Adverse reactions : תופעות לוואי

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 occurring in patients receiving POTELIGEO (N=184) System organ class (SOC)                       Frequency           Adverse reaction Anaemia, neutropenia, leukopenia,
Blood and lymphatic system disorders           Common
Thrombocytopenia
Endocrine disorders                            Common              Hypothyroidism Constipation, diarrhoea, nausea,
Very common
Gastrointestinal disorders                                         stomatitis Common              Vomiting
General disorders and administration site
Very common         Fatigue, oedema peripheral, pyrexia conditions
Hepatobiliary disorders                        Uncommon            Hepatitis acute, hepatitis Very common         Infectionsa
Infections and infestations
Common              Upper respiratory tract infection
Injury, poisoning and procedural
Very common         Infusion related reaction complications
Alanine aminotransferase increased,
aspartate aminotransferase increased,
Investigations                                 Common 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 
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 Study 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 studies 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.

Safety post last dose
Of the 320 subjects exposed to mogamulizumab in Study 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 population
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 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. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il