ADCETRIS Brentuximab Vedotin 50mg Powder for Concentrate for Solution for IV Infusion 30mL

Hodgkin lymphoma: BRENTUXIMAB VEDOTIN (ADCETRIS) is indicated for adult patients with previously untreated CD30+ Stage IV Hodgkin lymphoma (HL) in combination with doxorubicin, vinblastine and dacarbazine (AVD) (see Dosage & Administration and Pharmacology: Pharmacodynamics under Actions).
BRENTUXIMAB VEDOTIN (ADCETRIS) is indicated for the treatment of adult patients with CD30+ HL at increased risk of relapse or progression following autologous stem cell transplant (ASCT) (see Pharmacology: Pharmacodynamics under Actions).
BRENTUXIMAB VEDOTIN (ADCETRIS) is indicated for the treatment of adult patients with relapsed or refractory CD30+ Hodgkin lymphoma (HL): 1. following ASCT, or; 2. following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option.
Previously untreated systemic anaplastic large cell lymphoma (sALCL) or other CD30-expressing peripheral T-cell lymphomas (PTCL), in combination with chemotherapy: BRENTUXIMAB VEDOTIN (ADCETRIS) is indicated for the treatment of adult patients with previously untreated sALCL or other CD30-expressing PTCL, including angioimmunoblastic T-cell lymphoma and PTCL not otherwise specified, in combination with cyclophosphamide, doxorubicin, and prednisone.
BRENTUXIMAB VEDOTIN (ADCETRIS) is indicated for the treatment of adult patients with relapsed or refractory (sALCL).
Cutaneous T-cell lymphoma: BRENTUXIMAB VEDOTIN (ADCETRIS) is indicated for the treatment of adult patients with CD30+ cutaneous T-cell lymphoma (CTCL) after at least 1 prior systemic therapy (see Pharmacology: Pharmacodynamics under Actions).

 

BRENTUXIMAB VEDOTIN (ADCETRIS) should be administered under the supervision of a physician experienced in the use of anti-cancer agents.
Posology: Previously Untreated HL: The recommended dose in combination with chemotherapy (doxorubicin [A], vinblastine [V] and dacarbazine [D] [AVD]) is 1.2 mg/kg administered as an intravenous infusion over 30 minutes on days 1 and 15 of each 28-day cycle for 6 cycles (see Pharmacology: Pharmacodynamics under Actions).
Primary prophylaxis with growth factor support (G-CSF), beginning with the first dose, is recommended for all adult patients with previously untreated HL receiving combination therapy (see Precautions).
Refer to the summary of product characteristics (SmPC) of chemotherapy agents given in combination with BRENTUXIMAB VEDOTIN (ADCETRIS) for patients with previously untreated HL.
HL at increased risk of relapse or progression: The recommended dose is 1.8 mg/kg administered as an intravenous infusion over 30 minutes every 3 weeks.
BRENTUXIMAB VEDOTIN (ADCETRIS) treatment should start following recovery from ASCT based on clinical judgment. These patients should receive up to 16 cycles (see Pharmacology: Pharmacodynamics under Actions).
Relapsed or refractory HL: The recommended dose is 1.8 mg/kg administered as an intravenous infusion over 30 minutes every 3 weeks.
The recommended starting dose for the retreatment of patients who have previously responded to treatment with BRENTUXIMAB VEDOTIN (ADCETRIS) is 1.8 mg/kg administered as an intravenous infusion over 30 minutes every 3 weeks. Alternatively, treatment may be started at the last tolerated dose (see Pharmacology: Pharmacodynamics under Actions).
Treatment should be continued until disease progression or unacceptable toxicity (see Precautions).
Patients who achieve stable disease or better should receive a minimum of 8 cycles and up to a maximum of 16 cycles (approximately 1 year) (see Pharmacology: Pharmacodynamics under Actions).
Previously untreated sALCL or other CD30-expressing peripheral T-cell lymphomas: The recommended dose in combination with chemotherapy (cyclophosphamide [C], doxorubicin [H] and prednisone [P] [CHP]) is 1.8 mg/kg administered as an intravenous infusion over 30 minutes every 3 weeks for 6 to 8 cycles (see Pharmacology: Pharmacodynamics under Actions).
Primary prophylaxis with G-CSF, beginning with the first dose, is recommended for all adult patients with previously untreated sALCL or other CD30-expressing peripheral T-cell lymphomas, receiving combination therapy (see Precautions).
Refer to the SmPCs of chemotherapy agents given in combination with BRENTUXIMAB VEDOTIN (ADCETRIS) for patients with previously untreated sALCL or other CD30-expressing peripheral T-cell lymphomas.
Relapsed or refractory sALCL: The recommended dose is 1.8 mg/kg administered as an intravenous infusion over 30 minutes every 3 weeks.
The recommended starting dose for the retreatment of patients who have previously responded to treatment with BRENTUXIMAB VEDOTIN (ADCETRIS) is 1.8 mg/kg administered as an intravenous infusion over 30 minutes every 3 weeks. Alternatively, treatment may be started at the last tolerated dose (see Pharmacology: Pharmacodynamics under Actions).
Treatment should be continued until disease progression or unacceptable toxicity (see Precautions).
Patients who achieve stable disease or better should receive a minimum of 8 cycles and up to a maximum of 16 cycles (approximately 1 year) (see Pharmacology: Pharmacodynamics under Actions).
CTCL: The recommended dose is 1.8 mg/kg administered as an intravenous infusion over 30 minutes every 3 weeks.
Patients with CTCL should receive up to 16 cycles (see Pharmacology: Pharmacodynamics under Actions).
General: If the patient's weight is more than 100 kg, the dose calculation should use 100 kg (see Special precautions for disposal and other handling under Cautions for Usage).
Complete blood counts should be monitored prior to administration of each dose of this treatment (see Precautions).
Patients should be monitored during and after infusion (see Precautions).
Dose adjustments: Neutropenia: If neutropenia develops during treatment, it should be managed by dose delays. See Table 15 and Table 16 for appropriate dosing recommendations for monotherapy and combination therapy, respectively (see also Precautions). (See Tables 15 and 16.)

