ZYNLONTA 10mg powder for concentrate infusion solution medication leaflet

Zynlonta 10 mg powder for concentrate for solution for infusion

Each vial of powder for concentrate for solution for infusion contains 10 mg of loncastuximab tesirine.

After reconstitution, each mL contains 5 mg of loncastuximab tesirine.

Loncastuximab tesirine is a CD19-directed antibody and alkylating agent conjugate, consisting of ahumanised IgG1 kappa monoclonal antibody, produced in Chinese Hamster Ovary cells byrecombinant DNA technology, and conjugated to SG3199, a pyrrolobenzodiazepine (PBD) dimercytotoxic alkylating agent, through a protease-cleavable valine-alanine linker. SG3199 attached to thelinker is designated as SG3249, also known as tesirine.

For the full list of excipients, see section 6.1.

Powder for concentrate for solution for infusion (powder for concentrate).

White to off-white lyophilised powder, which has a cake-like appearance.

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

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

The recommended dose of Zynlonta is 0.15 mg/kg every 21 days for 2 cycles, followed by0.075 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 dailyfor 3 days, beginning the day before administering Zynlonta to mitigate pyrrolobenzodiazepine(PBD)-related toxicities. If dexamethasone administration does not begin the day before Zynlonta, oralor intravenous dexamethasone should begin at least 2 hours prior to administration of Zynlonta.

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

For dose modification for haematologic and nonhaematologic adverse reactions (see section 4.8), see

Table 1 below.

Table 1: Zynlonta dose modification for haematologic and nonhaematologic adverse reactions

Adverse reactions Severity Dose modification

Neutropenia (see section 4.8) Absolute neutrophil count Withhold Zynlonta until neutrophilless than 1 x 109/L count returns to 1 x 109/L or higher

Thrombocytopenia Platelet count less than Withhold Zynlonta until platelet(see section 4.8) 50,000/mcL count returns to 50,000/mcL orhigher

Nonhaematologic adverse reactions

Oedema or effusion Withhold Zynlonta until the toxicity(see section 4.8) Grade 2 or higher resolves to Grade 1 or less

Other adverse reactions Grade 3 or higher Withhold Zynlonta until the toxicity(see section 4.8) resolves to Grade 1 or less

If dosing is delayed by more than 3 weeks due to toxicity related to Zynlonta, subsequent doses shouldbe 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 discontinuationof Zynlonta should be considered.

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

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

Zynlonta has not been studied in patients with severe renal impairment (CLcr 15 to 29 mL/min). Theeffect of severe renal impairment, and end-stage renal disease, with or without haemodialysis, onloncastuximab tesirine pharmacokinetics is unknown. Additional monitoring for adverse reactionsmay 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 dataare available.

No dose adjustment is recommended for patients with mild hepatic impairment (total bilirubin ≤ upperlimit 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.

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

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 possiblesubcutaneous infiltration during medicinal product administration.

Zynlonta must be reconstituted and diluted using aseptic technique under the supervision of ahealthcare 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) andcatheter.

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

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

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 numberof 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 withheldfor Grade 2 or greater oedema or effusion until the toxicity resolves. Diagnostic imaging should beconsidered in patients who develop symptoms of pleural effusion or pericardial effusion, such as newor 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 mayrequire more frequent lab monitoring and/or interruption, dose reduction, or discontinuation of

Zynlonta. Prophylactic granulocyte colony-stimulating factor administration should be considered, asapplicable (see section 4.2).

Fatal and serious infections, including opportunistic infections, have been reported in patients treatedwith 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 studieswith Zynlonta oral and topical corticosteroids and anti-pruritic therapy were used to treat cutaneousreactions (see section 4.8).

Patients should be monitored for new or worsening cutaneous reactions, including photosensitivityreactions. 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 orartificial sunlight including exposure through glass windows. Patients should be instructed to protectskin from exposure to sunlight by wearing sun-protective clothing and/or the use of sunscreenproducts. 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 containsa 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 treatmentwith Zynlonta and for 10 months after the last dose. Men with partners of childbearing potentialshould be advised to use effective contraception during treatment with Zynlonta, and for 7 monthsafter the last dose (see section 4.6).

In non-clinical studies, loncastuximab tesirine was associated with testicular toxicity so may impairmale 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/Contraception in men and women

Women of childbearing potential should be advised to use effective contraception during treatmentwith 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 beadvised to use effective contraception during treatment with loncastuximab tesirine and for at least7 months after the last dose.

