4.1. Therapeutic indications

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

4.2. Posology and method of administration

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

Posology

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

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

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

Dose modification

Dermatologic reactions

Patients receiving mogamulizumab have experienced drug rash (drug eruption), some of which were severe 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 appropriately until rash improves to Grade 1 or less (mild severity), at which time mogamulizumab treatment may be resumed.

• POTELIGEO should be permanently discontinued for a life-threatening (Grade 4) rash (see section 4.4).

Infusion-related reactions

• 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 least 50% when re-starting the infusion after symptoms resolve. If reaction recurs, discontinuing the infusion 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).

Special populations

Paediatric population

The safety and efficacy of POTELIGEO in children and adolescents aged below 18 years have not been established. No data are available.

Elderly

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

Renal impairment

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

Hepatic impairment

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

Method of administration

POTELIGEO is for intravenous use. It should be administered by intravenous infusion only, over at least 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.

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.

Dermatologic reactions

Patients receiving mogamulizumab have experienced drug rash (drug eruption), some of which were severe 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 during the post-marketing period; some of these cases were reported with fatal outcomes. Patients should be closely monitored for symptoms or signs that suggest SJS or TEN. If they occur, POTELIGEO should be interrupted and treatment should not restart unless SJS or TEN is ruled out and cutaneous reaction has resolved to Grade 1 or less. If SJS/TEN occur, appropriate medical therapy should be administered. See section 4.2 for dose modification information.

Infusion-related reactions

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 severe reactions (Grade 3). The majority of IRRs occur during or shortly after the first infusion (all within 24 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 and appropriate 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.

Infections

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

Patients should be tested for hepatitis B infection before initiating treatment with mogamulizumab. For patients who test positive for current/previous hepatitis B infection, consultation with a physician with expertise in the treatment of hepatitis B is recommended for advice concerning appropriate measures against 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 patients with 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 short time frame (approximately 50 days) before HSCT. Follow patients closely for early evidence of transplant-related complications.

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

Tumour lysis syndrome

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

Cardiac disorders

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

Large cell transformation (LCT)

There are limited data available on patients with LCT.

Other

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

This medicinal product contains less than 1 mmol sodium per dose, that is to say essentially 'sodium free'.

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

No interaction studies have been performed.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential/Contraception in females

Women of childbearing potential should use effective contraception during treatment with POTELIGEO and for at least 6 months after treatment.

Pregnancy

There are no data from the use of mogamulizumab in pregnant women. Although mogamulizumab crosses 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 mogamulizumab during pregnancy.

Breast-feeding

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

Fertility

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

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of the safety profile

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

The most frequently reported adverse reactions were infusion-related reaction and rash (drug eruption); 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 were polymyositis and sepsis (0.5% each).

Tabulated list of adverse reactions

The adverse reactions are presented by system organ class and frequency categories, defined using the following 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 the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 1: Adverse drug reactions identified with POTELIGEO

System organ class (SOC)

Frequency

Adverse reaction

Blood and lymphatic system disorders

Common

Anaemia, neutropenia, leukopenia, Thrombocytopenia

Endocrine disorders

Common

Hypothyroidism

Gastrointestinal disorders

Very common

Constipation, diarrhoea, nausea, stomatitis

Common

Vomiting

Common

Colitis

General disorders and administration site conditions

Very common

Fatigue, oedema peripheral, pyrexia

Hepatobiliary disorders

Uncommon

Hepatitis acute, hepatitis

Infections and infestations

Very common

Infectionsa

Common

Upper respiratory tract infection

Injury, poisoning and procedural complications

Very common

Infusion related reaction

Investigations

Common

Alanine aminotransferase increased, 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)

Not known

Granulomab

a Folliculitis, Cellulitis, Candidiasis, Pneumonia, Sepsis, Skin infection, Otitis externa, Herpes zoster, Staphylococcal skin infection, Urinary tract infection, Herpes simplex and cytomegalovirus

b Including cases of granuloma of the skin (scalp, periauricular area, and trunk) and bone (sternum, skull, spine, costa, and pelvis).

Description of selected adverse reactions

Dermatologic reactions

Patients receiving POTELIGEO have experienced drug rash (drug eruption), some of which were severe 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 was identified for drug eruptions and rashes; both early and late-onset events occurred.

Infusion-related reactions

Infusion-related reactions have been observed in 33% of patients treated with POTELIGEO. The majority of treatment-related infusion-related reactions were Grade 1 or 2 and occurred during or shortly 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.

Serious infections

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

Immunogenicity

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

Gastrointestinal disorders

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

Safety post last dose

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

Of these, SADRs that were reported in more than one patient were coded under the SOCs Infections and 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 and connective 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 in one patient (0.3%).

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

Elderly

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 older subjects.

Reporting 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

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