Adcetris

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ANNEX I  
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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This medicinal product is subject to additional monitoring. This will allow quick identification of 
new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 
See section 4.8 for how to report adverse reactions. 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
ADCETRIS 50 mg powder for concentrate for solution for infusion. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each vial contains 50 mg of brentuximab vedotin.  
 
After reconstitution (see section 6.6), each mL contains 5 mg of brentuximab vedotin. 
 
ADCETRIS is an antibody-drug conjugate composed of a CD30-directed monoclonal antibody 
(recombinant chimeric immunoglobulin G1 [IgG1], produced by recombinant DNA technology in 
Chinese Hamster ovary cells) that is covalently linked to the antimicrotubule agent monomethyl 
auristatin E (MMAE). 
 
Excipient with known effect 
 
Each vial contains approximately 13.2 mg of sodium.  
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Powder for concentrate for solution for infusion. 
 
White to off-white cake or powder.  
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Hodgkin lymphoma 
 
ADCETRIS is indicated for adult patients with previously untreated CD30+ Stage IV Hodgkin 
lymphoma (HL) in combination with doxorubicin, vinblastine and dacarbazine (AVD) (see 
sections 4.2 and 5.1). 
 
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 section 5.1). 
 
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. 
 



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Systemic anaplastic large cell lymphoma 
 
ADCETRIS in combination with cyclophosphamide, doxorubicin and prednisone (CHP) is indicated 
for adult patients with previously untreated systemic anaplastic large cell lymphoma (sALCL) (see 
section 5.1). 
 
ADCETRIS is indicated for the treatment of adult patients with relapsed or refractory sALCL. 
 
Cutaneous T-cell lymphoma  
 
ADCETRIS is indicated for the treatment of adult patients with CD30+ cutaneous T-cell lymphoma 
(CTCL) after at least 1 prior systemic therapy (see section 5.1). 
 
4.2 Posology and method of administration 
 
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 section 5.1). 
 
Primary prophylaxis with growth factor support (G-CSF), beginning with the first dose, is 
recommended for all patients with previously untreated HL receiving combination therapy (see 
section 4.4). 
 
Refer to the summary of product characteristics (SmPC) of chemotherapy agents given in combination 
with 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. 
 
ADCETRIS treatment should start following recovery from ASCT based on clinical judgment. These 
patients should receive up to 16 cycles (see section 5.1). 
 
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 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 section 5.1). 
 
Treatment should be continued until disease progression or unacceptable toxicity (see section 4.4). 
 
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 section 5.1).  
 



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Previously untreated sALCL 
 
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 section 5.1).  
 
Primary prophylaxis with G-CSF, beginning with the first dose, is recommended for all patients with 
previously untreated sALCL receiving combination therapy (see section 4.4). 
 
Refer to the SmPCs of chemotherapy agents given in combination with ADCETRIS for patients with 
previously untreated sALCL.  
 
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 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 section 5.1). 
 
Treatment should be continued until disease progression or unacceptable toxicity (see section 4.4). 
 
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 section 5.1).  
 
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 section 5.1). 
 
General 
 
If the patient’s weight is more than 100 kg, the dose calculation should use 100 kg (see section 6.6). 
 
Complete blood counts should be monitored prior to administration of each dose of this treatment (see 
section 4.4).  
 
Patients should be monitored during and after infusion (see section 4.4).  
 



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Dose adjustments 
 
Neutropenia 
 
If neutropenia develops during treatment it should be managed by dose delays. See Table 1 and 
Table 2 for appropriate dosing recommendations for monotherapy and combination therapy, 
respectively (see also section 4.4).  
 
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 x 109/L) or 
Grade 2 (< 1500-1000/mm3 
                          < 1.5-1.0 x 109/L) 

Continue with the same dose and schedule. 

Grade 3 (< 1,000-500/mm3 
                < 1.0-0.5 x 109/L) or 
Grade 4 (< 500/mm3 
                          < 0.5 x 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 x 109/L) or 
Grade 2 (< 1500-1000/mm3 
                          < 1.5-1.0 x 109/L) 
Grade 3 (< 1,000-500/mm3 
                < 1.0-0.5 x 109/L) or 
Grade 4 (< 500/mm3 
                          < 0.5 x 109/L) 

Primary prophylaxis with G-CSF, beginning with the first 
dose, is recommended for all 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. 

