POTELIGEO 4mg / ml concentrate for solution for infusion medication leaflet

POTELIGEO 4 mg/mL concentrate for solution for infusion

Each vial contains 20 mg of mogamulizumab in 5 mL, corresponding to 4 mg/mL.

Mogamulizumab is produced in Chinese hamster ovary cells by recombinant DNA technology.

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion.

Clear to slightly opalescent, colourless solution.

POTELIGEO is indicated for the treatment of adult patients with mycosis fungoides (MF) or Sézarysyndrome (SS) who have received at least one prior systemic therapy.

Treatment must be initiated and supervised by physicians experienced in the treatment of cancer, andshould only be administered by healthcare professionals in an environment where resuscitationequipment is available.

The recommended dose is 1 mg/kg mogamulizumab administered as an intravenous infusion over atleast 60 minutes. Administration is weekly on days 1, 8, 15 and 22 of the first 28-day cycle, followedby infusions every two weeks on Days 1 and 15 of each subsequent 28-day cycle until diseaseprogression or unacceptable toxicity.

POTELIGEO should be administered within 2 days of the scheduled day. If a dose is missed by morethan 2 days, the next dose should be administered as soon as possible, after which the dosing scheduleshould be resumed with doses given based on the new scheduled days.

Pre-medication with anti-pyretic and anti-histamine is recommended for the first POTELIGEOinfusion. If an infusion reaction occurs, administer pre-medication for subsequent POTELIGEOinfusions.

Patients receiving mogamulizumab have experienced drug rash (drug eruption), some of which weresevere and/or serious.

* In the event of a rash (drug related) with severity of Grade 2 or 3 (moderate or severe),treatment with mogamulizumab must be interrupted and the rash should be treated appropriatelyuntil rash improves to Grade 1 or less (mild severity), at which time mogamulizumab treatmentmay be resumed.

* POTELIGEO should be permanently discontinued for a life-threatening (Grade 4) rash (seesection 4.4).

* The infusion of POTELIGEO should be temporarily interrupted for mild to severe (Grades 1-3)infusion-related reactions and symptoms treated. The infusion rate should be reduced by at least50% when re-starting the infusion after symptoms resolve. If reaction recurs, discontinuing theinfusion should be considered (see section 4.4).

* POTELIGEO should be permanently discontinued for a life-threatening (Grade 4)infusion-related reaction (see section 4.4).

The safety and efficacy of POTELIGEO in children and adolescents aged below 18 years have notbeen established. No data are available.

No dose adjustment is required in elderly patients (see section 5.2).

Based on a population pharmacokinetic analysis, no dose adjustment is recommended in patients withmild to severe renal impairment (see section 5.2).

Based on a population pharmacokinetic analysis, no dose adjustment is recommended in patients withmild or moderate hepatic impairment. POTELIGEO has not been studied in patients with severehepatic impairment (see section 5.2).

POTELIGEO is for intravenous use. It should be administered by intravenous infusion only, over atleast 60 minutes. See above recommendations in case of infusion-related reaction.

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

Patients receiving mogamulizumab have experienced drug rash (drug eruption), some of which weresevere and/or serious.

When mogamulizumab has been administered to patients with T-cell lymphomas other than MF or SS,serious skin reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis(TEN), have been reported in less than 1% of patients during clinical trials, and also reported duringthe post-marketing period; some of these cases were reported with fatal outcomes. Patients should beclosely monitored for symptoms or signs that suggest SJS or TEN. If they occur, POTELIGEO shouldbe interrupted and treatment should not restart unless SJS or TEN is ruled out and cutaneous reactionhas resolved to Grade 1 or less. If SJS/TEN occur, appropriate medical therapy should beadministered. See section 4.2 for dose modification information.

Acute infusion-related reactions (IRRs) have been observed in patients treated with mogamulizumab.

The IRRs were mostly mild or moderate in severity, although there have been a few reports of severereactions (Grade 3). The majority of IRRs occur during or shortly after the first infusion (all within24 hours of administration), with the incidence decreasing over subsequent treatments.

Patients should be carefully monitored during and after infusion. If an anaphylactic reaction occurs,administration of mogamulizumab should be immediately and permanently discontinued andappropriate medical therapy should be administered.

If an IRR occurs, the infusion should be interrupted and appropriate medical management instituted.

The infusion may be restarted at a slower rate after symptom resolution. See section 4.2 for pre-medication and dose modification information.