There are no data on the use of loncastuximab tesirine in pregnant women. No animal reproductionstudies were conducted with loncastuximab tesirine. Zynlonta may cause embryo-foetal toxicity whenadministered to a pregnant woman, because it contains a genotoxic compound (SG3199) and affectsactively dividing cells. Zynlonta is not recommended during pregnancy unless the potential benefit forthe woman outweighs the potential risk to the foetus. Zynlonta is not recommended in women ofchildbearing 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 onthe 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 afterthe last dose.

Based on the results from animal studies, loncastuximab tesirine may impair male fertility (seesection 5.3). Therefore, men being treated with this medicine should be advised to consider havingsperm samples preserved and stored before initiating treatment.

Zynlonta has no or negligible influence on the ability to drive and use machines. However, fatigue hasbeen reported in patients taking loncastuximab tesirine and this should be taken into account whendriving or using machines.

The most frequent reported adverse reactions with loncastuximab tesirine were γ-glutamyltransferaseincreased (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 severeadverse 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 reactionassociated with fatal outcome (0.5%).

The most frequent adverse reactions leading to treatment withdrawal were γ-glutamyltransferaseincreased (8.8%), peripheral oedema (2.8%), thrombocytopenia (1.9%), pleural and pericardialeffusion (1.4% each).

The frequency of dose modification or interruption due to adverse reactions was 47.4%. The mostfrequent adverse reaction leading to dose reduction was γ-glutamyltransferase increased (3.3%), andthe 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). Thesepatients 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 eventfrequencies in the clinical studies, where a proportion of the events for an adverse reaction may haveother causes than the medicinal product, such as the disease, other medicinal products or unrelatedcauses.

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 theavailable data). Within each frequency grouping, adverse reactions are presented by seriousness fromhighest 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 Pneumoniaa (includes lunginfestations infection)

Upper respiratory tractinfection

Lower respiratory tractinfection

Blood and Anaemia Febrile neutropenialymphatic Neutropeniasystem Thrombocytopeniadisorders

Metabolism and Decreased appetite Fluid retention Fluid overloadnutritiondisorders

Nervous system Lethargydisorders

Cardiac Pericardial effusion Pericarditisdisorders

Respiratory, Pleural effusionthoracic and Dyspnoeabmediastinaldisorders

Gastrointestinal Abdominal painc Ascitesdisorders Diarrhoea

Nausea

Skin and Rash Photosensitivity reaction Pustular rashsubcutaneous Pruritus Maculopapular rashtissue disorders Erythema Skin hyperpigmentation

Pruritic rash

Swelling face

Bullous dermatitis

Musculoskeletal Neck pain Musculoskeletaland connective Pain in extremity discomforttissue disorders Back pain Limb discomfort

Musculoskeletal pain

Myalgia

Musculoskeletal chest pain

General Oedema peripheral Face oedema Generalised oedemadisorders and Fatigue Asthenia Oedemaadministration Peripheral swellingsite conditions Swelling

Non-cardiac chest pain

Investigations γ-glutamyltransferaseincreased

Aspartateaminotransferaseincreased

Alanineaminotransferaseincreased

Blood alkalinephosphataseincreaseda Grade 5 associated adverse reactionsb Dyspnoea includes dyspnoea, and dyspnoea exertionalc Abdominal pain includes abdominal pain, abdominal discomfort, abdominal pain lower, andabdominal pain upper

Effusion and oedema

Serious effusion and oedema occurred in patients treated with Zynlonta. Grade ≥3 oedema andeffusion 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 todiscontinuation 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 in24.2%, 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 neutropenialed to discontinuation of treatment in 1.9% and 0.5% of patients, respectively. No patientsdiscontinued treatment due to anaemia (see section 4.4). Median time to onset for Grade 3 or 4neutropenia, 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 reactionsoccurred 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 5cutaneous reactions. Three (3) patients (1.4%) discontinued Zynlonta due to Grade 1-2 cutaneousreactions, and no patients discontinued Zynlonta due to a severe cutaneous reaction. Median time toonset for Grade 3 photosensitivity reactions was 32.0 days and for Grade 3 non-photosensitivitycutaneous reactions was 56.0 days (see section 4.4).

Serious cutaneous reactions have been reported in patients treated with Zynlonta. In clinical studieswith Zynlonta oral and topical corticosteroids and anti-pruritic therapy were used to treat cutaneousreactions (see section 4.4).

Abnormal liver function tests of severity Grade ≥3 occurred in 19.5% of patients, with Grade 3 or 4γ-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 3alanine 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 in2.8% of patients, with Grade 3 occuring in 1.4% of patients.

