MINJUVI 200mg powder for concentrate infusion solution medication leaflet

MINJUVI 200 mg powder for concentrate for solution for infusion

One vial of powder contains 200 mg of tafasitamab.

After reconstitution each mL of solution contains 40 mg of tafasitamab.

Tafasitamab is a humanised CD19-specific monoclonal antibody of the immunoglobulin G (IgG)subclass produced in mammalian (Chinese hamster ovary) cells by recombinant DNA technology.

Each vial of MINJUVI contains 7.4 mg of sodium. For the full list of excipients, see section 6.1.

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

White to slightly yellowish lyophilised powder.

MINJUVI is indicated in combination with lenalidomide followed by MINJUVI monotherapy for thetreatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) whoare not eligible for autologous stem cell transplant (ASCT).

MINJUVI must be administered by a healthcare professional experienced in treatment of cancerpatients.

Recommended premedication

A premedication to reduce the risk of infusion-related reactions should be administered 30 minutes to2 hours prior to tafasitamab infusion. For patients not experiencing infusion-related reactions duringthe first 3 infusions, premedication is optional for subsequent infusions.

The premedication may include antipyretics (e.g. paracetamol), histamine H1 receptor blockers (e.g.diphenhydramine), histamine H2 receptor blockers (e.g. cimetidine), or glucocorticosteroids (e.g.methylprednisolone).

Treatment of infusion-related reactions

If an infusion-related reaction occurs (Grade 2 and higher), the infusion should be interrupted. Inaddition, appropriate medical treatment of symptoms should be initiated. After signs and symptomsare resolved or reduced to Grade 1, MINJUVI infusion can be resumed at a reduced infusion speed(see Table 1).

If a patient has experienced a Grade 1 to 3 infusion-related reaction, premedication should beadministered before subsequent tafasitamab infusions.

The recommended dose of MINJUVI is 12 mg per kg body weight administered as an intravenousinfusion according to the following schedule:

* Cycle 1: infusion on day 1, 4, 8, 15 and 22 of the cycle.

* Cycles 2 and 3: infusion on day 1, 8, 15 and 22 of each cycle.

* Cycle 4 until disease progression: infusion on day 1 and 15 of each cycle.

Each cycle has 28 days.

In addition, patients should self-administer lenalidomide capsules at the recommended starting dose of25 mg daily on days 1 to 21 of each cycle. The starting dose and subsequent dosing may be adjustedaccording to the lenalidomide Summary of Product Characteristics (SmPC).

MINJUVI plus lenalidomide in combination is given for up to twelve cycles.

Treatment with lenalidomide should be stopped after a maximum of twelve cycles of combinationtherapy. Patients should continue to receive MINJUVI infusions as single agent on day 1 and 15 ofeach 28-day cycle, until disease progression or unacceptable toxicity.

Table 1 provides dose modifications in case of adverse reactions. For dose modifications regardinglenalidomide, please also refer to the lenalidomide SmPC.

Table 1: Dose modifications in case of adverse reactions

Adverse reaction Severity Dosage modification

Infusion-related * Interrupt MINJUVI infusionreactions immediately and manage signs andsymptoms.

* Once signs and symptoms resolve orreduce to Grade 1, resume MINJUVIinfusion at no more than 50% of the rate

Grade 2 (moderate) at which the reaction occurred. If thepatient does not experience furtherreaction within 1 hour and vital signsare stable, the infusion rate may beincreased every 30 minutes as toleratedto the rate at which the reactionoccurred.

* Interrupt MINJUVI infusionimmediately and manage signs andsymptoms.

* Once signs and symptoms resolve orreduce to Grade 1, resume MINJUVIinfusion at no more than 25% of the rate

Grade 3 (severe) at which the reaction occurred. If thepatient does not experience furtherreaction within 1 hour and vital signsare stable, the infusion rate may beincreased every 30 minutes as toleratedto a maximum of 50% of the rate atwhich the reaction occurred.