Subjects with MF or SS treated with mogamulizumab are at increased risk of serious infection and/orviral reactivation. The combination of mogamulizumab with systemic immune modulating medicinalproducts or with other licensed therapies for MF or SS has not been studied and is, therefore, notrecommended, especially in consideration of the risk of severe infections in patients treated withmogamulizumab. Topical steroids or low doses of systemic corticosteroids may be used duringtreatment with mogamulizumab; however, the risk of serious infection and/or viral reactivation may behigher in case of concomitant administration with systemic immunosuppressive agents. Patientsshould be monitored for signs and symptoms of infection and treated promptly.

Patients should be tested for hepatitis B infection before initiating treatment with mogamulizumab. Forpatients who test positive for current/previous hepatitis B infection, consultation with a physician withexpertise in the treatment of hepatitis B is recommended for advice concerning appropriate measuresagainst hepatitis B reactivation.

Complications of allogeneic hematopoietic stem cell transplantation (HSCT) after mogamulizumab

Complications, including severe graft versus host disease (GVHD), have been reported in patientswith T-cell lymphomas other than MF or SS who received allogeneic HSCT after mogamulizumab.

A higher risk of transplant complications has been reported if mogamulizumab is given within a shorttime frame (approximately 50 days) before HSCT. Follow patients closely for early evidence oftransplant-related complications.

The safety of treatment with mogamulizumab after autologous or allogeneic HSCT has not beenstudied.

Tumour lysis syndrome (TLS) has been observed in patients receiving mogamulizumab. TLS wasobserved most frequently during the first month of treatment. Patients with rapidly proliferatingtumour and high tumour burden are at risk of TLS. Patients should be monitored closely byappropriate laboratory and clinical tests for electrolyte status, hydration and renal function, particularlyin the first month of treatment, and managed according to best medical practice. Management of TLSmay include aggressive hydration, correction of electrolyte abnormalities, anti-hyperuricaemictherapy, and supportive care.

One case of acute myocardial infarction has been observed in a clinical trial patient with MF/SSreceiving mogamulizumab. In clinical trial patients with other T-cell lymphomas there have beenreports of stress cardiomyopathy (one case) and acute myocardial infarction (one case). The subjectshad a medical history including various risk factors. Patients who have risk factors associated withcardiac disease should be monitored and appropriate precautions taken.

There are limited data available on patients with LCT.

Mogamulizumab should not be administered subcutaneously or intramuscularly, by rapid intravenousadministration, or as an intravenous bolus.

This medicinal product contains less than 1 mmol sodium per dose, that is to say essentially ‘sodiumfree’.

This medicine contains 1 mg of polysorbate 80 in each vial which is equivalent to 0.2mg/mL.

Polysorbates may cause allergic reactions.

No interaction studies have been performed.

Women of childbearing potential should use effective contraception during treatment with

POTELIGEO and for at least 6 months after treatment.

There are no data from the use of mogamulizumab in pregnant women. Although mogamulizumabcrosses the placental barrier in cynomolgus monkey, apart from the pharmacological effect in foetuses,animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity(see section 5.3). As a precautionary measure, it is preferable to avoid the use of mogamulizumabduring pregnancy.

It is unknown whether mogamulizumab is excreted in human milk. Human IgGs are known to beexcreted in breast milk during the first few days after birth, which is decreasing to low concentrationssoon afterwards; consequently, a risk to the breast-fed child cannot be excluded during this shortperiod. Afterwards POTELIGEO could be used during breast-feeding if clinically needed.

There are no clinical data available on the effect of mogamulizumab on human fertility. No specificstudies in animals have been performed to evaluate the effect of mogamulizumab on fertility. Noadverse effects on male and female reproductive organs were observed in repeat-dose toxicity studiesin cynomolgus monkeys (see section 5.3).

Mogamulizumab has minor influence on the ability to drive and use machines. Fatigue may occurfollowing administration of mogamulizumab (see section 4.8).

The most frequently reported serious adverse reactions were pneumonia, pyrexia, infusion relatedreaction and cellulitis.

The most frequently reported adverse reactions were infusion-related reaction and rash (drugeruption); most of these reactions were non-serious and Grades 1 or 2.

Severe adverse reactions included Grade 4 respiratory failure (1.1%) and Grade 5 reactions werepolymyositis and sepsis (0.5% each).