Peripheral neuropathy: If peripheral sensory or motor neuropathy emerges or worsens during treatment see Tables 17 and 18 as follows for appropriate dosing recommendations for monotherapy and combination therapy (see Precautions). (See Tables 17 and 18.)

Special patient populations: Renal and hepatic impairment: Combination therapy: Patients with renal impairment should be closely monitored for adverse events. There is no clinical trial experience using BRENTUXIMAB VEDOTIN (ADCETRIS) 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 VEDOTIN (ADCETRIS) in combination with chemotherapy should be avoided in patients with severe renal impairment.
Patients with hepatic impairment should be closely monitored for adverse events. The recommended starting dose in patients with mild hepatic impairment receiving BRENTUXIMAB VEDOTIN (ADCETRIS) 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 (ADCETRIS) 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 (ADCETRIS) 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 (ADCETRIS) in combination with chemotherapy should be avoided in patients with moderate and severe hepatic impairment.
Monotherapy: 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 (see Pharmacology: Pharmacokinetics under Actions).
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 (see Pharmacology: Pharmacokinetics under Actions).
Elderly: The dosing recommendations for patients aged 65 and older are the same as for adults. Currently available data are described in Adverse Reactions, Pharmacology: Pharmacodynamics and Pharmacokinetics under Actions.
Paediatric population: The safety and efficacy of BRENTUXIMAB VEDOTIN (ADCETRIS) in children less than 18 years have not yet been established. Currently available data are described in Adverse Reactions and Pharmacology: Pharmacodynamics and Pharmacokinetics under Actions but no recommendation on a posology can be made.
In nonclinical studies, thymus depletion has been observed (see Pharmacology: Toxicology: Preclinical safety data under Actions).
Method of administration: The recommended dose of BRENTUXIMAB VEDOTIN (ADCETRIS) is infused over 30 minutes.
For instructions on reconstitution and dilution of the medicinal product before administration, see Special precautions for disposal and other handling under Cautions for Usage.
BRENTUXIMAB VEDOTIN (ADCETRIS) must not be administered as an intravenous push or bolus. BRENTUXIMAB VEDOTIN (ADCETRIS) should be administered through a dedicated intravenous line and it must not be mixed with other medicinal products (see Incompatibilities under Cautions for Usage).