* If after rechallenge the reaction returns,stop the infusion immediately.

Adverse reaction Severity Dosage modification

Grade 4 (life-threatening) * Stop the infusion immediately andpermanently discontinue MINJUVI.

Myelosuppression * Withhold MINJUVI and lenalidomideand monitor complete blood countweekly until platelet count is 50,000/µL

Platelet count of less than or higher.50,000/µL * Resume MINJUVI at the same dose andlenalidomide at a reduced dose ifplatelets return to ≥ 50,000/µL. Refer tothe lenalidomide SmPC for dosagemodifications.

Neutrophil count of less than * Withhold MINJUVI and lenalidomide1,000/µL for at least 7 days and monitor complete blood countweekly until neutrophil count isor 1,000/µL or higher.

* Resume MINJUVI at the same dose and

Neutrophil count of less than lenalidomide at a reduced dose if1,000/µL with an increase of neutrophils return to ≥ 1000/µL. Referbody temperature to 38 °C or to the lenalidomide SmPC for dosagehigher modifications.

or

Neutrophil count lessthan 500/µL

The safety and efficacy of MINJUVI in children under 18 years have not been established.

No data are available.

No dose adjustment is needed for elderly patients (≥ 65 years).

No dose adjustment is needed for patients with mild or moderate renal impairment (see section 5.2).

There are no data in patients with severe renal impairment for dosing recommendations.

No dose adjustment is needed for patients with mild hepatic impairment (see section 5.2). There are nodata in patients with moderate or severe hepatic impairment for dosing recommendations.

MINJUVI is for intravenous use after reconstitution and dilution.

* For the first infusion of cycle 1, the intravenous infusion rate should be 70 mL/h for the first30 minutes. Afterwards, the rate should be increased to complete the first infusion within a2.5-hour period.

* All subsequent infusions should be administered within a 1.5 to 2-hour period.

* In case of adverse reactions, consider the recommended dose modifications provided in Table 1.

* MINJUVI must not be co-administered with other medicinal products through the same infusionline.

* MINJUVI must not be administered as an intravenous push or bolus.

For instructions on reconstitution and dilution of the medicinal product before administration, seesection 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.

Infusion-related reactions may occur and have been reported more frequently during the first infusion(see section 4.8). Patients should be monitored closely throughout the infusion. Patients should beadvised to contact their healthcare professionals if they experience signs and symptoms ofinfusion-related reactions including fever, chills, rash or breathing problems within 24 hours ofinfusion. A premedication should be administered to patients prior to starting tafasitamab infusion.

Based on the severity of the infusion-related reaction, tafasitamab infusion should be interrupted ordiscontinued and appropriate medical management should be instituted (see section 4.2).

Treatment with tafasitamab can cause serious and/or severe myelosuppression including neutropenia,thrombocytopenia and anaemia (see section 4.8). Complete blood counts should be monitoredthroughout treatment and prior to administration of each treatment cycle. Based on the severity of theadverse reaction, tafasitamab infusion should be withheld (see Table 1). Refer to the lenalidomide

SmPC for dosage modifications.

Neutropenia, including febrile neutropenia, has been reported during treatment with tafasitamab.

Administration of granulocyte colony-stimulating factors (G-CSF) should be considered, in particularin patients with Grade 3 or 4 neutropenia. Any symptoms or signs of developing infection should beanticipated, evaluated and treated.

Thrombocytopenia has been reported during treatment with tafasitamab. Withholding of concomitantmedicinal products that may increase bleeding risk (e.g. platelet inhibitors, anticoagulants) should beconsidered. Patients should be advised to report signs or symptoms of bruising or bleedingimmediately.

Fatal and serious infections, including opportunistic infections, occurred in patients during treatmentwith tafasitamab. Tafasitamab should be administered to patients with an active infection only if theinfection is treated appropriately and well controlled. Patients with a history of recurring or chronicinfections may be at increased risk of infection and should be monitored appropriately.