The adverse reactions are presented by system organ class and frequency categories, defined using thefollowing convention: 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), not known (cannot be estimated from theavailable data). Within each frequency grouping, undesirable effects are presented in order ofdecreasing seriousness.

Table 1: Adverse drug reactions occurring in patients receiving POTELIGEO (N=184)

System organ class (SOC) Frequency Adverse reaction

Blood and lymphatic system disorders Common Anaemia, neutropenia, leukopenia,

Endocrine disorders Common Hypothyroidism

Very common Constipation, diarrhoea, nausea,

Gastrointestinal disorders stomatitis

Common Vomiting

Common Colitis

General disorders and administration siteconditions Very common Fatigue, oedema peripheral, pyrexia

Hepatobiliary disorders Uncommon Hepatitis acute, hepatitisa

Infections and infestations Very common Infections

Common Upper respiratory tract infection

Injury, poisoning and proceduralcomplications Very common Infusion related reaction

Alanine aminotransferase increased,

Investigations Common aspartate aminotransferase increased,blood alkaline phosphatase increased,lymphocyte count decreased

Metabolism and nutrition disorders Uncommon Tumour lysis syndrome

Nervous system disorders Very common Headache

Skin and subcutaneous tissue disorders Very common Drug eruption (including skin rash)a Folliculitis, Cellulitis, Candidiasis, Pneumonia, Sepsis, Skin infection, Otitis externa, Herpes zoster,

Staphylococcal skin infection, Urinary tract infection, Herpes simplex and cytomegalovirus

Patients receiving POTELIGEO have experienced drug rash (drug eruption), some of which weresevere and/or serious. The majority of treatment-related dermatologic reactions were Grade 1 or 2,with Grade ≥3 drug rash occurring in 4.3% of patients. No trend in latency to event onset wasidentified for drug eruptions and rashes; both early and late-onset events occurred.

Infusion-related reactions have been observed in 33% of patients treated with POTELIGEO. Themajority of treatment-related infusion-related reactions were Grade 1 or 2 and occurred during orshortly after the first infusion. Severe reactions (Grade 3) were experienced by 4% of patients.

The incidence of infusion related reactions was highest after the first infusion (28.8% of subjects),reducing to ≤ 3.8% of subjects after two or more infusions.

Infusion interruptions occurred in approximately 6% of patients, most of which (approximately 90%)occurred within the first cycle of treatment with mogamulizumab.

Less than 1% of patients treated in Clinical Trial 0761-010 discontinued treatment due to infusion-related reactions.

Patients with MF or SS are at increased risk of serious infection due to the disruption of dermalintegrity caused by cutaneous disease, as well as the immunosuppressive effects of extracutaneousdisease, and treatment with mogamulizumab may increase that risk. Serious infections, includingsepsis, pneumonia and skin infections, were experienced by 14.3% of subjects receivingmogamulizumab. The latency to event onset following the first dose varied considerably. The majorityof patients recovered from infection. In the clinical trial (0761-010), there were 2 reports of respiratoryfailure with fatal outcome in patients with severe pneumonia occurring more than 9 months afterstarting treatment with mogamulizumab.

Following infusion of POTELIGEO during clinical trials of the use of POTELIGEO in patients withadult T-cell leukaemia-lymphoma or cutaneous T-cell lymphoma, approximately 14% of patients (44out of 313 evaluable patients) tested positive for treatment emergentanti-mogamulizumab antibodies. There were no patients identified to have positive neutralisingantibody responses.

Colitis was mainly characterized by watery diarrhoea, in some cases excessive.

Of the 320 subjects exposed to mogamulizumab in Clinical Trial 0761-010, 21 (6.6%), experienced atleast one serious adverse drug reaction (SADR) that occurred within 90 days from the date of laststudy drug administration.

Of these, SADRs that were reported in more than one patient were coded under the SOCs Infectionsand infestations (7 [2.2%] patients), General disorders and administration site conditions (5 [1.6%]patients), Respiratory, thoracic and mediastinal disorders (4 [1.3%] patients), Musculoskeletal andconnective tissue disorders (3 [0.9%] patients), Hepatobiliary disorders (2 [0.6%] patients), and Injury,poisoning and procedural complications (2 [0.6%] patients). All remaining SOCs reported SADRs inone patient (0.3%).

The safety profile observed in the 90 days following the last dose of mogamulizumab is consistentwith the safety profile observed during the study treatment period.