 

Overdosage

Hypersensitivity to the active substance or to any of the excipients listed in Description.
Combined use of bleomycin and BRENTUXIMAB VEDOTIN (ADCETRIS) causes pulmonary toxicity (see Interactions).

Progressive multifocal leukoencephalopathy: John Cunningham virus (JCV) reactivation resulting in progressive multifocal leukoencephalopathy (PML) and death can occur in BRENTUXIMAB VEDOTIN (ADCETRIS)-treated patients. PML has been reported in patients who received this treatment after receiving multiple prior chemotherapy regimens. PML is a rare demyelinating disease of the central nervous system that results from reactivation of latent JCV and is often fatal.
Patients should be closely monitored for new or worsening neurological, cognitive, or behavioural signs or symptoms, which may be suggestive of PML. BRENTUXIMAB VEDOTIN (ADCETRIS) should be held for any suspected case of PML. Suggested evaluation of PML includes neurology consultation, gadolinium-enhanced magnetic resonance imaging of the brain and cerebrospinal fluid analysis for JCV DNA by polymerase chain reaction or a brain biopsy with evidence of JCV. A negative JCV PCR does not exclude PML. Additional follow up and evaluation may be warranted if no alternative diagnosis can be established. BRENTUXIMAB VEDOTIN (ADCETRIS) dosing should be permanently discontinued if a diagnosis of PML is confirmed.
The physician should be particularly alert to symptoms suggestive of PML that the patient may not notice (e.g., cognitive, neurological, or psychiatric symptoms).
Pancreatitis: Acute pancreatitis has been observed in patients treated with BRENTUXIMAB VEDOTIN (ADCETRIS). Fatal outcomes have been reported.
Patients should be closely monitored for new or worsening abdominal pain, which may be suggestive of acute pancreatitis. Patient evaluation may include physical examination, laboratory evaluation for serum amylase and serum lipase, and abdominal imaging, such as ultrasound and other appropriate diagnostic measures. BRENTUXIMAB VEDOTIN (ADCETRIS) should be held for any suspected case of acute pancreatitis. BRENTUXIMAB VEDOTIN (ADCETRIS) should be discontinued if a diagnosis of acute pancreatitis is confirmed.
Pulmonary toxicity: Cases of pulmonary toxicity, including pneumonitis, interstitial lung disease, and acute respiratory distress syndrome (ARDS), some with fatal outcomes, have been reported in patients receiving BRENTUXIMAB VEDOTIN (ADCETRIS). Although a causal association with BRENTUXIMAB VEDOTIN (ADCETRIS) has not been established, the risk of pulmonary toxicity cannot be ruled out. In the event of new or worsening pulmonary symptoms (e.g. cough, dyspnoea), a prompt diagnostic evaluation should be performed and patients should be treated appropriately. Consider holding BRENTUXIMAB VEDOTIN (ADCETRIS) dosing during evaluation and until symptomatic improvement.
Serious infections and opportunistic infections: Serious infections such as pneumonia, staphylococcal bacteraemia, sepsis/septic shock (including fatal outcomes) and herpes zoster, cytomegalovirus (CMV) (reactivation) and opportunistic infections such as Pneumocystis jiroveci pneumonia and oral candidiasis have been reported in patients treated with BRENTUXIMAB VEDOTIN (ADCETRIS). Patients should be carefully monitored during treatment for the emergence of possible serious and opportunistic infections.
Infusion-related reactions: Immediate and delayed infusion-related reactions (IRR), as well as anaphylactic reactions, have been reported.
Patients should be carefully monitored during and after infusion. If an anaphylactic reaction occurs, administration of BRENTUXIMAB VEDOTIN (ADCETRIS) 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. Patients who have experienced a prior IRR should be premedicated for subsequent infusions. Premedication may include paracetamol, an antihistamine and a corticosteroid.
IRRs are more frequent and more severe in patients with antibodies to brentuximab vedotin (see Adverse Reactions).
Tumour lysis syndrome: Tumour lysis syndrome (TLS) has been reported with BRENTUXIMAB VEDOTIN (ADCETRIS). Patients with rapidly proliferating tumour and high tumour burden are at risk of tumour lysis syndrome. These patients should be monitored closely and managed according to best medical practice. Management of TLS may include aggressive hydration, monitoring of renal function, correction of electrolyte abnormalities, anti-hyperuricaemic therapy, and supportive care.
Peripheral neuropathy: BRENTUXIMAB VEDOTIN (ADCETRIS) may cause peripheral neuropathy, both sensory and motor. BRENTUXIMAB VEDOTIN (ADCETRIS)-induced peripheral neuropathy is typically an effect of cumulative exposure to this medicinal product and is reversible in most cases. In clinical trials, the majority of patients had resolution or improvement of their symptoms (see Adverse Reactions).
