Minjuvi, 200 mg powder for concentrate for solution for infusion

Summary of Product Characteristics Updated 30-May-2022 | Incyte Biosciences UK Ltd

 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

1. Name of the medicinal product

MINJUVI 200 mg powder for concentrate for solution for infusion

2. Qualitative and quantitative composition

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.

Excipient with known effect

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

3. Pharmaceutical form

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

White to slightly yellowish lyophilised powder.

4. Clinical particulars
4.1 Therapeutic indications

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

4.2 Posology and method of administration

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

Recommended pre-medication

A pre-medication to reduce the risk of infusion-related reactions should be administered 30 minutes to 2 hours prior to tafasitamab infusion. For patients not experiencing infusion-related reactions during the first 3 infusions, pre-medication is optional for subsequent infusions.

The pre-medication 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. In addition, appropriate medical treatment of symptoms should be initiated. After signs and symptoms are 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, pre-medication should be administered before subsequent tafasitamab infusions.

Posology

The recommended dose of MINJUVI is 12 mg per kg body weight administered as an intravenous infusion 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 of 25 mg daily on days 1 to 21 of each cycle. The starting dose and subsequent dosing may be adjusted according 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 combination therapy. Patients should continue to receive MINJUVI infusions as single agent on day 1 and 15 of each 28-day cycle, until disease progression or unacceptable toxicity.

Dose modifications

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

Table 1: Dose modifications in case of adverse reactions

Adverse reaction

Severity

Dosage modification

Infusion-related reactions

Grade 2 (moderate)

Interrupt MINJUVI infusion immediately and manage signs and symptoms.

Once signs and symptoms resolve or reduce to Grade 1, resume MINJUVI infusion at no more than 50% of the rate at which the reaction occurred. If the patient does not experience further reaction within 1 hour and vital signs are stable, the infusion rate may be increased every 30 minutes as tolerated to the rate at which the reaction occurred.

Grade 3 (severe)

Interrupt MINJUVI infusion immediately and manage signs and symptoms.

Once signs and symptoms resolve or reduce to Grade 1, resume MINJUVI infusion at no more than 25% of the rate at which the reaction occurred. If the patient does not experience further reaction within 1 hour and vital signs are stable, the infusion rate may be increased every 30 minutes as tolerated to a maximum of 50% of the rate at which the reaction occurred.

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

Grade 4 (life-threatening)

Stop the infusion immediately and permanently discontinue MINJUVI.

Myelosuppression

Platelet count of less than 50,000/µL

Withhold MINJUVI and lenalidomide and monitor complete blood count weekly until platelet count is 50,000/µL or higher.

Resume MINJUVI at the same dose and lenalidomide at a reduced dose if platelets return to ≥ 50,000/µL. Refer to the lenalidomide SmPC for dosage modifications.

Neutrophil count of less than 1,000/µL for at least 7 days

or

Neutrophil count of less than 1,000/µL with an increase of body temperature to 38 °C or higher

or

Neutrophil count less than 500/µL

Withhold MINJUVI and lenalidomide and monitor complete blood count weekly until neutrophil count is 1,000/µL or higher.

Resume MINJUVI at the same dose and lenalidomide at a reduced dose if neutrophils return to ≥ 1000/µL. Refer to the lenalidomide SmPC for dosage modifications.

Special populations

Paediatric population

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

No data are available.

Elderly

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

Renal impairment

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.

Hepatic impairment

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

Method of administration

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 first 30 minutes. Afterwards, the rate should be increased to complete the first infusion within a 2.5-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 infusion line.

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

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

Infusion-related reactions

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 be advised to contact their healthcare professionals if they experience signs and symptoms of infusion-related reactions including fever, chills, rash or breathing problems within 24 hours of infusion. 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 or discontinued and appropriate medical management should be instituted (see section 4.2).