The safety profile in elderly patients (≥ 65 years) was generally consistent with that of adult patients,except for dermatologic reactions and infusion related reactions which were seen more often in oldersubjects.

Reporting suspected adverse reactions

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.

There is no information on overdose with mogamulizumab. In case of overdose, the patient, includingtheir vital signs, should be closely monitored (for at least 1 hour) and supportive treatment should beadministered if required.

Pharmacotherapeutic group: Antineoplastic and immunomodulating agents, monoclonal antibodies

ATC code: L01FX09

Mogamulizumab is a defucosylated, humanised IgG1 kappa immunoglobulin that selectively binds to

CCR4, a G protein-coupled receptor for CC chemokines that is involved in the trafficking oflymphocytes to various organs including the skin, resulting in depletion of the target cells. CCR4 isexpressed on the surface of some cancer cells including T cell malignancies, such as MF and SS inwhich CCR4 expression is inherent.

The efficacy of mogamulizumab in the treatment of patients with mycosis fungoides (MF) or Sézarysyndrome (SS) was established in a Phase 3, multicentre, open-label, clinical trial (0761-010) of 372adult patients randomised 1:1 to treatment with either mogamulizumab or vorinostat. Each armenrolled 186 patients. Mogamulizumab infusion was administered at a dose of 1 mg/kg once weeklyfor the first 28-day cycle (on Days 1, 8, 15 and 22), and on days 1 and 15 of subsequent 28-day cycles.

Vorinostat was administered at a starting dose of 400 mg orally, once daily beginning on day 1 for 28-day cycles. Vorinostat patients with disease progression or unacceptable toxicities were permitted tocross over to mogamulizumab therapy. Crossover patients received up to 46 months ofmogamulizumab therapy, as of December 2016 data cut. Treatment with mogamulizumab continueduntil disease progression or unacceptable toxicity. The trial excluded patients with active autoimmunediseases, central nervous system metastasis, and medical conditions that required systemiccorticosteroids or other immunosuppressive medicinal products, or an active infection requiringtherapy, including HIV, or hepatitis B or C. Patients with ECOG performance status ≥2 were alsoexcluded. At study baseline, 38% had stage IB-II disease, 10% stage III, 52% stage IV. This studyincluded patients regardless of their baseline level of CCR4 expression in skin biopsy.

The primary efficacy endpoint was progression-free survival (PFS) based on investigator assessmentusing a global composite response criteria that took into account all potentially affected diseasecompartments (skin, blood, lymph nodes and viscera). Response in skin and blood was evaluatedevery 4 weeks. Response in lymph nodes and viscera was evaluated at 4 weeks, then every 8 weeks inthe first year, and then every 16 weeks thereafter.

All patients had a histologically confirmed diagnosis of mycosis fungoides (MF), 56.5%, 53.2%, or

Sézary Syndrome (SS), 43.5%, 46.8%, in the mogamulizumab and vorinostat groups, respectively, andhad received at least one prior systemic therapy. The most common prior systemic therapies used bysubjects in Europe were bexarotene (70%), interferon (59%), methotrexate (49%), extracorporealphotopheresis (ECP) (31%) and gemcitabine/gemcitabine regimens (28%).

The median duration of exposure with mogamulizumab was 5.6 months (range: <1 to 45.3 months).56% of patients received mogamulizumab for at least 6 cycles, and 25% of patients receivedmogamulizumab for at least 12 cycles.

Patients were a median age of 64 years at the time of screening (range 25 to 101 years), 49.5% were65 years or older, and 58.1% were male.

CCR4 expression was assessed retrospectively on pretreatment skin biopsies (formalin fixed paraffinembedded) using immunohistochemistry. In the mogamulizumab arm, baseline CCR4 expressionlevels were available in 75% of patients (N=140). CCR4 was detected on ≥1% of lymphocytes in100% of patients, and 96% (134/140) had CCR4 detected on ≥10% of skin lymphocytes.

Of the patients randomised to vorinostat, 136 patients (73.1%) crossed over to mogamulizumab duringthe study. Reasons for crossover to mogamulizumab were disease progression (109 patients) andtreatment intolerance (27 patients). The number of infusions of mogamulizumab administered tocrossover patients ranged from 1 to 94 (up to 46 months of treatment) as of the December 2016datacut.