 



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Peripheral neuropathy 
 
If peripheral sensory or motor neuropathy emerges or worsens during treatment see Table 3 and 4 for 
appropriate dosing recommendations for monotherapy and combination therapy, respectively (see 
section 4.4). 
 
Table 3: Dosing recommendations for new or worsening peripheral sensory or motor 
neuropathy with monotherapy 

Severity of peripheral sensory or motor 
neuropathy  

(signs and symptoms [abbreviated 
description of CTCAEa]) 

Modification of dose and schedule 

Grade 1 (paraesthesia and/or loss of 
reflexes, with no loss of function) 

Continue with the same dose and schedule.  

Grade 2 (interfering with function but not 
with activities of daily living)  

 

Withhold dose until toxicity returns to ≤ Grade 1 or 
baseline, then restart treatment at a reduced dose of 
1.2 mg/kg up to a maximum of 120 mg every 3 weeks. 

Grade 3 (interfering with activities of daily 
living) 

Withhold dose until toxicity returns to ≤ Grade 1 or 
baseline, then restart treatment at a reduced dose of 
1.2 mg/kg up to a maximum of 120 mg every 3 weeks. 

Grade 4 (sensory neuropathy that is 
disabling or motor neuropathy 
that is life threatening or leads to 
paralysis) 

Discontinue treatment. 

a. Grading based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v3.0; 
see neuropathy: motor; neuropathy: sensory; and neuropathic pain.  

 



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Table 4: Dosing recommendations for new or worsening peripheral sensory or motor 
neuropathy during combination therapy 

 Combination therapy with 
AVD 

Combination therapy with 
CHP 

Severity of peripheral sensory or motor 
neuropathy  

(signs and symptoms [abbreviated 
description of CTCAEa]) 

Modification of dose and 
schedule  

Modification of dose and 
schedule  

Grade 1 (paraesthesia and/or loss of 
reflexes, with no loss of function) 

Continue with the same 
dose and schedule. 

Continue with the same 
dose and schedule. 

Grade 2 (interfering with function but not 
with activities of daily living) 

Reduce dose to 0.9 mg/kg 
up to a maximum of 90 mg 
every 2 weeks. 

Sensory neuropathy: 
Continue treatment at same 
dose level. 
Motor neuropathy: Reduce 
dose to 1.2 mg/kg, up to a 
maximum of 120 mg every 
3 weeks. 

Grade 3 (interfering with activities of daily 
living) 

Withhold treatment with 
ADCETRIS until toxicity is 
≤ Grade 2, then restart 
treatment at a reduced dose 
to 0.9 mg/kg up to a 
maximum of 90 mg every 
2 weeks. 

Sensory neuropathy: 
Reduce dose to 1.2 mg/kg 
up to a maximum of 120 mg 
every 3 weeks. 
Motor neuropathy: 
Discontinue treatment. 

Grade 4 (sensory neuropathy which is 
disabling or motor neuropathy 
that is life threatening or leads to 
paralysis) 

Discontinue treatment. Discontinue treatment. 

a. Grading based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03; 
see neuropathy: motor; neuropathy: sensory; and neuropathic pain.  

 
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 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 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 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 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 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 ADCETRIS in combination with chemotherapy should be 
avoided in patients with moderate and severe hepatic impairment. 
 



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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 section 5.2). 
 
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 section 5.2). 
 
Elderly 
 
The dosing recommendations for patients aged 65 and older are the same as for adults. Currently 
available data are described in sections 4.8, 5.1 and 5.2. 
 
Paediatric population  
 
The safety and efficacy of ADCETRIS in children less than 18 years have not yet been established. 
Currently available data are described in sections 4.8, 5.1 and 5.2 but no recommendation on a 
posology can be made. 
 
In nonclinical studies, thymus depletion has been observed (see section 5.3). 
 
Method of administration  
 
The recommended dose of ADCETRIS is infused over 30 minutes.  
 
For instructions on reconstitution and dilution of the medicinal product before administration, see 
section 6.6. 
 