Post marketing experience

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 isnot always possible to reliably estimate their frequency or establish a causal relationship to drugexposure.

Skin and Subcutaneous Tissue Disorders: telangiectasia, blister, rash vesicular (frequencyunknown).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

Pharmacotherapeutic group: Antineoplastic and immunomodulating agents, antineoplastic agents,monoclonal antibodies and antibody drug conjugates, other monoclonal antibodies and antibody drugconjugates, ATC code: L01FX22

Loncastuximab tesirine is an antibody-drug conjugate (ADC) targeting CD19. The monoclonal IgG1kappa antibody component binds to human CD19, a transmembrane protein expressed on the surfaceof cells of B-lineage origin. The small molecule component is SG3199, a PBD dimer and alkylatingagent.

Upon binding to CD19, loncastuximab tesirine is internalised followed by release of SG3199 viaproteolytic cleavage. The released SG3199 binds to the DNA minor groove and forms highlycytotoxic DNA interstrand crosslinks, subsequently inducing cell death.

Higher loncastuximab tesirine exposure in Cycle 1 was associated with higher efficacy over the doserange of 0.015-0.2 mg/kg (0.1 to 1.33 times the maximum recommended dose). Higher loncastuximabtesirine exposure in Cycle 1 was associated with higher incidence of some Grade ≥2 adverse reactions,including skin and nail reactions, liver function test abnormalities and increased γ-glutamyltransferase.

At the maximum recommended therapeutic dose of 0.15 mg/kg during Cycle 1 and Cycle 2,loncastuximab tesirine does not cause large mean increases (i.e., >20 msec) in the QTc interval.

The efficacy of Zynlonta was evaluated in ADCT-402-201 (LOTIS-2), an open-label, single-arm studyin 145 adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after at least2 prior systemic regimens. The study excluded patients with bulky disease (defined as any tumour≥10 cm in the longest dimension), due to lower response rate, and active central nervous systemlymphoma. Patients received Zynlonta 0.15 mg/kg every 3 weeks for 2 cycles, then 0.075 mg/kg every3 weeks for subsequent cycles. Patients received treatment for 1 year, or beyond if they were clinicallybenefitting, or until progressive disease or unacceptable toxicity.

Among the 145 patients who received Zynlonta, the median number of cycles was 3 (range 1 to 26),with 60% receiving three or more cycles and 34% receiving five or more cycles. Twelve (12) patientsreceived stem cell transplantation directly following treatment with Zynlonta.

Of the 145 patients enrolled, the median age was 66 years (range 23 to 94) while 14% were 75 yearsof age and older, 59% were male, and 94% had an Eastern Cooperative Oncology Group (ECOG)performance status of 0 to 1. Race was reported in 97% of patients; of these patients, 90% were White,3% were Black, and 2% were Asian. The diagnosis was DLBCL not otherwise specified (NOS) in88% (including 20% with DLBCL arising from low grade lymphoma) and high-grade B-celllymphoma in 7%. The median number of prior therapies was 3 (range 2 to 7). 43% of the patientsreceived 2 prior therapies whereas 24% received 3 prior therapies and 32% received more than 3 priortherapies. 63% of patients had refractory disease, 17% with prior stem cell transplant, and 9% withprior chimeric antigen receptor (CAR) T-cell therapy.

Efficacy was evaluated on the basis of overall response rate (ORR) as assessed by an Independent

Review Committee (IRC) using Lugano 2014 criteria (Table 3). The median follow-up time was7.8 months (range 0.3 to 31).

Table 3: Efficacy results in patients with relapsed or refractory DLBCL

Efficacy parameter Zynlonta

N = 145

Overall response rate by IRCa, (95% CI) 48.3% (39.9, 56.7)

Complete response rate (95% CI) 24.8% (18.0, 32.7)

Median time to response (range), months 1.3 (1.1, 8.1)

Duration of overall response N = 70

Median (95% CI), months 13.4 (6.9, NE)

CI = confidence interval, NE = not estimablea IRC = independent review committee using Lugano 2014 criteria

As with all therapeutic proteins, there is potential for an immune response in patients treated withloncastuximab tesirine. In ADCT-402-201 (LOTIS-2), 0 of 134 patients tested positive for antibodiesagainst loncastuximab tesirine after treatment.

Of the 145 patients with large B-cell lymphoma who received Zynlonta in the ADCT-402-201(LOTIS-2) study, 55% were 65 years of age and older. No overall differences in safety oreffectiveness were observed between these patients and younger patients.