Patients should be advised to contact their healthcare professionals if fever or other evidence ofpotential infection, such as chills, cough or pain on urination, develops.

Progressive Multifocal Leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) has been reported during combination therapywith tafasitamab. Patients should be monitored for new or worsening neurological symptoms or signsthat may be suggestive of PML. The symptoms of PML are nonspecific and can vary depending on theaffected region of the brain. These include altered mental status, memory loss, speech impairment,motor deficits (hemiparesis or monoparesis), limb ataxia, gait ataxia, and visual symptoms such ashemianopia and diplopia. If PML is suspected, further dosing of tafasitamab must be immediatelysuspended. Referral to a neurologist should be considered. Appropriate diagnostic measures mayinclude MRI scan, cerebrospinal fluid testing for JC viral DNA and repeat neurological assessments. If

PML is confirmed, tafasitamab must be permanently discontinued.

Patients with high tumour burden and rapidly proliferative tumour may be at increased risk of tumourlysis syndrome. In patients with DLBCL, tumour lysis syndrome during treatment with tafasitamabhas been observed. Appropriate measures/prophylaxis in accordance with local guidelines should betaken prior to treatment with tafasitamab. Patients should be monitored closely for tumour lysissyndrome during treatment with tafasitamab.

The safety of immunisation with live vaccines following tafasitamab therapy has not been investigatedand vaccination with live vaccines is not recommended concurrently with tafasitamab therapy.

Excipient

This medicinal product contains 37.0 mg sodium per 5 vials (the dose of a patient weighing 83 kg),equivalent to 1.85% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

No interaction studies have been performed.

Treatment with tafasitamab in combination with lenalidomide should not be initiated in femalepatients unless pregnancy has been excluded. Please also refer to the SmPC of lenalidomide.

Women of childbearing potential should be advised to use effective contraception during and for atleast 3 months after end of treatment with tafasitamab.

Reproductive and developmental toxicity studies have not been conducted with tafasitamab.

There are no data on the use of tafasitamab in pregnant women. However, IgG is known to cross theplacenta and tafasitamab may cause foetal B-cell depletion based on the pharmacological properties(see section 5.1). In case of exposure during pregnancy, newborns should be monitored for B-celldepletion and vaccinations with live virus vaccines should be postponed until the infant’s B-cell counthas recovered (see section 4.4).

Tafasitamab is not recommended during pregnancy and in women of childbearing potential not usingcontraception.

Lenalidomide can cause embryo-foetal harm and is contraindicated for use in pregnancy and inwomen of childbearing potential unless all of the conditions of the lenalidomide pregnancy preventionprogramme are met.

It is not known whether tafasitamab is excreted in human milk. However, maternal IgG is known to beexcreted in human milk. There are no data on the use of tafasitamab in breast-feeding women and arisk for breast-feeding children cannot be excluded. Women should be advised not to breast-feedduring and for at least 3 months after the last dose of tafasitamab.

No specific studies have been conducted to evaluate potential effects of tafasitamab on fertility. Noadverse effects on male and female reproductive organs were observed in a repeat-dose toxicity studyin animals (see section 5.3).

MINJUVI has no or negligible influence on the ability to drive and use machines. However, fatiguehas been reported in patients taking tafasitamab and this should be taken into account when driving orusing machines.

The most common adverse reactions are: infections (73%), neutropenia (51%), asthenia (40%),anaemia (36%), diarrhoea (36%), thrombocytopenia (31%), cough (26%), oedema peripheral (24%),pyrexia (24%), decreased appetite (22%).

The most common serious adverse reactions were infection (26%) including pneumonia (7%), andfebrile neutropenia (6%).

Permanent discontinuation of tafasitamab due to an adverse reaction occurred in 15% of patients. Themost common adverse reactions leading to permanent discontinuation of tafasitamab were infectionsand infestations (5%), nervous system disorders (2.5%), and respiratory, thoracic and mediastinaldisorders (2.5%).

