Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of the safety profile
The safety profile of ADCETRIS is based on available clinical trial data, the Named Patient Program (NPP), and post-marketing experience to date. Frequencies of adverse reactions described below and in Table 5 have been determined based on data generated from clinical studies.

Monotherapy

In the pooled dataset of ADCETRIS as monotherapy across HL, sALCL and CTCL studies (SG035- 0003, SG035-0004, SGN35-005, SGN35-006, C25001, C25006 and C25007, see section 5.1) the most frequent adverse reactions (≥10%) were infections, peripheral sensory neuropathy, nausea, fatigue, diarrhoea, pyrexia, neutropenia, upper respiratory tract infection, arthralgia,, rash, cough, vomiting, pruritus, peripheral motor neuropathy, infusion-related reactions, constipation, dyspnoea, myalgia, weight decreased, and abdominal pain.
Serious adverse drug reactions occurred in 12% of patients. The frequency of unique serious adverse drug reactions was ≤1%.

Adverse events led to treatment discontinuation in 24% of patients receiving ADCETRIS.

The safety data in patients retreated with ADCETRIS (SGN35-006, see section 5.1) were consistent with those observed in the combined pivotal phase 2 studies, with the exception of peripheral motor neuropathy, which had a higher incidence (28% vs. 9% in the pivotal phase 2 studies) and was primarily Grade 2. Patients also had a higher incidence of arthralgia, Grade 3 anaemia, and back pain compared to patients observed in the combined pivotal phase 2 studies.

The safety data in patients with relapsed or refractory HL who had not received an autologous stem cell transplant and were treated with the recommended dose of 1.8 mg/kg every three weeks in a single-arm phase 4 study (n=60), the phase 1 dose escalation and clinical pharmacology studies (n=15 patients) and in the NPP (n=26 patients) (see section 5.1) were consistent with the safety profile of the pivotal clinical studies.
Combination therapy

For safety information of chemotherapy agents given in combination with ADCETRIS (doxorubicin, vinblastine and dacarbazine (AVD) or cyclophosphamide, doxorubicin and prednisone (CHP)), refer to their summary of product characteristics.

In the studies of ADCETRIS as combination therapy in 662 patients with previously untreated advanced HL (C25003) and 223 patients with previously untreated CD30+ peripheral T-cell lymphoma (PTCL) (SGN35-014), the most common adverse reactions (≥ 10%) were: infections, neutropenia, peripheral sensory neuropathy, nausea, constipation, vomiting, diarrhoea, fatigue, pyrexia, alopecia, anaemia, weight decreased, stomatitis, febrile neutropenia, abdominal pain, decreased appetite, insomnia, bone pain, rash, cough, dyspnoea, arthralgia, myalgia, back pain, peripheral motor neuropathy, upper respiratory tract infection and dizziness.

In patients receiving ADCETRIS combination therapy, serious adverse reactions occurred in 34% of patients. Serious adverse reactions occurring in ≥ 3% of patients included febrile neutropenia (15%), pyrexia (5%), and neutropenia (3%).

Adverse events led to treatment discontinuation in 10% of patients. Adverse events that led to treatment discontinuation in ≥ 2% of patients included peripheral sensory neuropathy, and peripheral neuropathy.

Tabulated list of adverse reactions
Adverse reactions for ADCETRIS are listed by MedDRA System Organ Class and Preferred Term (see Table 5). Within each System Organ Class, adverse reactions are listed under frequency categories of: 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, adverse reactions are presented in the order of decreasing seriousness.