Patients should be monitored for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paraesthesia, discomfort, a burning sensation, neuropathic pain or weakness. Patients experiencing new or worsening peripheral neuropathy may require a delay and a dose reduction of BRENTUXIMAB VEDOTIN (ADCETRIS) or discontinuation of treatment (see Dosage & Administration).
Haematological toxicities: Grade 3 or Grade 4 anaemia, thrombocytopenia, and prolonged (≥ 1 week) Grade 3 or Grade 4 neutropenia can occur with BRENTUXIMAB VEDOTIN (ADCETRIS). Complete blood counts should be monitored prior to administration of each dose. If Grade 3 or Grade 4 neutropenia develops, refer to Dosage & Administration.
Febrile neutropenia: Febrile neutropenia (fever of unknown origin without clinically or microbiologically documented infection with an absolute neutrophil count < 1.0 x 10⁹/L, fever ≥ 38.5°C; ref CTCAE v3) has been reported with treatment with BRENTUXIMAB VEDOTIN (ADCETRIS). Complete blood counts should be monitored prior to administration of each dose of treatment. Patients should be monitored closely for fever and managed according to best medical practice if febrile neutropenia develops.
In combination therapy with AVD or CHP, advanced age was a risk factor for febrile neutropenia. When BRENTUXIMAB VEDOTIN (ADCETRIS) is administered in combination with AVD or CHP, primary prophylaxis with G-CSF, beginning with the first dose, is recommended for all adult patients regardless of age.
Severe cutaneous adverse reactions (SCARs): Cases of SCARs, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported with BRENTUXIMAB VEDOTIN (ADCETRIS). Fatal outcomes have been reported for SJS and TEN. If SJS, TEN or DRESS occur, BRENTUXIMAB VEDOTIN (ADCETRIS) should be discontinued and appropriate medical therapy should be administered.
Gastrointestinal complications: Gastrointestinal (GI) complications including intestinal obstruction, ileus, enterocolitis, neutropenic colitis, erosion, ulcer, perforation and haemorrhage, some with fatal outcomes, have been reported in patients treated with BRENTUXIMAB VEDOTIN (ADCETRIS). In the event of new or worsening GI symptoms, perform a prompt diagnostic evaluation and treat appropriately.
Hepatotoxicity: Hepatotoxicity in the form of elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) has been reported with BRENTUXIMAB VEDOTIN (ADCETRIS). Serious cases of hepatotoxicity, including fatal outcomes, have also occurred. Pre-existing liver disease, comorbidities, and concomitant medications may also increase the risk. Liver function should be tested before initiating the treatment and routinely monitored in patients receiving BRENTUXIMAB VEDOTIN (ADCETRIS). Patients experiencing hepatotoxicity may require a delay, change in dose or discontinuation of BRENTUXIMAB VEDOTIN (ADCETRIS).
Hyperglycaemia: Hyperglycaemia has been reported during clinical trials in patients with an elevated Body Mass Index (BMI) with or without a history of diabetes mellitus. However, any patient who experiences an event of hyperglycaemia should have their serum glucose closely monitored. Anti-diabetic treatment should be administered as appropriate.
Infusion site extravasation: Extravasation during intravenous infusion has occurred. Given the possibility of extravasation, it is recommended to closely monitor the infusion site for possible infiltration during drug administration.
Renal and hepatic impairment: There is limited experience in patients with renal and hepatic impairment. Available data indicate that MMAE clearance might be affected by severe renal impairment, hepatic impairment, and by low serum albumin concentrations (see Pharmacology: Pharmacokinetics under Actions).
CD30+ CTCL: The size of the treatment effect in CD30 + CTCL subtypes other than mycosis fungoides (MF) and primary cutaneous anaplastic large cell lymphoma (pcALCL) is not clear due to lack of high level evidence. In two single arm phase II studies of BRENTUXIMAB VEDOTIN (ADCETRIS), disease activity has been shown in the subtypes Sézary syndrome (SS), lymphomatoid papulosis (LyP) and mixed CTCL histology. These data suggest that efficacy and safety can be extrapolated to other CTCL CD30+ subtypes. Nevertheless, BRENTUXIMAB VEDOTIN (ADCETRIS) should be used with caution in other CD30+ CTCL patients after careful consideration of the potential benefit-risk on an individual basis (see Pharmacology: Pharmacodynamics under Actions).
Sodium content in excipients: This medicinal product contains 13.2 mg sodium per vial, equivalent to 0.7% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
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.
Effects on ability to drive and use machines: BRENTUXIMAB VEDOTIN (ADCETRIS) may have a moderate influence on the ability to drive and use machines (e.g. dizziness), see Adverse Reactions.

