Brentuximab vedotin interacts in the following cases:
Co-administration of brentuximab vedotin with ketoconazole, a strong CYP3A4 and P-gp inhibitor, increased the exposure to the antimicrotubule agent MMAE by approximately 73%, and did not alter the plasma exposure to brentuximab vedotin. Therefore, co-administration of brentuximab vedotin with strong CYP3A4 and P-gp inhibitors may increase the incidence of neutropenia. If neutropenia develops, refer to Tables 1 and 2 for dosing recommendations for neutropenia.
Table 1. Dosing recommendations for neutropenia with monotherapy:
| Severity grade of neutropenia (signs and symptoms [abbreviated description of CTCAEa]) | Modification of dosing schedule |
| Grade 1 (< LLN-1500/mm³ < LLN-1.5 × 109/L) or Grade 2 (< 1500-1000/mm³ < 1.5-1.0 × 109/L) | Continue with the same dose and schedule. |
| Grade 3 (< 1,000-500/mm³ < 1.0-0.5 × 109/L) or Grade 4 (< 500/mm³ < 0.5 × 109/L) | Withhold dose until toxicity returns to ≤ Grade 2 or baseline then resume treatment at the same dose and scheduleb. Consider G-CSF or GM-CSF in subsequent cycles for patients who develop Grade 3 or Grade 4 neutropenia. |
a Grading based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v3.0; see Neutrophils/granulocytes; LLN = lower limit of normal.
b Patients who develop Grade 3 or Grade 4 lymphopenia may continue treatment without interruption.
Table 2. Dosing recommendations for neutropenia during combination therapy:
| Severity grade of neutropenia (signs and symptoms [abbreviated description of CTCAEa]) | Modification of dosing schedule |
| Grade 1 (< LLN-1500/mm³ < LLN-1.5 × 109/L) or Grade 2 (< 1500-1000/mm³ < 1.5-1.0 × 109/L) Grade 3 (< 1,000-500/mm³ < 1.0-0.5 × 109/L) or Grade 4 (< 500/mm³ < 0.5 × 109/L) | Primary prophylaxis with G-CSF, beginning with the first dose, is recommended for all adult patients receiving combination therapy. Continue with the same dose and schedule. |
a Grading based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03; see Neutrophils/granulocytes; LLN = lower limit of normal.
Co-administration of brentuximab vedotin with rifampicin, a strong CYP3A4 inducer, did not alter the plasma exposure to brentuximab vedotin. Though PK data are limited, co administration of rifampicin appeared to reduce plasma concentrations of MMAE metabolites that could be assayed.
Patients with hepatic impairment should be closely monitored for adverse events. The recommended starting dose in patients with mild hepatic impairment receiving brentuximab vedotin in combination with AVD is 0.9 mg/kg administered as an intravenous infusion over 30 minutes every 2 weeks. The recommended starting dose in patients with mild hepatic impairment receiving brentuximab vedotin in combination with CHP is 1.2 mg/kg administered as an intravenous infusion over 30 minutes every 3 weeks. There is no clinical trial experience using brentuximab vedotin in combination with chemotherapy in patients with hepatic impairment, where total bilirubin is >1.5 times the upper limit of normal (ULN) (unless due to Gilbert syndrome), or aspartate aminotransferase (AST) or alanine aminotransferase (ALT) are >3 times the ULN, or >5 times the ULN if their elevation may be reasonably ascribed to the presence of HL in the liver. Use of brentuximab vedotin in combination with chemotherapy should be avoided in patients with moderate and severe hepatic impairment.
The recommended starting dose in patients with hepatic impairment is 1.2 mg/kg administered as an intravenous infusion over 30 minutes every 3 weeks. Patients with hepatic impairment should be closely monitored for adverse events.
Patients with renal impairment should be closely monitored for adverse events. There is no clinical trial experience using brentuximab in combination with chemotherapy in patients with renal impairment, where serum creatinine is ≥2.0 mg/dL and/or creatinine clearance or calculated creatinine clearance is ≤40 mL/minute. Use of brentuximab in combination with chemotherapy should be avoided in patients with severe renal impairment.
The recommended starting dose in patients with severe renal impairment is 1.2 mg/kg administered as an intravenous infusion over 30 minutes every 3 weeks. Patients with renal impairment should be closely monitored for adverse events.