Myelosuppression

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

Neutropenia

Neutropenia, including febrile neutropenia, has been reported during treatment with tafasitamab. Administration of granulocyte colony-stimulating factors (G-CSF) should be considered, in particular in patients with Grade 3 or 4 neutropenia. Any symptoms or signs of developing infection should be anticipated, evaluated and treated.

Thrombocytopenia

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

Infections

Fatal and serious infections, including opportunistic infections, occurred in patients during treatment with tafasitamab. Tafasitamab should be administered to patients with an active infection only if the infection is treated appropriately and well controlled. Patients with a history of recurring or chronic infections 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 of potential infection, such as chills, cough or pain on urination, develops.

Tumour lysis syndrome

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

Immunisations

The safety of immunisation with live vaccines following tafasitamab therapy has not been investigated and 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.

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

4.6 Fertility, pregnancy and lactation

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

Women of childbearing potential/Contraception in females

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

Pregnancy

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 the placenta 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-cell depletion and vaccinations with live virus vaccines should be postponed until the infant's B-cell count has recovered (see section 4.4).

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

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

Breast-feeding

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

Fertility

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

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of the safety profile

The most common adverse reactions are: infections (73%), neutropenia (51%), asthenia (38%), 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%), and febrile neutropenia (6%).

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

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

Tabulated list of adverse reactions

Adverse reactions reported in clinical trials are listed by MedDRA System Organ Class and by frequency. 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. The adverse 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 medicinal product, 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 (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 2: Adverse reactions in patients with relapsed or refractory DLBCL who received tafasitamab 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 fatal outcomes (e.g. bronchopulmonary aspergillosis, bronchitis, pneumonia and urinary tract infection)

Common

Sepsis (including neutropenic sepsis)

Neoplasms benign, malignant and unspecified (incl. cysts and polyps)

Common

Basal cell carcinoma

Blood and lymphatic system disorders

Very common

Febrile neutropenia+, neutropenia+, thrombocytopenia+, anaemia, leukopenia+

Common

Lymphopenia

Immune system disorders

Common

Hypogammaglobulinaemia

Metabolism and nutrition disorders

Very common

Hypokalaemia, decreased appetite

Common

Hypocalcaemia, hypomagnesaemia

Nervous system disorders

Common

Headache, paraesthesia, dysgeusia

Respiratory, thoracic and mediastinal disorders

Very common

Dyspnoea, cough

Common

Exacerbation of chronic obstructive pulmonary disease, 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 tissue disorders

Very common

Rash (includes different types of rash, e.g. rash, rash maculopapular, rash pruritic, rash erythematous)

Common

Pruritus, alopecia, erythema, hyperhidrosis

Musculoskeletal and connective tissue disorders

Very common

Back pain, muscle spasms

Common

Arthralgia, pain in extremity, musculoskeletal pain

Renal and urinary disorders

Common

Blood creatinine increased

General disorders and administration site conditions

Very common

Asthenia (includes malaise), fatigue, oedema peripheral, pyrexia

Common

Mucosal inflammation

Investigations

Common

Weight decreased, C-reactive protein increased

Injury, poisoning and procedural complications

Common

Infusion related reaction

+Further information on this adverse reaction is provided in the text below.

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

Description of selected adverse reactions

Myelosuppression

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 of tafasitamab and/or administration of G-CSF (see sections 4.2 and 4.4). Myelosuppression led to interruption 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 or 4 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).

Thrombocytopenia

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); median time to onset to first occurrence of thrombocytopenia was 71 days (range 1 – 358 days).

Anaemia

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

When patients in the L-MIND study were switched from tafasitamab and lenalidomide in the combination therapy phase to tafasitamab alone in the extended monotherapy phase, the incidences of haematological events decreased by at least 20% for neutropenia, thrombocytopenia and anaemia; no incidences of febrile neutropenia were reported with tafasitamab monotherapy (see sections 4.2 and 4.4).

Infections

In the L-MIND study, infections occurred in 73% of patients. Incidence of Grade 3 or 4 infections was 28%. The most frequently reported Grade 3 or higher infections were pneumonia (7%), respiratory tract 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 of any 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%.