ADCETRIS must not be administered as an intravenous push or bolus. ADCETRIS should be 
administered through a dedicated intravenous line and it must not be mixed with other medicinal 
products (see section 6.2). 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.  
 
Combined use of bleomycin and ADCETRIS causes pulmonary toxicity (see section 4.5).  
 
4.4 Special warnings and precautions for use 
 
Progressive multifocal leukoencephalopathy 
 
John Cunningham virus (JCV) reactivation resulting in progressive multifocal leukoencephalopathy 
(PML) and death can occur in 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. 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. 
ADCETRIS dosing should be permanently discontinued if a diagnosis of PML is confirmed. 



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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 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. ADCETRIS should be held for any suspected case of acute pancreatitis. 
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 
ADCETRIS. Although a causal association with 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 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 
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 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 
section 4.8). 
 
Tumour lysis syndrome 
 
Tumour lysis syndrome (TLS) has been reported with 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. 



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Peripheral neuropathy 
 
ADCETRIS may cause peripheral neuropathy, both sensory and motor. 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 section 4.8). 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 ADCETRIS or discontinuation of treatment (see section 4.2).  
 
Haematological toxicities 
 
Grade 3 or Grade 4 anaemia, thrombocytopenia, and prolonged (≥ 1 week) Grade 3 or Grade 4 
neutropenia can occur with ADCETRIS. Complete blood counts should be monitored prior to 
administration of each dose. If Grade 3 or Grade 4 neutropenia develops, refer to section 4.2. 
 
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 0C; ref CTCAE v3) has been 
reported with treatment with 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 ADCETRIS is administered in combination with AVD or CHP, primary prophylaxis with 
G-CSF, beginning with the first dose, is recommended for all patients regardless of age. 
 
Stevens-Johnson syndrome and toxic epidermal necrolysis 
 
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with 
ADCETRIS. Fatal outcomes have been reported. If SJS or TEN occur, 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 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 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 ADCETRIS. Patients experiencing 
hepatotoxicity may require a delay, change in dose or discontinuation of 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.  



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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 section 5.2).  
 
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 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, ADCETRIS should be used with caution in other CD30+ CTCL patients after careful 
consideration of the potential benefit-risk on an individual basis (see section 5.1). 
 
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. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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 1 and 2 for dosing recommendations for neutropenia (see section 4.2).  
 
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 metabolised 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. 
 



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Cyclophosphamide, Doxorubicin and Prednisone (CHP) 
 
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 ADCETRIS with bleomycin is contraindicated (see section 4.3). 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential  
 
Women of childbearing potential should be using two methods of effective contraception during 
treatment with ADCETRIS and until 6 months after treatment.  
 
Pregnancy 
 
There are no data from the use of ADCETRIS in pregnant women. Studies in animals have shown 
reproductive toxicity (see section 5.3).  
 
ADCETRIS 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 ADCETRIS. 
 
Breast-feeding 
 
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. 
 
Fertility 
 
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 (see section 5.3). 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.  
 
4.7 Effects on ability to drive and use machines 
 
ADCETRIS may have a moderate influence on the ability to drive and use machines (e.g. dizziness), 
see section 4.8.  
 



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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 and C25007, see section 5.1) 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 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. 
 



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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, 

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 transfusion 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 



15 

Skin and subcutaneous tissue disorders 
Very common: Rasha, pruritus Alopecia, rasha 
Common: Alopecia Pruritus 
Uncommon: Stevens-Johnson syndrome/toxic epidermal 

necrolysis 
Stevens-Johnson syndromeb 

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 
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. 
 
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 
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. 
 



16 

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 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 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). 
 



17 

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 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.  
 
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. 
 
Paediatric population 
 
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. 
 
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. 
 



18 

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. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
There is no known antidote for overdose of ADCETRIS. In case of overdose, the patient should be 
closely monitored for adverse reactions, particularly neutropenia, and supportive treatment should be 
administered (see section 4.4).  
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antineoplastic agents; other antineoplastic agents; monoclonal 
antibodies, ATC code: L01XC12. 
 