In non-clinical studies, brentuximab vedotin treatment has resulted in testicular toxicity, and may alter male fertility. MMAE has been shown to have aneugenic properties. Therefore, men being treated with this medicine are advised to have sperm samples frozen and stored before treatment. Men being treated with this medicine are advised not to father a child during treatment and for up to 6 months following the last dose.
There are no data from the use of brentuximab vedotin in pregnant women. Studies in animals have shown reproductive toxicity.
Brentuximab vedotin should not be used during pregnancy unless the benefit to the mother outweighs the potential risks to the foetus. If a pregnant woman needs to be treated she should be clearly advised on the potential risk to the foetus.
See the fertility section below pertaining to advice for women whose male partners are being treated with brentuximab vedotin.
There are no data as to whether brentuximab vedotin or its metabolites are excreted in human milk.
A risk to the newborn/infant cannot be excluded.
A decision should be made whether to discontinue breast-feeding or to discontinue/abstain from this therapy, taking into account a potential risk of breast-feeding for the child and the benefit of therapy for the woman.
Women of childbearing potential should be using two methods of effective contraception during treatment with brentuximab vedotin and until 6 months after treatment.
In non-clinical studies, brentuximab vedotin treatment has resulted in testicular toxicity, and may alter male fertility. MMAE has been shown to have aneugenic properties. Therefore, men being treated with this medicine are advised to have sperm samples frozen and stored before treatment. Men being treated with this medicine are advised not to father a child during treatment and for up to 6 months following the last dose.
Brentuximab vedotin may have a moderate influence on the ability to drive and use machines (e.g. dizziness).
The safety profile of brentuximab vedotin 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.
In the pooled dataset of brentuximab vedotin as monotherapy across HL, sALCL and CTCL studies (SG035-0003, SG035-0004, SGN35-005, SGN35-006, C25001, C25006 and C25007) 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 brentuximab vedotin.
The safety data in patients retreated with brentuximab vedotin (SGN35-006) 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) were consistent with the safety profile of the pivotal clinical studies.
For safety information of chemotherapy agents given in combination with brentuximab vedotin (doxorubicin, vinblastine and dacarbazine (AVD) or cyclophosphamide, doxorubicin and prednisone (CHP)), refer to their summary of product characteristics.
In the studies of brentuximab vedotin 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 brentuximab vedotin 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.
Adverse reactions for brentuximab vedotin are listed by MedDRA System Organ Class and Preferred Term (see table). 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.
Adverse reactions to brentuximab vedotin:
| 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, oral candidiasis | Pneumonia, oral candidiasis, sepsis/septic shock, herpes zoster |
| Uncommon: | Pneumocystis jiroveci pneumonia, staphylococcal bacteraemia, cytomegalovirus infection or reactivation, sepsis/septic shock | Herpes simplex, Pneumocystis jiroveci pneumonia |
| 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 motor neuropathy | Peripheral sensory neuropathya, 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, abdominal pain | Nausea, constipation, vomiting, diarrhoea, abdominal pain, stomatitis |
| Uncommon: | Pancreatitis acute | Pancreatitis acute |
| Hepatobiliary disorders | ||
| Common: | Alanine aminotransferase/aspartate aminotransferase (ALT/AST) increased | Alanine aminotransferase/aspartate aminotransferase (ALT/AST) increased |
| Skin and subcutaneous tissue disorders | ||
| Very common: | Rasha, pruritus | Alopecia, rasha |
| Common: | Alopecia | Pruritus |
| Uncommon: | Stevens-Johnson syndrome/toxic epidermal necrolysis | Stevens-Johnson syndromeb |
| 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.
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 1 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.
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.
In the clinical trials of brentuximab vedotin 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. The frequency of febrile neutropenia was 13% in patients who received primary prophylaxis with G-CSF.
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.
In the clinical trials of brentuximab vedotin 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.
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 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.
In the clinical trial of brentuximab vedotin 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 brentuximab vedotin + 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 brentuximab vedotin 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 brentuximab vedotin + 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).
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. Symptoms of an anaphylactic reaction may include, but are not limited to, urticaria, angioedema, hypotension and bronchospasm.
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. Symptoms of an anaphylactic reaction may include, but are not limited to, urticaria, angioedema, hypotension and bronchospasm.
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.
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.
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.
Safety was evaluated in a phase ½ study in paediatric patients aged 7-17 years of age (n=36) with relapsed or refractory (r/r) HL and sALCL. In this study in 36 patients, no new safety concerns were reported.
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. 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.
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.
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.
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