The frequency of dose modification or interruption due to adverse reactions was 65%. The mostcommon adverse reactions leading to tafasitamab treatment interruption were blood and lymphaticsystem disorders (41%).

Adverse reactions reported in clinical trials are listed by MedDRA System Organ Class and byfrequency. The frequencies of adverse reactions is based on the pivotal phase 2 trial MOR208C203(L-MIND) with 81 patients. Patients were exposed to tafasitamab for a median of 7.7 months. Theadverse reaction frequencies from clinical trials are based on all-cause adverse event frequencies,where a proportion of the events for an adverse reaction may have other causes than the medicinalproduct, such as the disease, other medicines or unrelated causes.

Frequencies 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); and not known (cannotbe estimated from the available data). Within each frequency grouping, adverse reactions are presentedin order of decreasing seriousness.

Table 2: Adverse reactions in patients with relapsed or refractory DLBCL who receivedtafasitamab in the clinical trial MOR208C203 (L-MIND)

System organ class Frequency Adverse reactions

Infections and infestations Very common Bacterial, viral and fungal infections+,including opportunistic infections with fataloutcomes (e.g. bronchopulmonaryaspergillosis, bronchitis, pneumonia andurinary tract infection)

Common Sepsis (including neutropenic sepsis)

Neoplasms benign, Common Basal cell carcinomamalignant and unspecified(incl. cysts and polyps)

Blood and lymphatic system Very common Febrile neutropenia+, neutropenia+,disorders thrombocytopenia+, anaemia, leukopenia+

Common Lymphopenia

Immune system disorders Common Hypogammaglobulinaemia

Metabolism and nutrition Very common Hypokalaemia, decreased appetitedisorders Common Hypocalcaemia, hypomagnesaemia

Nervous system disorders Common Headache, paraesthesia, dysgeusia

Respiratory, thoracic and Very common Dyspnoea, coughmediastinal disorders Common Exacerbation of chronic obstructive pulmonarydisease, nasal congestion

Gastrointestinal disorders Very common Diarrhoea, constipation, vomiting, nausea,abdominal pain

Hepatobiliary disorders Common Hyperbilirubinaemia, transaminases increased(includes ALT and/or AST increased),

Gamma-glutamyltransferase increased

Skin and subcutaneous Very common Rash (includes different types of rash, e.g. rash,tissue disorders rash maculopapular, rash pruritic, rasherythematous)

Common Pruritus, alopecia, erythema, hyperhidrosis

Musculoskeletal and Very common Back pain, muscle spasmsconnective tissue disorders Common Arthralgia, pain in extremity, musculoskeletalpain

Renal and urinary disorders Common Blood creatinine increased

General disorders and Very common Asthenia++ , oedema peripheral, pyrexiaadministration site Common Mucosal inflammationconditions

Investigations Common Weight decreased, C-reactive protein increased

Injury, poisoning and Common Infusion related reactionprocedural complications+Further information on this adverse reaction is provided in the text below.++ Asthenia includes asthenia, fatigue and malaise.

Compared with the incidences on combination therapy with lenalidomide, the incidences of non-haematological adversereactions on tafasitamab monotherapy decreased by at least 10% for decreased appetite, asthenia, hypokalaemia, constipation,nausea, muscle spasms, dyspnoea and C-reactive protein increased.

Treatment with tafasitamab can cause serious or severe myelosuppression including neutropenia,thrombocytopenia and anaemia (see sections 4.2 and 4.4).

In the L-MIND study, myelosuppression (i.e. neutropenia, febrile neutropenia, thrombocytopenia,leukopenia, lymphopenia or anaemia) occurred in 65.4% of patients treated with tafasitamab.

Myelosuppression was managed by reduction or interruption of lenalidomide, interruption oftafasitamab and/or administration of G-CSF (see sections 4.2 and 4.4). Myelosuppression led tointerruption of tafasitamab in 41% and to tafasitamab discontinuation in 1.2%.