Mechanism of action 
 
Brentuximab vedotin is an ADC that delivers an antineoplastic agent that results in apoptotic cell 
death selectively in CD30-expressing tumour cells. Nonclinical data suggest that the biological 
activity of brentuximab vedotin results from a multi-step process. Binding of the ADC to CD30 on the 
cell surface initiates internalisation of the ADC-CD30 complex, which then traffics to the lysosomal 
compartment. Within the cell, a single defined active species, MMAE, is released via proteolytic 
cleavage. Binding of MMAE to tubulin disrupts the microtubule network within the cell, induces cell 
cycle arrest and results in apoptotic death of the CD30-expressing tumour cell. 
 
Classical HL, sALCL and subtypes of CTCL (including MF and pcALCL) express CD30 as an 
antigen on the surface of their malignant cells. This expression is independent of disease stage, line of 
therapy or transplant status. These features make CD30 a target for therapeutic intervention. Because 
of the CD30-targeted mechanism of action brentuximab vedotin is able to overcome chemo-resistance 
as CD30 is consistently expressed in patients who are refractory to multi-agent chemotherapy, 
irrespective of prior transplant status. The CD30-targeted mechanism of action of brentuximab 
vedotin, the consistent expression of CD30 throughout the classical HL, sALCL and CD30+ CTCL 
disease and therapeutic spectrums and clinical evidence in CD30-positive malignancies following 
multiple lines of treatment provide a biologic rationale for its use in patients with relapsed and 
refractory classical HL, sALCL with or without prior ASCT and CD30+ CTCL after at least 1 prior 
systemic therapy. 
 
Contributions to the mechanism of action by other antibody associated functions have not been 
excluded.  
 
Pharmacodynamic effects 
 
Cardiac electrophysiology 
 
Forty-six (46) patients with CD30-expressing haematologic malignancies were evaluable of the 
52 patients who received 1.8 mg/kg of brentuximab vedotin every 3 weeks as part of a phase 1, 
single-arm, open-label, multicenter cardiac safety study. The primary objective was to evaluate the 
effect of brentuximab vedotin on cardiac ventricular re-polarization and the predefined primary 
analysis was the change in QTc from baseline to multiple time points in Cycle 1. 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


19 

The upper 90% confidence interval (CI) around the mean effect on QTc was < 10 msec at each of the 
Cycle 1 and Cycle 3 post-baseline time points. These data indicate the absence of clinically relevant 
QT prolongation due to brentuximab vedotin administered at a dose of 1.8 mg/kg every 3 weeks in 
patients with CD30-expressing malignancies. 
 
Clinical efficacy and safety 
 
Hodgkin lymphoma 
 
Study C25003 
 
The efficacy and safety of ADCETRIS were evaluated in a randomised, open-label, 2-arm, multicenter 
trial in 1334 patients with previously untreated advanced HL in combination with chemotherapy 
(doxorubicin [A], vinblastine [V] and dacarbazine [D] [AVD]). All patients had a histologically 
confirmed CD30-expressing disease. Sixty-two percent of patients had extranodal site involvement. Of 
the 1334 patients, 664 patients were randomised to the ADCETRIS + AVD arm and 670 patients were 
randomised to the ABVD (doxorubicin [A], bleomycin [B], vinblastine [V] and dacarbazine [D]) arm 
and stratified by number of International Prognostic Factor Project (IPFP) risk factors and region. 
Patients were treated on days 1 and 15 of each 28-day cycle with 1.2 mg/kg of ADCETRIS 
administered as an intravenous infusion over 30 minutes + doxorubicin 25 mg/m2, 
vinblastine 6 mg/m2, and dacarbazine 375 mg/m2. The median number of cycles received was 6 
(range, 1 to 6 cycles). Table 6 provides a summary of the baseline patient and disease characteristics. 
There were no relevant differences in the patient and disease characteristics between the two arms.  
 