At 6, 12, 18 and 24 months after the start of randomised treatment, the percent of subjects alivewithout disease progression was higher for mogamulizumab (55.3%, 38.3%, 28.0%, and 14.1%,respectively) compared to vorinostat (28.8%, 15.3%, 7.2%, and 7.2%, respectively). Median PFS forthe mogamulizumab group was 7.70 months (95% CI: 5.67, 10.33) and 3.10 months (95% CI: 2.87,4.07) for the vorinostat group with resultant hazard ration of 0.53 (95% CI: 0.41, 0.69), p<0.0001 (2-sided, stratified log rank test).

The Kaplan-Meier curve for PFS is shown Figure 1.

Figure 1: Plot of Kaplan-Meier curve of progression-free survival by investigator’s assessment(ITT) population

Key secondary endpoints were overall response rate (ORR), ORR after crossover, duration of response(DOR), and changes from baseline of the Skindex-29 Symptoms and Functional Scales, and

Functional Assessment of Cancer Therapy-General (FACT-G) Physical and Functional Well-beingdomains.

Overall response was reported as a composite score from measures in each compartment, and aresponse had to be demonstrated at two successive overall disease assessments (at least 8 weeks apartduring the first year and 16 weeks apart thereafter) in order to be confirmed. Patients were included inthe analysis for a specific compartment if they had presence of disease in that compartment atbaseline, or had any post-baseline response assessment for that compartment.

Table 2 summarises ORR and DOR, and response by compartment. The study demonstratedstatistically significant improvements in ORR and response by compartment in the blood, skin, andlymph nodes as compared to vorinostat. Response in the viscera could not be evaluated due to limitedefficacy data in subjects with visceral involvement; the benefit-risk of mogamulizumab in subjectswith visceral involvement is currently undetermined due to lack of data.

Table 2: Response during randomised treatment period in clinical trial 0761-010 (intent-to-treat)

Mogamulizumab Vorinostat

N=186 N=186

Overall response rate 28.0 4.8(confirmed CR + PR, %)95% CI (21.6, 35.0) (2.2, 9.0)

P-valuea <.0001

Duration of response (months)

Median (95% CI) 14.1 (9.4, 19.2) 9.13 (4.7,-)

Response by compartment

Blood n=124 n=125

Response rate (confirmed CR + PR, %) 66.9 18.495% CI (57.9, 75.1) (12.0, 26.3)

P-valuea <0.0001

Skin n=186 n=186

Overall response rate (confirmed CR + PR, %) 41.9 15.695% CI (34.8, 49.4) (10.7, 21.6)

P-valuea <.0001

Lymph nodes n=136 n=133

Overall response rate (confirmed CR + PR, %) 15.4 3.895% CI (9.8, 22.6) (1.2, 8.6)

P-valuea 0.0008

Viscera n=6 n=4

Overall response rate (confirmed CR + PR, %) 0 095% CI (0.0, 45.9) (0.0, 60.2)

Note: Overall response rate is based on Global Composite Response score.a: P-value was obtained from Cochran-Mantel-Haenszel test adjusting for disease type, disease stage, and region.

CI=confidence interval; CR=complete response; PR=partial response

Treatment with mogamulizumab resulted in 8 confirmed complete responses (complete clearing of allaffected compartments) compared with 0 patients on vorinostat: 4 of these 8 patients were initiallyrandomized to mogamulizumab and 4 had crossed over to mogamulizumab during the study. Forty-one of the 136 cross-over patients (30.1%) responded with either partial or complete response withmogamulizumab.

There are limited efficacy data in patients with low (<10%) CCR4 expression in the skin. In Clinical

Trial 0761-010 there were 10/290 evaluable patients with CCR4 expression <10%, of which 6 wererandomised to mogamulizumab, and 4 were randomised to vorinostat and subsequently crossed over tomogamulizumab. No confirmed responses were observed in these 10 subjects with low (<10%) CCR4expression. Compartmental responses were seen in 3 of 10 evaluable subjects treated withmogamulizumab in the randomised or cross over phase.

Patients with stage IB/II disease treated with mogamulizumab had confirmed ORR of 17.6%compared to 8.3% for vorinostat, and compartment level (blood, skin, lymph node) response rates thatwere higher than those for vorinostat treated patients (Table 3). Overall, the median period ofprogression free survival for stage IB/II subjects treated with mogamulizumab was 4.7 monthscompared to 3.9 months for vorinostat-treated patients (Table 4). In patients with stage IB/II disease,given the limited number of subjects with a response and immaturity of the data, no conclusion onduration of response can be made.