Neutropenia/febrile neutropenia

Incidence of neutropenia was 51%. Incidence of Grade 3 or 4 neutropenia was 49% and of Grade 3 or4 febrile neutropenia was 12%. Median duration of any adverse reaction of neutropenia was 8 days(range 1 - 222 days); median time to onset to first occurrence of neutropenia was 49 days (range 1 -994 days).

Incidence of thrombocytopenia was 31%. Incidence of Grade 3 or 4 thrombocytopenia was 17%.

Median duration of any adverse reaction thrombocytopenia was 11 days (range 1 - 470 days); mediantime to onset to first occurrence of thrombocytopenia was 71 days (range 1 - 358 days).

Incidence of anaemia was 36%. Incidence of Grade 3 or 4 anaemia was 7%. Median duration of anyadverse reaction of anaemia was 15 days (range 1 - 535 days); median time to onset to first occurrenceof anaemia was 49 days (range 1 - 1129 days).

When patients in the L-MIND study were switched from tafasitamab and lenalidomide in thecombination therapy phase to tafasitamab alone in the extended monotherapy phase, the incidences ofhaematological events decreased by at least 20% for neutropenia, thrombocytopenia and anaemia; noincidences of febrile neutropenia were reported with tafasitamab monotherapy (see sections 4.2 and4.4).

In the L-MIND study, infections occurred in 73% of patients. Incidence of Grade 3 or 4 infections was28%. The most frequently reported Grade 3 or higher infections were pneumonia (7%), respiratorytract infections (4.9%), urinary tract infections (4.9%) and sepsis (4.9%). Infection was fatal in < 1%of patients (pneumonia) within 30 days of last treatment.

Median time to first onset of Grade 3 or 4 infection was 62.5 days (4 - 1014 days). Median duration ofany infection was 11 days (1 - 392 days).

Recommendations for management of infections are provided in section 4.4.

Infection led to dose interruption of tafasitamab in 27% and tafasitamab discontinuation in 4.9%.

In the L-MIND study, infusion-related reactions occurred in 6% of patients. All infusion relatedreactions were Grade 1 and resolved on the day of occurrence. Eighty percent of these reactionsoccurred during cycle 1 or 2. Symptoms included chills, flushing, dyspnoea and hypertension (seesections 4.2 and 4.4).

In 245 patients treated with tafasitamab, no treatment-emergent or treatment-boosted anti-tafasitamabantibodies were observed. Pre-existing anti-tafasitamab antibodies were detected in 17/245 patients(6.9%) with no impact on pharmacokinetics, efficacy or safety of tafasitamab.

Among 81 patients treated in the L-MIND study, 56 (69%) patients were > 65 years of age. Patients> 65 years of age had a numerically higher incidence of serious treatment emergent adverse events(TEAEs) (55%) than patients ≤ 65 years (44%).

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.

In the case of an overdose, patients should be carefully observed for signs or symptoms of adversereactions and supportive care should be administered, as appropriate.

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01FX12.

Tafasitamab is an Fc-enhanced monoclonal antibody that targets the CD19 antigen expressed on thesurface of pre-B and mature B lymphocytes.

Upon binding to CD19, tafasitamab mediates B-cell lysis through:

* engagement of immune effector cells like natural killer cells, γδ T cells and phagocytes

* direct induction of cell death (apoptosis)

The Fc modification results in enhanced antibody-dependent cellular cytotoxicity andantibody-dependent cellular phagocytosis.

In patients with relapsed or refractory DLBCL, tafasitamab led to a reduction in peripheral blood

B-cell counts. The reduction relative to baseline B-cell count reached 97% after eight days oftreatment in the L-MIND study. The maximum B-cell reduction at approximately 100% (median) wasreached within 16 weeks of treatment.