 

Use In Pregnancy & Lactation

Summary of the safety profile: The safety profile of BRENTUXIMAB VEDOTIN (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 19 have been determined based on data generated from clinical studies.
Monotherapy: In the pooled dataset of BRENTUXIMAB VEDOTIN (ADCETRIS) as monotherapy 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 events led to treatment discontinuation in 24% of patients receiving BRENTUXIMAB VEDOTIN (ADCETRIS).
The safety data in patients retreated with BRENTUXIMAB VEDOTIN (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 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 Pharmacology: Pharmacodynamics under Actions) were consistent with the safety profile of the pivotal clinical studies.
Combination therapy: For safety information of chemotherapy agents given in combination with BRENTUXIMAB VEDOTIN (ADCETRIS) (doxorubicin, vinblastine and dacarbazine (AVD) or cyclophosphamide, doxorubicin and prednisone (CHP)), refer to their summary of product characteristics
In the studies of BRENTUXIMAB VEDOTIN (ADCETRIS) as combination therapy with in 662 patients with previously untreated advanced HL (C25003) and 223 patients with previously untreated CD30+ 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 (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, peripheral neuropathy.
Tabulated list of adverse reactions: Adverse reactions for BRENTUXIMAB VEDOTIN (ADCETRIS) are listed by MedDRA System Organ Class and Preferred Term (see Table 19). 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 19.)

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 BRENTUXIMAB VEDOTIN (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 Dosage & Administration). The frequency of febrile neutropenia was 13% in patients who received primary prophylaxis with G-CSF.

 

Interaction with medicinal products metabolised through CYP3A4 route (CYP3A4 inhibitors/inducers): 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 15 & 16 for dosing recommendations for neutropenia (see Dosage & Administration).
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.
Co-administration of midazolam, a CYP3A4 substrate, with brentuximab vedotin did not alter the metabolism of midazolam; therefore, brentuximab vedotin is not expected to alter the exposure to medicines that are metabolized by CYP3A4 enzymes.
Doxorubicin, vinblastine and dacarbazine (AVD): The serum and plasma pharmacokinetic characteristics of antibody drug conjugate (ADC) and MMAE respectively following administration of brentuximab vedotin in combination with AVD were similar to that in monotherapy.
Co-administration of brentuximab vedotin did not affect the plasma exposure of AVD.
Cyclophosphamide, Doxorubicin and Prednisone: The serum and plasma pharmacokinetic characteristics of ADC and MMAE, respectively, following administration of brentuximab vedotin in combination with CHP were similar to that in monotherapy.
Co-administration of brentuximab vedotin is not expected to affect the exposure of CHP.
Bleomycin: There were no formal drug-drug interaction studies with brentuximab vedotin and bleomycin(B). In a phase 1 dose finding and safety study (SGN35-009), unacceptable pulmonary toxicity (including 2 fatal events) was noted in 11 of 25 patients (44%) treated with brentuximab vedotin plus ABVD. No pulmonary toxicity or fatal events were reported with brentuximab vedotin + AVD. Therefore, co-administration of BRENTUXIMAB VEDOTIN (ADCETRIS) with bleomycin is contraindicated (see Dosage & Administration).

 

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