Table 5: Adverse reactions to ADCETRIS

System organ class                    Adverse reactions (monotherapy)                  Adverse reactions (combination therapy)
Infections and infestations
Very common:                          Infectiona, upper respiratory tract infection    Infectiona, upper respiratory tract infection
Common:                               Herpes zoster, pneumonia, herpes simplex,        Pneumonia, oral candidiasis, oral candidiasis                                sepsis/septic shock, herpes zoster Uncommon:                          Pneumocystis jiroveci pneumonia,                Herpes simplex, Pneumocystis staphylococcal bacteraemia,                     jiroveci pneumonia cytomegalovirus infection or reactivation,
sepsis/septic shock
Frequency not known:               Progressive multifocal leukoencephalopathy Blood and lymphatic system disorders
Very common:                       Neutropenia                                     Neutropeniaa, anaemia, febrile neutropenia
Common:                              Anaemia, thrombocytopenia                     Thrombocytopenia Uncommon:                            Febrile neutropenia
Immune system disorders
Uncommon:                            Anaphylactic reaction                         Anaphylactic reaction Metabolism and nutrition disorders
Very common:                                                                       Decreased appetite Common:                              Hyperglycaemia                                Hyperglycaemia Uncommon:                            Tumour lysis syndrome                         Tumour lysis syndrome Psychiatric disorders
Very common:                                                                       Insomnia Nervous system disorders
Very common:                         Peripheral sensory neuropathy, peripheral     Peripheral sensory neuropathya, motor neuropathy                              peripheral motor neuropathya, dizziness
Common:                             Dizziness
Uncommon:                           Demyelinating polyneuropathy
Respiratory, thoracic and mediastinal disorders
Very common:                        Cough, dyspnoea                                Cough, dyspnoea Gastrointestinal disorders
Very common:                        Nausea, diarrhoea, vomiting, constipation,     Nausea, constipation, vomiting, abdominal pain                                 diarrhoea, abdominal pain, stomatitis
Uncommon:                            Pancreatitis acute                            Pancreatitis acute Hepatobiliary disorders
Common:                              Alanine aminotransferase/aspartate            Alanine aminotransferase/aspartate aminotransferase (ALT/AST) increased          aminotransferase (ALT/AST) increased
Skin and subcutaneous tissue disorders
Very common:                         Rasha, pruritus                               Alopecia, rasha Common:                             Alopecia                                       Pruritus Uncommon:                           Stevens-Johnson syndrome/ toxic epidermal      Stevens-Johnson syndromeb necrolysis
Not known:                          Drug reaction with eosinophilia and systemic symptoms (DRESS)
Musculoskeletal and connective tissue disorders
Very common:                        Arthralgia, myalgia                            Bone pain, arthralgia, myalgia back pain
Common:                            Back pain
General disorders and administration site conditions
Very common:                       Fatigue, pyrexia, infusion-related reactionsa   Fatigue, pyrexia Common:                            Chills                                          Infusion-related reactionsa, chills Not known:                         Infusion site extravasationc
Investigations
Very common:                       Weight decreased                                Weight decreased a.
Represents pooling of preferred terms.
b.
Toxic epidermal necrolysis was not reported in the combination therapy setting.
c.
Extravasation may result in related reactions include skin redness, pain, swelling, blistering, exfoliation, or cellulitis at or surrounding the infusion site.

Description of selected adverse reactions

Neutropenia and febrile neutropenia
Monotherapy

In clinical trials, neutropenia led to dose delays in 13% of patients. Grade 3 neutropenia was reported in 13% and Grade 4 neutropenia was reported in 5% of patients. One patient required dose reduction and one patient discontinued treatment for neutropenia.

Severe and prolonged (≥1 week) neutropenia can occur with this treatment which may increase the risk of patients developing serious infections. Febrile neutropenia reported in <1% of the patients (see section 4.2).

In the pivotal phase 2 population (SG035-0003 and SG035-0004), the median duration of Grade 3 or Grade 4 neutropenia was limited (1 week); 2% of patients had Grade 4 neutropenia that lasted ≥7 days.
Less than half of the patients in the pivotal phase 2 population with Grade 3 or Grade 4 neutropenia had temporally associated infections, and the majority of temporally associated infections were Grade 1 or Grade 2.

Combination therapy

In the clinical trials of ADCETRIS as combination therapy, neutropenia led to dose delays in 19% of patients. Grade 3 neutropenia was reported in 17% and Grade 4 neutropenia was reported in 41% of patients. Two percent of patients required dose reduction and < 1% discontinued one of more of the study drugs due to neutropenia.

Febrile neutropenia was reported in 20% of the patients who did not receive primary prophylaxis with G-CSF (see section 4.2). The frequency of febrile neutropenia was 13% in patients who received primary prophylaxis with G-CSF.

Serious infections and opportunistic infections

Monotherapy
In clinical trials, serious infections and opportunistic infections occurred in 10 % of patients sepsis or septic shock occurred in <1% of the patients. The most commonly reported opportunistic infections were herpes zoster and herpes simplex.

Combination therapy

In the clinical trials of ADCETRIS as combination therapy, serious infections including opportunistic infections occurred in 15% of patients; sepsis, neutropenic sepsis, septic shock or bacteraemia occurred in 4% of the patients. The most commonly reported opportunistic infections were herpes viral infections.

Peripheral neuropathy

Monotherapy
In clinical trials treatment emergent neuropathy occurred in 57 % of the population, peripheral motor neuropathy occurred in 13% of patients. Peripheral neuropathy led to treatment discontinuation in 15%, dose reductions in 15%, and dose delays in 16% of patients.

For patients who experienced peripheral neuropathy the median time of onset of peripheral neuropathy was 12 weeks. The median duration of treatment for patients who discontinued due to peripheral neuropathy was 11 cycles.

Among patients who experienced peripheral neuropathy in the pivotal phase 2 studies (SG035-0003 and SG035-0004) and randomised phase 3 monotherapy studies (SGN35-005 and C25001), the median follow up time from end of treatment until last evaluation ranged from 48.9 to 98 weeks. At the time of last evaluation, most of the patients (82-85%) who experienced peripheral neuropathy had resolution or improvement of their peripheral neuropathy symptoms. The median time from onset to resolution or improvement for all events ranged from 16 to 23.4 weeks.

In patients with relapsed or refractory HL or sALCL who were retreated with ADCETRIS (SGN35- 006), the majority of patients (80%) also had improvement or resolution of their peripheral neuropathy symptoms at the time of last evaluation.