Although the depletion of B-cells in the peripheral blood is a measurable pharmacodynamic effect, itis not directly correlated with the depletion of B-cells in solid organs or in malignant deposits.

Tafasitamab plus lenalidomide followed by tafasitamab monotherapy was studied in the L-MINDstudy, an open-label multicentre single-arm study. This study was conducted in adult patients withrelapsed or refractory DLBCL after 1 to 3 prior systemic DLBCL therapies, who at the time of the trialwere not candidates for high dose chemotherapy followed by ASCT or who had refused ASCT. Oneof the prior systemic therapies had to include a CD20 targeted therapy. The study excluded patientswith severe hepatic impairment (total serum bilirubin > 3 mg/dL) and patients with renal impairment(CrCL< 60 mL/min.), as well as patients with history or evidence of clinically significantcardiovascular, CNS and/or other systemic disease. Patients with a known history of“double/triple-hit” genetics DLBCL were also excluded at study entry.

For the first three cycles, patients received 12 mg/kg tafasitamab via infusion on day 1, 8, 15 and 22 ofeach 28-day cycle, plus a loading dose on day 4 of cycle 1. Thereafter, tafasitamab was administeredon days 1 and 15 of each cycle until disease progression. Premedication including antipyretics,histamine H1 and H2 receptor blockers and glucocorticosteroids was given 30 to 120 minutes prior tothe first three tafasitamab infusions.

Patients self-administered 25 mg lenalidomide daily on days 1 to 21 of each 28-day cycle, up to12 cycles.

A total of 81 patients were enrolled in the L-MIND study. The median age was 72 years (range 41 to86 years), 89% were white and 54% were males. Out of 81 patients, 74 (91.4%) had ECOGperformance score of 0 or 1 and 7 (8.6%) had ECOG score of 2. The median number of prior therapieswas two (range: 1 to 4), with 40 patients (49.4%) receiving one prior therapy and 35 patients (43.2%)receiving 2 prior lines of treatment. Five patients (6.2%) had 3 prior lines of therapies and 1 (1.2%)had 4 prior lines of treatment. All patients had received a prior anti-CD20-containing therapy. Eightpatients had a diagnosis of DLBCL transformed from low-grade lymphoma. Fifteen patients (18.5%)had primary refractory disease, 36 (44.4%) were refractory to their last prior therapy, and 34 (42.0%)were refractory to rituximab. Nine patients (11.1%) had received prior ASCT. The primary reasons forpatients not being candidates for ASCT included age (45.7%), refractory to salvage chemotherapy(23.5%), comorbidities (13.6%) and refusal of high dose chemotherapy/ASCT (16.0%).

One patient received tafasitamab, but not lenalidomide. The remaining 80 patients received at least onedose of tafasitamab and lenalidomide. All patients enrolled in the L-MIND study had a diagnosis of

DLBCL based on local pathology. However, as per central pathology review, 10 patients could not beclassified as DLBCL.

The median duration of exposure to treatment was 9.2 months (range: 0.23, 54.67 months). Thirty-two(39.5%) patients completed 12 cycles of tafasitamab. Thirty (37.0%) patients completed 12 cycles oflenalidomide.

The primary efficacy endpoint was best objective response rate (ORR), defined as the proportion ofcomplete and partial responders, as assessed by an independent review committee (IRC). Otherefficacy endpoints included duration of response (DoR), progression-free survival (PFS) and overallsurvival (OS). The efficacy results are summarised in Table 3.