Time to compartment level response in Stage IB/II patients was approximately 3 months, which isconsistent with time to response for the ITT population overall (approximately 3 months). If acompartment level response or overall response is not observed after 3 months of treatment,discontinuation of treatment should be considered.

T able 3: Overall and Compartmental Response Rate in Early Disease Stages

Mogamulizumab Vorinostat Risk Diff (M vs. V)

Disease stage IB/II N=68 N=72

Overall response rate (ORR), n (%) 12 (17.6) 6 (8.3) 9.3

Compartment:

Blood (n) 17 23

Response Rate (n, %) 8 (47.1) 4 (17.4) 29.795% CIa (23.0, 72.2) (5.0, 38.8) (-2.2, 57.1)

Skin (n) 68 72

Response Rate (n, %) 19 (27.9) 14 (19.4) 8.595% CIa (17.7, 40.1) (11.1, 38.8) (-8.3, 24.9)

Nodal (n) 41 40

Response Rate (n, %) 4 (9.8) 1 (2.5) 7.395% CIa (2.7, 23.1) (0.1, 13.2) (-14.3, 28.6)

M=mogamulizumab. V= vorinostat

Table 4: Progression Free Survival (PFS) by Treatment Group and Disease Stage (Randomised

Treatment Period)

Mogamulizumab Vorinostat P value

PFS, months

ITT Population 7.70 (5.67, 10.33) 3.10 (2.87, <0.00014.07)

IB/II 4.7 (2.9 -7.47) 3.9 (2.87- 0.67904.73)

III/IV 10.9 (7.03-15.03) 3.0 (2.83- <0.00013.87)

ITT=intent to treat

The European Medicines Agency has waived the obligation to submit the results of studies withmogamulizumab in all subsets of the paediatric population in cutaneous T-cell lymphoma (CTCL)(MF and SS are subtypes of CTCL). See section 4.2 for information on paediatric use.

The pharmacokinetics (PK) of mogamulizumab was evaluated in adult patients with T-cell leukaemia-lymphoma (ATL) and CTCL over a dose range of 0.01 to 1 mg/kg administered as multiple doses ofmogamulizumab every week or every 2 weeks, and included the recommended 1.0 mg/kg dose andregimen (days 1, 8, 15 and 22 for the first 28-day cycle and on Days 1 and 15 for subsequent 28-daycycles). The population PK analysis included 444 patients receiving mogamulizumab in six clinicaltrials. The exposure to mogamulizumab increased proportionally with dose over the dose range of 0.1to 1.0 mg/kg.

Mogamulizumab is dosed via intravenous route and therefore is immediately and completelybioavailable.

Based on a population PK analysis, the geometric mean [% coefficient of variation (CV%)] centralvolume of distribution (Vc) was 3.57 L (20.1%).

The metabolic pathway of mogamulizumab has not been characterised. Mogamulizumab is expectedto be degraded into small peptides and amino acids via catabolic pathways in the same manner asendogenous IgG.

Based on a population PK analysis, the geometric mean (% coefficient of variation [CV%]) clearance(CL) is 12.0 mL/h (83.7%) and geometric mean elimination half-life (t1/2) is 17 days (65.5%).

Mogamulizumab exhibits linear PK from the dose in a dose range of 0.01 mg/kg to 1 mg/kg. Based ona population PK analysis, the steady-state concentrations of mogamulizumab were reached after12 weeks of repeated dosing when administered using the recommended regimen, and systemicaccumulation was 1.7-fold. On a power model analysis, no deviation from dose proportionality wasevident.

The effect of renal impairment on the clearance of mogamulizumab was evaluated by a population PKanalysis in patients with mild (creatinine clearance [CrCL] between 60 and 89; n= 157), moderate(CrCL between 59 and 30; n= 80), or severe renal impairment (CrCL less than 30 mL/min; n= 2). Noclinically important differences in the clearance of mogamulizumab were found between patients withmild to severe renal impairment and patients with normal renal function.

The effect of hepatic impairment on the clearance of mogamulizumab was evaluated by a population

PK analysis in patients with mild hepatic impairment (total bilirubin [TB] less than or equal to theupper limit of normal [ULN] and AST greater than ULN or TB less than 1 to 1.5 times ULN and any

AST; n= 80) or moderate (TB greater than 1.5 to 3 times ULN and any AST; n=3) hepatic impairment.