20 

Table 6: Summary of baseline patient and disease characteristics in the phase 3 previously 
untreated HL study 
 
Patient Characteristics  ADCETRIS + AVD 

n = 664 
ABVD 
n = 670 

Median age (range)  35 years (18-82) 37 years (18-83) 
Patients ≥ 65 years old n (%) 60 (9) 62 (9) 
Gender, n (%) 378M (57) 

286F (43) 
398M (59) 
272F (41) 

ECOG status, n (%)   
0  376 (57) 378 (57) 
1  260 (39) 263 (39) 
2 28 (4) 27 (4) 
Missing 0 2 

Disease Characteristics    
Median time from HL diagnosis to first dose (range) 0.92 mo (0.1-21.4) 0.89 mo (0.0-81.4) 
Disease stagea at initial diagnosis of HL, n (%)   

III 237 (36) 246 (37) 
IV 425 (64) 421 (63) 
Not applicable 1 (< 1) 1 (< 1) 
Missing 0 2 (< 1 ) 

Extranodal involvement at time of diagnosis, n (%) 411 (62) 416 (62) 
IPFPb risk factors, n (%)   

0-1 141 (21) 141 (21) 
2-3 354 (53) 351 (52) 
4-7 169 (25) 178 (27) 

Bone marrow involvement at time of diagnosis or 
study entry, n (%) 

147(22) 151 (23) 

B symptomsa n (%) 400 (60) 381 (57) 
a Per Ann Arbor Staging. 
bIPFP = International Prognostic Factor Project. 
 
The primary endpoint in Study C25003 was modified PFS (mPFS) per independent review facility 
(IRF), defined as time from randomisation to disease progression, death, or evidence of non-complete 
response (non-CR) after completion of first-line therapy per IRF followed by subsequent anticancer 
therapy. Timing of the modified event was the date of the first PET scan post completion of first-line 
therapy demonstrating the absence of complete response (CR), defined as Deauville score of ≥3. The 
median modified PFS by IRF assessment was not reached in either treatment arm. The results in the 
intent-to-treat (ITT) population showed a statistically significant improvement in modified PFS for 
ADCETRIS+ AVD, with a stratified hazard ratio of 0.770 (95% CI, 0.603; 0.983, p = 0.035), 
indicating a 23% reduction in the risk of modified PFS events for ADCETRIS+ AVD versus ABVD.  
 
A pre-specified subgroup analysis of mPFS by disease stage showed that patients with Stage IV disease 
had a larger effect compared with the ITT population, with an unstratified hazard ratio of 0.71 (95% CI, 
0.53; 0.96), compatible with a 29% reduction in the risk of modified PFS events for ADCETRIS+ 
AVD versus ABVD. Of the ITT population, 846 patients (64%) had Stage IV disease. 
 
Table 7 provides the efficacy results for modified PFS and overall survival (OS) in the ITT population 
and patients with Stage IV disease. 



21 

 
Table 7: Efficacy results for previously untreated HL patients treated with 1.2 mg/kg of 
ADCETRIS + AVD on days 1 and 15 of a 28-day cycle (ITT and Stage IV) 
 

 

Intent to Treat (ITT) Population Patients with Stage IV Disease 

ADCETRIS 
+ AVD 
n = 664 

ABVD 
n = 670 

Stratified 
Hazard Ratio 
and p-value 

ADCETRIS 
+ AVD 
n = 425 

ABVD 
n = 421 

Unstratified 
Hazard Ratio 
and p-valuec 

Number of 
events (%) 117 (18) 146 (22) 0.77 

(95% CI [0.60, 
0.98]) 

p-value=0.035 

77 (18) 102 (24) 
0.71  

(95% CI [0.53, 
0.96]) 

p-value=0.023 
Estimated 
mPFSa per IRF 
at 2 Year (%) 

82.1 
(95% CI 

[78.8, 85.0]) 

77.2 
(95% CI 

[73.7, 
80.4]) 

82.0 (95% 
CI [77.8, 

85.5]) 

75.3 (95% 
CI [70.6, 

79.3]) 

Overall 
Survivalb 
Number of 
deaths (%) 

28 (4) 39 (6) 

0.73 
(95% CI [0.45, 

1.18]) 
p-value=0.199 

14 (3) 26 (6) 

0.51  
(95% CI [0.27, 

0.97]) 
p-value=0.037 

aAt the time of analysis, the median modified PFS follow-up time for both arms was 24.6 months. 
bData from an interim OS analysis.  
cp-value for Stage IV disease is not adjusted for multiplicity. 
 