Table 3: Efficacy results in patients with relapsed or refractory diffuse large B-cell lymphomain the MOR208C203 (L-MIND) study

Efficacy parameter Tafasitamab + lenalidomide(N = 81 [ITT]*)30-NOV-2019 cut-off 30-OCT-2020 cut-off(24 months analysis) (35 months analysis)

Primary endpoint

Best objective response rate (per IRC)

Overall response rate, n (%) 46 (56.8) 46 (56.8)(95% CI) [45.3, 67.8] [45.3, 67.8]

Complete response rate, n 32 (39.5) 32 (39.5)(%) [28.8, 51.0] [28.8, 51.0](95% CI)

Partial response rate, n (%) 14 (17.3) 14 (17.3)(95% CI) [ 9.8, 27.3] [ 9.8, 27.3]

Secondary endpoint

Overall duration of response (complete + partial response) a

Median, months 34.6 43.9(95% CI) [26.1, NR] [26.1, NR]

ITT = intention to treat; NR = not reached

*One patient received only tafasitamab

CI: Binomial exact confidence interval using Clopper Pearson methoda Kaplan Meier estimates

Overall survival (OS) was a secondary endpoint in the study. After a median follow up time of42.7 months (95% CI: 38.0; 47.2), the median OS was 31.6 months (95% CI: 18.3; not reached).

Amongst the eight patients who had a DLBCL transformed from a prior indolent lymphoma, sevenpatients had an objective response (three patients a CR, four patients a PR) and one patient had astable disease as the best response to tafasitamab+ lenalidomide treatment.

In the ITT set, 36 of 81 patients were ≤ 70 years and 45 of 81 patients were > 70 years. No overalldifferences in efficacy were observed for patients ≤ 70 years versus patients > 70 years of age.

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

MINJUVI in all subsets of the paediatric population in diffuse large B-cell lymphoma (see section 4.2for 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 absorption, distribution, biotransformation and elimination were documented based on apopulation pharmacokinetic analysis.

Based on an analysis of tafasitamab in combination with lenalidomide, tafasitamab average serumtrough concentrations (± standard deviation) were 179 (± 53) μg/mL during weekly (plus an additionaldose on day 4 of cycle 1) intravenous administrations of 12 mg/kg. During administration every14 days from cycle 4 onwards, average trough serum concentrations were 153 (± 68) μg/mL. Overallmaximum tafasitamab serum concentrations were 483 (± 109) μg/mL.

The total volume of distribution for tafasitamab was 9.3 L.

The exact pathway through which tafasitamab is metabolised has not been characterised. As a human

IgG monoclonal antibody, tafasitamab is expected to be degraded into small peptides and amino acidsvia catabolic pathways in the same manner as endogenous IgG.

The clearance of tafasitamab was 0.41 L/day and terminal elimination half-life was 16.9 days.

Following long-term observations, tafasitamab clearance was found to decrease over time to0.19 L/day after two years.

Age, body weight, sex, tumour size, disease type, B-cell or absolute lymphocyte counts, anti-drugantibodies, lactate dehydrogenase and serum albumin levels had no relevant effect on thepharmacokinetics of tafasitamab. The influence of race and ethnicity on the pharmacokinetics oftafasitamab is unknown.

The effect of renal impairment was not formally tested in dedicated clinical trials; however, noclinically meaningful differences in the pharmacokinetics of tafasitamab were observed for mild tomoderate renal impairment (creatinine clearance (CrCL) ≥ 30 and < 90 mL/min estimated by the

Cockcroft-Gault equation). The effect of severe renal impairment to end-stage renal disease (CrCL< 30 mL/min) is unknown.

The effect of hepatic impairment was not formally tested in dedicated clinical trials; however noclinically meaningful differences in the pharmacokinetics of tafasitamab were observed for mildhepatic impairment (total bilirubin ≤ upper limit of normal (ULN) and aspartate aminotransferase(AST) > ULN, or total bilirubin 1 to 1.5 times ULN and any AST). The effect of moderate to severehepatic impairment (total bilirubin > 1.5 times ULN and any AST) is unknown.

Preclinical data reveal no special hazards for humans.

Repeat dose toxicology studies

Tafasitamab has shown to be highly specific to the CD19 antigen on B cells. Toxicity studiesfollowing intravenous administration to cynomolgus monkeys have shown no other effect than theexpected pharmacological depletion of B-cells in peripheral blood and in lymphoid tissues. Thesechanges reversed after cessation of treatment.