Infusion-related reactions

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

Immunogenicity

In 245 patients treated with tafasitamab, no treatment-emergent or treatment-boosted anti-tafasitamab antibodies 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.

Special populations

Elderly

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 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

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

5. Pharmacological properties
5.1 Pharmacodynamic properties

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

Mechanism of action

Tafasitamab is an Fc-enhanced monoclonal antibody that targets the CD19 antigen expressed on the surface 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 and antibody-dependent cellular phagocytosis.

Pharmacodynamic effects

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 of treatment in the L-MIND study. The maximum B-cell reduction at approximately 100% (median) was reached within 16 weeks of treatment.

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

Clinical efficacy

Tafasitamab plus lenalidomide followed by tafasitamab monotherapy was studied in the L-MIND study, an open-label multicentre single-arm study. This study was conducted in adult patients with relapsed or refractory DLBCL after 1 to 3 prior systemic DLBCL therapies, who at the time of the trial were not candidates for high dose chemotherapy followed by ASCT or who had refused ASCT. One of the prior systemic therapies had to include a CD20 targeted therapy. The study excluded patients with 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 significant cardiovascular, 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 of each 28-day cycle, plus a loading dose on day 4 of cycle 1. Thereafter, tafasitamab was administered on days 1 and 15 of each cycle until disease progression. Pre-medication including antipyretics, histamine H1 and H2 receptor blockers and glucocorticosteroids was given 30 to 120 minutes prior to the first three tafasitamab infusions.

Patients self-administered 25 mg lenalidomide daily on days 1 to 21 of each 28-day cycle, up to 12 cycles.

A total of 81 patients were enrolled in the L-MIND study. The median age was 72 years (range 41 to 86 years), 89% were white and 54% were males. Out of 81 patients, 74 (91.4%) had ECOG performance score of 0 or 1 and 7 (8.6%) had ECOG score of 2. The median number of prior therapies was 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 CD20-containing therapy. Eight patients 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 for patients 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 one dose 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 be classified 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 of lenalidomide.

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

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

Efficacy parameter

Tafasitamab + lenalidomide

(N = 81 [ITT]*)

30-NOV-2019 cut-off

(24 months analysis)

30-OCT-2020 cut-off

(35 months analysis)

Primary endpoint

Best objective response rate (per IRC)

Overall response rate, n (%)

(95% CI)

46 (56.8)

[45.3, 67.8]

46 (56.8)

[45.3, 67.8]

Complete response rate, n (%)

(95% CI)

32 (39.5)

[28.8, 51.0]

32 (39.5)

[28.8, 51.0]

Partial response rate, n (%)

(95% CI)

14 (17.3)

[ 9.8, 27.3]

14 (17.3)

[ 9.8, 27.3]

Secondary endpoint

Overall duration of response (complete + partial response) a

Median, months

(95% CI)

34.6

[26.1, NR]

43.9

[26.1, NR]

ITT=intention to treat; NR = not reached

*One patient received only tafasitamab

CI: Binomial exact confidence interval using Clopper Pearson method

a Kaplan Meier estimates

Overall survival (OS) was a secondary endpoint in the study. After a median follow up time of 42.7 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, seven patients had an objective response (three patients a CR, four patients a PR) and one patient had a stable disease as the best response to tafasitamab+ lenalidomide treatment.

Elderly

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

Paediatric population

The Medicines and Healthcare products Regulatory 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 4.2 for information on paediatric use).

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

The Medicines and Healthcare products Regulatory Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.

5.2 Pharmacokinetic properties

The absorption, distribution, biotransformation and elimination were documented based on a population pharmacokinetic analysis.

Absorption

Based on an analysis of tafasitamab in combination with lenalidomide, tafasitamab average serum trough concentrations (± standard deviation) were 179 (± 53) μg/mL during weekly (plus an additional dose on day 4 of cycle 1) intravenous administrations of 12 mg/kg. During administration every 14 days from cycle 4 onwards, average trough serum concentrations were 153 (± 68) μg/mL. Overall maximum tafasitamab serum concentrations were 483 (± 109) μg/mL.