No clinically important differences in the clearance of mogamulizumab were found between patientswith mild to moderate hepatic impairment and patients with normal hepatic function. Mogamulizumabhas not been studied in patients with severe hepatic impairment (TB greater than 3 times ULN and any

AST).

The effects of various covariates on the PK s of mogamulizumab were assessed in population PKanalyses. The following factors had no clinically important effect on the CL of mogamulizumab: age(range: 22 to 101 years), sex, ethnicity (other than Japanese, limited data are available in other ethnicpopulations), renal impairment, mild or moderate hepatic impairment, disease subtype (mycosisfungoides (MF) or Sézary Syndrome (SS)), degree of CCR4 expression or ECOG status, although itshould be noted that patients with ECOG PS ≥2 were excluded from the clinical trials.

Exposure-Response analysis indicated that efficacy was not correlated with mogamulizumab exposurein the pivotal study. Efficacy, as measured by improvement in PFS based on investigator assessment,was not associated with increasing mogamulizumab exposure.

Non-clinical data reveal no special hazard for humans based on conventional studies of repeat dosetoxicity. Carcinogenicity or genotoxicity studies have not been conducted with mogamulizumab. Nospecific studies have been conducted to evaluate potential effects on fertility.

No mogamulizumab-related toxic effects in the male and female reproductive organs were observed inrepeat-dose toxicology studies in sexually mature monkeys up to 26 weeks.

In an animal reproductive and developmental toxicity study, administration of mogamulizumab topregnant cynomolgus monkeys from the start of organogenesis through delivery did not show apotential for embryo-foetal lethality, teratogenicity, or foetal growth retardation. In general, IgGmolecules are known to cross the placental barrier and mogamulizumab concentrations in foetusplasma were detected. Pharmacological activity of mogamulizumab was noted in foetuses as wasevident from a decrease in CCR4 expressing lymphocytes.

Citric acid monohydrate

Glycine

Polysorbate 80

Sodium hydroxide (for pH adjustment)

Hydrochloric acid (for pH adjustment)

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts. Mogamulizumab should not be infused concomitantly in the same intravenous line withother medicinal products.

Unopened vial3 years.

POTELIGEO does not contain a preservative. Once opened, the medicinal product should be dilutedand infused immediately (see section 6.6).

Chemical and physical in-use stability has been demonstrated for 24 hours at room temperature (at25°C) under ambient room light.

These time limits include storage of the infusion solution in the infusion bag through the duration ofinfusion. From a microbiological point of view, the product must be used immediately.

If not used immediately, in-use storage times and conditions prior to use are the responsibility of theuser and must not be longer than a total of 24 hours at 2°C - 8°C provided that dilution has taken placeunder controlled and validated aseptic conditions.

Store in a refrigerator (2ºC to 8ºC).

Do not freeze.

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

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

5 mL solution in a 10 mL glass vial (type I glass) with a rubber stopper, an aluminium seal and apolypropylene flip-off cap.

Pack of 1 vial.

* Visually inspect the medicinal product for particulate matter and discolouration prior toadministration. POTELIGEO is a clear to slightly opalescent, colourless solution. Discard thevial if cloudiness, discolouration or particulates are observed.

* Calculate the required volume of POTELIGEO needed to prepare the infusion solution for the1 mg/kg dose based on patient weight (see section 4.2). Aseptically withdraw the requiredvolume of POTELIGEO into the syringe and transfer into an infusion bag containing 9mg perml (0.9%) sodium chloride solution for injection. Mix diluted solution by gentle inversion. Donot shake. The final concentration of the diluted solution should be between 0.1 mg/mL to3.0 mg/mL.

* Each vial is for single use only. Discard any unused portion left in the vial in accordance withlocal requirements.

* The diluted solution is compatible with polyvinyl chloride (PVC) or polyolefin (PO) infusionbags.

* Do not mix POTELIGEO with, or administer as an infusion with, other medicinal products.

* POTELIGEO is intended for intravenous use only, and should not be administeredsubcutaneously, intramuscularly, as a bolus dose or by rapid intravenous administration.

* Administer infusion solution over at least 60 minutes through an intravenous line containing asterile, low protein binding 0.22 micron (or equivalent) in-line filter.

Kyowa Kirin Holdings B.V.

Bloemlaan 22132NP Hoofddorp

Netherlandsmedinfo@kyowakirin.com

EU/1/18/1335/001

Date of first authorisation: 22 November 2018

Date of latest renewal: 01 September 2023

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

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