The European Medicines Agency has deferred the obligation to submit the results of studies with

Zynlonta in one or more subsets of the paediatric population in treatment of B-cell non-Hodgkin

Lymphoma (B-NHL) (see section 4.2 for information on paediatric use).

This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. Thismeans that further evidence on this medicinal product is awaited.

The European Medicines Agency will review new information on this medicinal product at least everyyear and this SmPC will be updated as necessary.

The exposure of loncastuximab tesirine at the approved recommended dosage in Cycle 2 and at steadystate is shown in Table 4. Loncastuximab tesirine steady state Cmax was 39.0% lower than the Cmaxafter the second dose. The time to reach steady state was approximately 15 weeks.

Table 4: Loncastuximab tesirine exposure parameters

Time Cmax (ng/mL) AUCtau (ng * day/mL)

Cycle 2 2795 (36.4%) 22,082 (46.0%)

Steady state 1705 (31.6%) 16,265 (34.9%)

Cmax = Maximum predicted serum concentration; AUCtau = Area under curve over the dosing interval.

Data presented as geometric mean and coefficient of variation (%CV)

Zynlonta is administered as an intravenous infusion. There have been no studies performed with otherroutes of administration.

The geometric mean (CV%) loncastuximab tesirine volume of distribution was 7.14 (22.9%) L.

In Vitro Studies

SG3199 is a substrate of P-glycoprotein (P-gp), but not a substrate of breast cancer resistance protein(BCRP), organic anion-transporting polypeptide (OATP)1B1, OATP1B3, or organic cation transporter(OCT)1.

SG3199 does not inhibit P-gp, BCRP, OATP1B1, OATP1B3, organic anion transporter (OAT)1,

OAT3, OCT2, OCT1, multi-antimicrobial extrusion protein (MATE)1, MATE2-K, or bile salt exportpump (BSEP) at clinically relevant unconjugated SG3199 concentrations.

The monoclonal antibody portion of loncastuximab tesirine is expected to be metabolised into smallpeptides by catabolic pathways. The small molecule cytotoxin, SG3199, is metabolised by CYP3A4/5in vitro.

Cytochrome P450 (CYP) enzymes: SG3199 does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8,

CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4/5 at clinically relevant unconjugated SG3199concentrations.

The geometric mean (CV%) loncastuximab tesirine clearance decreased with time from 0.34 L/day(53.2%) after a single dose to 0.26 L/day (37.2%) at steady state. The mean (standard deviation)half-life of loncastuximab tesirine was 15.8 (6.26) days in Cycle 1 and 20.5 (5.72) days at steady state.

Excretion

The major excretion pathways of SG3199 have not been studied in humans. Data collected in ananimal model (rat) show minimal renal excretion. No clinical data are available.

No clinically significant differences in the pharmacokinetics of loncastuximab tesirine were observedbased on age (20 - 94 years), sex, race (White vs. Black), body weight (42.1 to 160.5 kg), ECOGstatus (0 to 2) or mild to moderate renal impairment (CLcr 30 to <90 mL/min using the

Cockcroft-Gault equation).

The clearance of loncastuximab tesirine in patients with mild to moderate renal impairment(CLcr 30 to <90 mL/min using the Cockcroft-Gault equation) was not significantly different frompatients with normal renal function.

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

Mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin >1 to 1.5 × ULNand any AST) may increase the exposure of unconjugated SG3199, however there was no clinicallysignificant effect on loncastuximab tesirine pharmacokinetics.

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

Carcinogenicity studies have not been conducted with loncastuximab tesirine or SG3199.

SG3199 was genotoxic in an in vitro micronucleus test and a chromosome aberration assay usinghuman lymphocytes through a clastogenic mechanism. These results are consistent with thepharmacological effect of SG3199 as a covalent DNA crosslinking agent. Results of a bacterialreverse mutation assay (Ames test) were inconclusive due to cytotoxicity.

No dedicated reproductive toxicity studies in animals have been conducted with loncastuximabtesirine.

However, the cytotoxic component of Zynlonta, SG3199, crosslinks DNA, is genotoxic, and is toxic torapidly dividing cells, suggesting it has the potential to cause embryo-foetal toxicity.

Fertility studies have not been conducted with loncastuximab tesirine.

Results from repeat-dose toxicity studies with intravenous administration of loncastuximab tesirine incynomolgus monkeys indicate the potential for impaired male reproductive function and fertility.