Mutagenicity/carcinogenicity

As tafasitamab is a monoclonal antibody, genotoxicity and carcinogenicity studies have not beenconducted, since such tests are not relevant for this molecule in the proposed indication.

Reproductive and developmental toxicity studies as well as specific studies to evaluate the effects onfertility have not been conducted with tafasitamab. However, no adverse effects on reproductiveorgans in males and females and no effects on menstrual cycle length in females were observed in the13-week repeat-dose toxicity study in cynomolgus monkeys.

Sodium citrate dihydrate

Citric acid monohydrate

Trehalose dihydrate

Polysorbate 20

This medicinal product must not be mixed with other medicinal products except those mentioned insection 6.6.

No incompatibilities have been observed with standard infusion materials.

Unopened vial5 years

Reconstituted solution (prior to dilution)

Chemical and physical in-use stability has been demonstrated for up to 30 days at 2 °C - 8 °C or up to24 hours at 25 °C.

From a microbiological point of view, the reconstituted solution should be used immediately. If notused immediately, in-use storage times and conditions are the responsibility of the user and wouldnormally not be longer than 24 hours at 2 - 8 °C, unless reconstitution has taken place in controlledand validated aseptic conditions. Do not freeze or shake.

Diluted solution (for infusion)

Chemical and physical in-use stability has been demonstrated for a maximum of 14 days at 2 °C -8 °C followed by up to 24 hours at up to 25 °C.

From a microbiological point of view, the diluted solution should be used immediately. If not usedimmediately, in-use storage times and conditions prior to use are the responsibility of the user andwould normally not be longer than 24 hours at 2 - 8 °C, unless dilution has taken place in controlledand validated aseptic conditions. Do not freeze or shake.

Store in a refrigerator (2 °C - 8 °C).

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.

Clear type I glass vial with a butyl rubber stopper, aluminium seal and a plastic flip-off cap containing200 mg tafasitamab. Pack size of one vial.

MINJUVI is provided in sterile, preservative-free single-use vials.

MINJUVI should be reconstituted and diluted prior to intravenous infusion.

Use appropriate aseptic technique for reconstitution and dilution.

* Determine the dose of tafasitamab based on patient weight by multiplying 12 mg by the patientweight (kg). Then calculate the number of tafasitamab vials needed (each vial contains 200 mgtafasitamab) (see section 4.2).

* Using a sterile syringe, gently add 5.0 mL sterile water for injections into each MINJUVI vial.

Direct the stream toward the walls of each vial and not directly on the lyophilised powder.

* Gently swirl the reconstituted vial(s) to aid the dissolution of the lyophilised powder. Do notshake or swirl vigorously. Do not remove the contents until all of the solids have beencompletely dissolved. The lyophilised powder should dissolve within 5 minutes.

* The reconstituted solution should appear as a colourless to slightly yellow solution. Beforeproceeding, ensure there is no particulate matter or discolouration by inspecting visually. If thesolution is cloudy, discoloured or contains visible particles, discard the vial(s).

* An infusion bag containing 250 mL sodium chloride 9 mg/mL (0.9%) solution for injectionshould be used.

* Calculate the total volume of the 40 mg/mL reconstituted tafasitamab solution needed.

Withdraw a volume equal to this from the infusion bag and discard the withdrawn volume.

* Withdraw the total calculated volume (mL) of reconstituted tafasitamab solution from the vial(s)and slowly add to the sodium chloride 9 mg/mL (0.9%) infusion bag. Discard any unusedportion of tafasitamab remaining in the vial.

* The final concentration of the diluted solution should be between 2 mg/mL to 8 mg/mL oftafasitamab.

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

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

Incyte Biosciences Distribution B.V.

Paasheuvelweg 251105 BP Amsterdam

Netherlands

EU/1/21/1570/001

Date of first authorisation: 26 August 2021

Date of latest renewal: 17 July 2024

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

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