Distribution

The total volume of distribution for tafasitamab was 9.3 L.

Biotransformation

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 acids via catabolic pathways in the same manner as endogenous IgG.

Elimination

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 to 0.19 L/day after two years.

Special populations

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

Renal impairment

The effect of renal impairment was not formally tested in dedicated clinical trials; however, no clinically meaningful differences in the pharmacokinetics of tafasitamab were observed for mild to moderate 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.

Hepatic impairment

The effect of hepatic impairment was not formally tested in dedicated clinical trials; however no clinically meaningful differences in the pharmacokinetics of tafasitamab were observed for mild hepatic 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 severe hepatic impairment (total bilirubin > 1.5 times ULN and any AST) is unknown.

5.3 Preclinical safety data

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 studies following intravenous administration to cynomolgus monkeys have shown no other effect than the expected pharmacological depletion of B-cells in peripheral blood and in lymphoid tissues. These changes reversed after cessation of treatment.

Mutagenicity/carcinogenicity

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

Reproductive toxicity

Reproductive and developmental toxicity studies as well as specific studies to evaluate the effects on fertility have not been conducted with tafasitamab. However, no adverse effects on reproductive organs in males and females and no effects on menstrual cycle length in females were observed in the 13-week repeat-dose toxicity study in cynomolgus monkeys.

6. Pharmaceutical particulars
6.1 List of excipients

Sodium citrate dihydrate

Citric acid monohydrate

Trehalose dihydrate

Polysorbate 20

6.2 Incompatibilities

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

No incompatibilities have been observed with standard infusion materials.

6.3 Shelf life

Unopened vial

4 years

Reconstituted solution (prior to dilution)

Chemical and physical in-use stability has been demonstrated for up to 24 hours at 2 °C – 25 °C.

From a microbiological point of view, unless the method of reconstitution precludes the risk of microbial contamination, the reconstituted solution should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user. Do not freeze or shake.

Diluted solution (for infusion)

Chemical and physical in-use stability has been demonstrated for a maximum of 36 hours 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 used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 – 8 °C, unless dilution has taken place in controlled and validated aseptic conditions. Do not freeze or shake.

6.4 Special precautions for storage

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.

6.5 Nature and contents of container

Clear type I glass vial with a butyl rubber stopper, aluminium seal and a plastic flip-off cap containing 200 mg tafasitamab. Pack size of one vial.

6.6 Special precautions for disposal and other handling

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.

Instructions for reconstitution

• Determine the dose of tafasitamab based on patient weight by multiplying 12 mg by the patient weight (kg). Then calculate the number of tafasitamab vials needed (each vial contains 200 mg tafasitamab) (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 not shake or swirl vigorously. Do not remove the contents until all of the solids have been completely dissolved. The lyophilised powder should dissolve within 5 minutes.

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

Instructions for dilution

• An infusion bag containing 250 mL sodium chloride 9 mg/mL (0.9%) solution for injection should 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 unused portion of tafasitamab remaining in the vial.

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

• 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 local requirements.

7. Marketing authorisation holder

Incyte Biosciences UK Ltd

First Floor Q1, The Square

Randalls Way, Leatherhead

KT22 7TW, UK

8. Marketing authorisation number(s)

PLGB 42338/0016

9. Date of first authorisation/renewal of the authorisation

08/10/2021

10. Date of revision of the text

20/05/2022

Detailed information on this medicinal product is available on the website of the Medicines and Healthcare products Regulatory Agency http://www.mhra.gov.uk.

Company Contact Details
Incyte Biosciences UK Ltd
Address

First Floor Q1, The Square, Randalls Way, Leatherhead, Surrey, KT22 7TW, UK

Telephone

+44 800 7833711

Medical Information Direct Line

00800 000 274 23

WWW

http://www.incyte.com

Fax

0800 0669105

Medical Information e-mail