Administration of loncastuximab tesirine to cynomolgus monkeys every 3 weeks at 0.6 mg/kg for atotal of 2 doses, or every 3 weeks at 0.3 mg/kg for 13 weeks for a total of 5 doses resulted in adversefindings that included decreased weight and/or size of the testes and epididymis, atrophy of theseminiferous tubules, germ cell degeneration, and/or reduced epididymal sperm content. The dose of0.3 mg/kg in animals results in an exposure (AUC) that is approximately 3 times the exposure at themaximum recommended human dose [MRHD] of 0.15 mg/kg. Findings were not reversible at the endof the 12-week recovery period following 4 or 13 weeks of dosing.

Toxicities

In repeat-dose toxicity studies in cynomolgus monkeys, intravenous administration of loncastuximabtesirine was associated with renal toxicity including increased kidney weights and nephropathy withvariable reversible inflammation and fibrosis.

Black skin spots potentially related to phototoxicity were observed in cynomolgus monkeys and werestill present after a 12-week treatment-free period.

L-histidine

L-histidine monohydrochloride

Polysorbate 20

Sucrose

This medicinal product must not be mixed with or administered as an infusion with other medicinalproducts except those mentioned in section 6.6.

Unopened vial5 years

From a microbiological point of view, the reconstituted solution should be used immediately. If notused immediately, in-use storage times and conditions prior to use are the responsibility of the userand should not be longer than 4 hours refrigerated (2℃ - 8℃) or 4 hours at room temperature(20℃ - 25℃), unless reconstitution has taken place in controlled and validated aseptic conditions.

Chemical and physical in-use stability of the reconstituted solution has been demonstrated for up to4 hours refrigerated (2℃ - 8℃) or 4 hours at room temperature (20℃ - 25℃).

From a microbiological point of view, the prepared solution for infusion should be used immediately.

If not used immediately, in-use storage times and conditions prior to use are the responsibility of theuser and should not be longer than 24 hours refrigerated (2℃ - 8℃) or 8 hours at room temperature(20℃ - 25℃), unless dilution has taken place in controlled and validated aseptic conditions. Chemicaland physical in-use stability of the prepared solution for infusion has been demonstrated for up to24 hours at room temperature (20℃ - 25℃).

Do not use the medicinal product if the storage conditions exceed the limits.

Store in a refrigerator (2°C - 8°C).

Do not freeze.

Keep the vial in the outer carton in order to protect from light.

For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.

Vial (clear Type 1 glass) closed with a stopper (teflon coated rubber), with an aluminium seal withplastic flip-off cap containing 10 mg loncastuximab tesirine. Pack size of one vial.

Zynlonta contains a cytotoxic component and should be administered under the supervision of aphysician experienced in the use of cytotoxic agents. Procedures for proper handling and disposal ofantineoplastic and cytotoxic medicinal products should be used.

Proper aseptic technique throughout the handling of this medicinal product should be followed.

The reconstituted product contains no preservative and is intended for single-dose only.

Zynlonta must be reconstituted using sterile water for injections and diluted into an intravenousinfusion bag containing 5% glucose prior to administration.

Both the reconstituted solution and the diluted solution for infusion should not be frozen or exposed todirect sunlight.

Dose calculation

Calculate the total dose (mg) required based on the patient’s weight and prescribed dose(see section 4.2).

* More than one vial may be needed to achieve the calculated dose.

Reconstitution of powder for concentrate

* Reconstitute each vial of powder for concentrate using 2.2 mL of sterile water for injectionswith the stream directed toward the inside wall of the vial to obtain a final concentration of5 mg/mL.

* Swirl the vial gently until the powder is completely dissolved. Do not shake.

* Inspect the reconstituted solution for particulate matter and discolouration. The solution shouldappear clear to slightly opalescent, colourless to slightly yellow. Do not use if the reconstitutedsolution is discoloured, is cloudy, or contains visible particulates.

* Discard unused vial after reconstitution if the recommended storage time is exceeded.

Dilution in intravenous infusion bag

* Withdraw the required volume of reconstituted solution from the vial using a sterile syringe.

Discard any unused portion left in the vial.

* Add the calculated dose volume of Zynlonta reconstituted solution into a 50 mL intravenousinfusion bag of 5% glucose.

* Gently mix the intravenous infusion bag by slowly inverting the bag. Do not shake.

* No incompatibilities have been observed between Zynlonta and intravenous infusion bags withproduct-contacting materials of polyvinylchloride (PVC), polyolefin (PO), and PAB (copolymerof ethylene and propylene).

* Zynlonta 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) andcatheter.

Zynlonta is for single-use only.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Swedish Orphan Biovitrum AB (publ)

SE-112 76 Stockholm

Sweden

EU/1/22/1695/001

Date of first authorisation: 20 December 2022

Date of latest renewal: 15 November 2023

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.