-haematologic adverse reactions

Adverse reactions

Severity

Dose modification

Haematologic adverse reactions

Neutropenia (see section 4.8)

Absolute neutrophil count less than 1 x 109/L

Withhold Zynlonta until neutrophil count returns to 1 x 109/L or higher

Thrombocytopenia (see section 4.8)

Platelet count less than 50,000/mcL

Withhold Zynlonta until platelet count returns to 50,000/mcL or higher

Non-haematologic adverse reactions

Oedema or effusion (see section 4.8)

Grade 2 or higher

Withhold Zynlonta until the toxicity resolves to Grade 1 or less

Other adverse reactions (see section 4.8)

Grade 3 or higher

Withhold Zynlonta until the toxicity resolves to Grade 1 or less

If dosing is delayed by more than 3 weeks due to toxicity related to Zynlonta, subsequent doses should be reduced by 50%. If toxicity requires dose reduction following the second dose of 0.15 mg/kg (Cycle 2), the patient should receive the dose of 0.075 mg/kg for Cycle 3.

If toxicity reoccurs after two dose reductions following an adverse reaction, permanent discontinuation of Zynlonta should be considered.

Elderly

No dose adjustment of Zynlonta is required in patients ≥65 years of age (see section 5.1).

Renal impairment

No dose adjustment of Zynlonta is required for patients with mild to moderate renal impairment (see section 5.2).

Zynlonta has not been studied in patients with severe renal impairment (CLcr 15 to 29 mL/min). The effect of severe renal impairment, and end-stage renal disease, with or without haemodialysis, on loncastuximab tesirine pharmacokinetics is unknown. Additional monitoring for adverse reactions may be warranted in these patients when loncastuximab tesirine is administered.

For SG3199, data collected in an animal model (rat) show minimal renal excretion. No clinical data are available.

Hepatic impairment

No dose adjustment is recommended for patients with mild hepatic impairment (total bilirubin ≤ upper limit of normal [ULN] and aspartate aminotransferase [AST] > ULN or total bilirubin >1 to 1.5 × ULN and any AST).

Zynlonta has not been studied in patients with moderate or severe hepatic impairment (total bilirubin >1.5 × ULN and any AST).

In patients with hepatic impairment, monitoring for adverse reactions is recommended.

Paediatric population

The safety and efficacy of loncastuximab tesirine in children and adolescents aged less than 18 years have not yet been established. No data are available.

Method of administration

Zynlonta is for intravenous use.

The infusion is administered over 30 minutes through an intravenous line.

Extravasation of Zynlonta has been associated with irritation, swelling, pain, and/or tissue damage, which may be severe (see section 4.8). The infusion site should be monitored for possible subcutaneous infiltration during medicinal product administration.

Zynlonta must be reconstituted and diluted using aseptic technique under the supervision of a healthcare professional. It must be administered using a dedicated infusion line equipped with a sterile, non-pyrogenic, low-protein binding in-line or add-on filter (0.2 or 0.22 micrometre pore size) and catheter.

For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.

Precautions to be taken before handling or administering the medicinal product

This medicinal product contains a cytotoxic component, which is covalently attached to the monoclonal antibody (see special handling and disposal procedures in section 6.6).

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

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.

Effusion and oedema

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). In patients with worsening effusion or oedema, who have signs and symptoms of weight gain, severe hypotension, hypoalbuminemia, and/or haemoconcentration (by elevated haemoglobin/haematocrit, etc.), capillary leak syndrome should be considered and appropriate medical management instituted.

Myelosuppression

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. Cytopenia 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).

Infections

Fatal and serious infections, including opportunistic infections and sepsis, 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).

Photosensitivity and cutaneous reactions

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).

Embryo-foetal toxicity

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).

Fertility

In non-clinical studies, loncastuximab tesirine was associated with testicular toxicity so may impair male reproductive function and fertility (see section 5.3).

Polysorbates

This medicinal product contains 0.4 mg of polysorbate 20 in each vial, which is equivalent to 0.2 mg/mL.

Polysorbates may cause allergic reactions.

4.5. Interaction with other medicinal products and other forms of interaction

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).

4.6. Fertility, pregnancy and lactation

Women of childbearing potential/Contraception in men and women

Women

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.

Men

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.

Pregnancy

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.

Breast-feeding

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.

Fertility

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.

4.7. Effects on ability to drive and use machines

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.

4.8. Undesirable effects

Summary of the safety profile

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%).

Tabulated list of adverse reactions

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), very rare (<1/10 000), and 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

Not knownd

Infections and infestations

Pneumoniaa (includes lung infection)

Upper respiratory tract infection

Sepsis

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

Bullous dermatitis

Photosensitivity reaction

Swelling face

Maculopapular rash

Pruritic rash

Skin hyperpigmentation

Pustular rash

Telangiectasia

Blister

Rash vesicular

Cutaneous collagenous vasculopathy

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

Oedema

Investigations

γ‑glutamyltransferase increased

Aspartate aminotransferase increased

Alanine aminotransferase increased

Blood alkaline phosphatase increased

a Grade 5 associated adverse reactions

b Dyspnoea includes dyspnoea, and dyspnoea exertional

c Abdominal pain includes abdominal pain, abdominal discomfort, abdominal pain lower, and abdominal pain upper

d These 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.

Description of selected adverse reactions

Effusion and oedema

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).

Myelosuppression

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).

Infections

Fatal and serious infections, including opportunistic infections and sepsis, 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.

Cutaneous reactions

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).

Liver function tests

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 occurring in 1.4% of patients.

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 Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Symptomatic treatment and standard supportive care measures for the management of any observed toxicity should be applied.