Adcetris

Adcetris Adverse Reactions

brentuximab vedotin

Manufacturer:

Takeda

Distributor:

DKSH
Full Prescribing Info
Adverse Reactions
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 as follows and in Table 17 have been determined based on data generated from clinical studies.
Monotherapy: In the pooled dataset of ADCETRIS as monotherapy in 482 patients across HL, sALCL and CTCL studies (SG035-0003, SG035-0004, SGN35-005, SGN35-006, C25001 and C25007, see Pharmacology: Pharmacodynamics under Actions) the most frequent adverse reactions (≥10%) were infections, peripheral sensory neuropathy, nausea, fatigue, diarrhoea, pyrexia, upper respiratory tract infection, neutropenia, rash, cough, vomiting, arthralgia, peripheral motor neuropathy, infusion-related reactions, pruritus, constipation, dyspnoea, weight decreased, myalgia and abdominal pain.
Serious adverse drug reactions occurred in 12% of patients. The frequency of unique serious adverse drug reactions was ≤1%.
Adverse reactions led to treatment discontinuation in 24% of patients receiving ADCETRIS.
The safety data in patients retreated with ADCETRIS (SGN35-006, see Pharmacology: Pharmacodynamics under Actions) 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 the 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 Pharmacology: Pharmacodynamics under Actions) were consistent with the safety profile of the pivotal clinical studies.
Combination Therapy: For the safety information of chemotherapy agents given in combination with ADCETRIS (doxorubicin, vinblastine and dacarbazine [AVD] or cyclophosphamide, doxorubicin, and prednisone [CHP]), refer to their product information.
In the studies of ADCETRIS as combination therapy in 662 patients with previously untreated advanced HL (C25003) and patients with 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 ≥2% of patients included febrile neutropenia (15%), pyrexia (5%), neutropenia (3%), pneumonia (2%) and sepsis (2%).
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. Additionally, there were more serious adverse events and dose modifications (including dose delays, reductions, and discontinuations) reported in the elderly patient population (≥65 years of age) in both arms. 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.
Tabulated list of adverse reactions: Adverse reactions for ADCETRIS are listed by MedDRA System Organ Class and Preferred Term (see Table 17). 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. (See Table 17.)

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Description of selected adverse reactions: Neutropenia and febrile neutropenia: Monotherapy: In clinical trials, neutropenia led to dose delays in 14% of patients. Grade 3 neutropenia was reported in 13% and Grade 4 neutropenia was reported in 5% of patients. No patients required dose reduction or 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 Dosage & Administration).
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 or more of the study drugs due to neutropenia. Febrile neutropenia was reported in 21% of the patients who did not receive primary prophylaxis with G-CSF (see Dosage & Administration). The frequency of febrile neutropenia was 11% in patients who received primary prophylaxis with G-CSF.
Febrile neutropenia was reported in 20% of the patients who did not receive primary prophylaxis with G-CSF (see Dosage & Administration). 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 59% of the population, peripheral motor neuropathy occurred in 14% of patients. Peripheral neuropathy led to treatment discontinuation in 15%, dose reductions in 15%, and dose delays in 17% 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 12 cycles.
Among patients who experienced peripheral neuropathy in the pivotal phase 2 studies (SG035-0003 and SG035-0004) and randomized phase 3 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 brentuximab vedotin (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 91 weeks. At the time of last evaluation, most of the patients (76%) 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 10 weeks (ranged from 0 weeks to 139 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 13% of patients. Anaphylactic reactions have been reported (see Precautions). 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 Precautions). 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 ADCETRIS using a sensitive electro chemiluminescent immunoassay. There was a higher incidence of infusion-related reactions observed in patients with antibodies to ADCETRIS relative to patients who tested transiently positive or negative.
The presence of antibodies to ADCETRIS did not correlate with a clinically meaningful reduction in serum ADCETRIS levels and did not result in a decrease in the efficacy of ADCETRIS. While the presence of antibodies to ADCETRIS does not necessarily predict the development of an IRR, there was a higher incidence of IRRs observed in patients with persistently positive ADA relative to patients with transiently positive ADA and never positive ADA.
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