Combination therapy

In the clinical trial of ADCETRIS as combination therapy with AVD, treatment emergent neuropathy occurred in 67% of the population; peripheral motor neuropathy occurred in 11% of patients.
Peripheral neuropathy led to treatment discontinuation in 7%, dose reductions in 21%, and dose delays in 1% of patients. For patients who experienced peripheral neuropathy the median time of onset of peripheral neuropathy was 8 weeks. Patients who discontinued due to peripheral neuropathy received a median of 8 doses of ADCETRIS+AVD (A+AVD) before discontinuation of one or more agents.

Among patients who experienced peripheral neuropathy, the median follow up time from end of treatment until last evaluation was approximately 286 weeks. At the time of last evaluation, most of the patients (86%) who experienced peripheral neuropathy had resolution or improvement of their peripheral neuropathy symptoms. The median time from onset to resolution or improvement of peripheral neuropathy events was 17 weeks (ranged from 0 weeks to 283 weeks).

In the clinical trial of ADCETRIS as combination therapy with CHP, treatment emergent neuropathy occurred in 52% of the population; peripheral motor neuropathy occurred in 9% of patients. Peripheral neuropathy led to treatment discontinuation in 1%, dose reductions in 7% and dose delays in <1% of patients. For patients who experienced peripheral neuropathy the median time of onset was 9.1 weeks.

Patients who discontinued due to peripheral neuropathy received a median of 5 doses of ADCETRIS+CHP (A+CHP) before discontinuation of one or more agents.

Among patients who experienced peripheral neuropathy, the median follow up time from end of treatment until last evaluation was approximately 177 weeks. At the time of last evaluation, 64% who experienced peripheral neuropathy had resolution or improvement of their peripheral neuropathy symptoms. The median time from onset to resolution or improvement of peripheral neuropathy events was 19.0 weeks (ranged from 0 weeks to 205 weeks).

Infusion-related reactions

Monotherapy
IRRs, such as headache, rash, back pain, vomiting, chills, nausea, dyspnoea, pruritus and cough were reported in 12 % of patients.


Anaphylactic reactions have been reported (see section 4.4). Symptoms of an anaphylactic reaction may include, but are not limited to, urticaria, angioedema, hypotension and bronchospasm.

Combination therapy

IRRs, such as headache, rash, back pain, vomiting, chills, nausea, dyspnoea, pruritus, cough, infusion site pain and pyrexia were reported in 8% of patients. Anaphylactic reactions have been reported (see section 4.4). Symptoms of an anaphylactic reaction may include, but are not limited to, urticaria, angioedema, hypotension and bronchospasm.

Immunogenicity

In clinical trials, patients were periodically tested for antibodies to brentuximab vedotin using a sensitive electrochemiluminescent immunoassay. There was a higher incidence of infusion-related reactions observed in patients with antibodies to brentuximab vedotin relative to patients who tested transiently positive or negative.

The presence of antibodies to brentuximab vedotin did not correlate with a clinically meaningful reduction in serum brentuximab vedotin levels and did not result in a decrease in the efficacy of brentuximab vedotin. While the presence of antibodies to brentuximab vedotin does not necessarily predict the development of an IRR, there was a higher incidence of IRRs observed in patients with persistently positive anti-drug antibodies (ADA) relative to patients with transiently positive ADA and never positive ADA.

Monotherapy Study C25002

There was a trend of increased clearance of brentuximab vedotin in paediatric patients confirmed positive for ADAs. No patients aged <12 years (0 of 11) and 2 patients aged ≥ 12 years (2 of 23) became persistently ADA positive.

Combination Use Study C25004

The rate of ADA positivity was low in Study C25004; 4 patients (aged ≥ 12 years) of 59 patients became transiently ADA positive, and no patients became persistently ADA positive. Due to the small number of transiently ADA positive patients, the impact of ADA on efficacy is inconclusive.

Paediatric population

Monotherapy Study C25002
Safety was evaluated in a phase 1/2 study in paediatric patients aged 7-17 years of age (n = 36) with relapsed or refractory (r/r) HL and sALCL (see section 5.1). In this study in 36 patients, no new safety concerns were reported.

Combination Use Study C25004

Safety was evaluated in an open-label, multicenter trial in 59 paediatric patients aged 6-17 years of age with previously untreated advanced-stage classical CD30+ HL in combination with chemotherapy (see section 5.1). In this study, no new safety concerns were reported. The most common serious adverse reaction reported in this study was febrile neutropenia (17%). G-CSF prophylaxis was considered at the physician’s discretion. Peripheral neuropathy events (per Standardized MedDRA Query) were reported in 24% of paediatric patients in this study.

Elderly

Monotherapy

The safety profile in elderly patients is generally in line with that of adult patients. However, elderly patients may be more susceptible to events such as pneumonia, neutropenia and febrile neutropenia.
Combination therapy

In older patients (≥ 60 years of age; n = 186 [21%]), the incidence of adverse events was similar across treatment arms. More serious adverse events and dose modifications (including dose delays, reductions, and discontinuations) were reported in the older patients compared with the overall study population. Advanced age was a risk factor for febrile neutropenia in patients in both arms. Older patients who received G-CSF primary prophylaxis had lower incidence of neutropenia and febrile neutropenia than those who did not receive G-CSF primary prophylaxis.

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