Figure 1: Modified progression-free survival per IRF in the ITT population (ADCETRIS + AVD 
vs. ABVD) 
 

Number of Patients-at-Risk
664 637 623 600 541 528 513 493 463 439 347 328 309 196 185 169 96 85 77 26 24 21 4 4 4 0 0
670 636 626 593 521 490 474 459 432 413 326 306 292 177 164 153 76 66 62 16 13 12 1 1 1 0 0ABVD

A+AVD

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52

Time (Months) from Randomization

0.0

0.2

0.4

0.6

0.8

1.0

Pr
og

re
ss

io
n-

Fr
ee

 S
ur

vi
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Pr

ob
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ty

 o
f m

od
ifi

ed

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52

Time (Months) from Randomization

0.0

0.2

0.4

0.6

0.8

1.0

Pr
og

re
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io
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Fr
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ifi

ed

CensoredABVD
CensoredA+AVD

Num of events  A+AVD: 117  ABVD: 146
Hazard ratio (95% CI):  0.770 ( 0.603,  0.983)
Log-rank test p-value: 0.035

 
 



22 

Figure 2: Modified progression-free survival per IRF in patients with Stage IV disease 
(ADCETRIS + AVD vs. ABVD) 
 

Number of Patients-at-Risk
425 411 403 384 345 334 326 317 301 286 227 215 205 131 124 113 65 57 53 16 15 13 2 2 2 0 0
421 402 396 376 325 302 293 285 269 256 207 195 186 107 99 93 48 41 38 11 8 7 0 0 0 0 0ABVD

A+AVD

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52

Time (Months) from Randomization

0.0

0.2

0.4

0.6

0.8

1.0

Pr
og

re
ss

io
n-

Fr
ee

 S
ur

vi
va

l
Pr

ob
ab

il
it

y 
of

 m
od

if
ie

d

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52

Time (Months) from Randomization

0.0

0.2

0.4

0.6

0.8

1.0

Pr
og

re
ss

io
n-

Fr
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vi
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Pr

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y 
of

 m
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if
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d

CensoredABVD
CensoredA+AVD

Num of events  A+AVD: 77  ABVD: 102
Hazard ratio (95% CI):  0.711 ( 0.529,  0.956)
Log-rank test p-value: 0.023

 
 
Other secondary efficacy endpoints including CR rate and ORR at the end of randomisation regimen, 
CR rate at the end of first-line therapy, and the rate of PET negativity at the end of Cycle 2, duration 
of response (DOR), duration of complete remission (DOCR), disease-free survival (DFS) and 
event-free survival (EFS) all trended in favour of ADCETRIS + AVD in both the ITT and Stage IV 
population. 
 
Pre-specified subgroup analyses of modified PFS per IRF were performed for the ITT population 
including age, region, cancer stage at baseline, baseline extranodal sites, number of IPFP risk factors, 
baseline B symptoms, Cycle 2 PET assessment, Cycle 2 PET Deauville score, and receipt of 
alternative first-line medication (AFM). The analyses showed a consistent trend towards benefit for 
patients who received ADCETRIS + AVD compared with patients who received ABVD in most 
subgroups. The efficacy in elderly patient population (patients ≥ 60 years of age [n = 186] [HR = 1.00, 
95% CI (0.58, 1.72)] and ≥ 65 years of age [n = 122] [HR = 1.01, 95% CI (0.53, 1.94)]) and patients 
with no extranodal sites (n = 445) (HR = 1.04, 95% CI [0.67, 1.62]) showed no clinically meaningful 
difference between the two arms. 
 
Post-hoc subgroup analyses of modified PFS per IRF for patients with Stage IV disease were 
performed including age, region, baseline extranodal sites, number of IPFP risk factors, baseline B 
symptoms, baseline ECOG status and gender. The analyses showed a consistent trend towards benefit 
for patients who received ADCETRIS + AVD compared with patients who received ABVD in most 
subgroups. Patients with Stage IV disease for whom extranodal disease was reported ([n = 722] 
[HR = 0.69, 95% CI (0.50, 0.94)]) showed an mPFS (per IRF) benefit. In patients with Stage IV 
disease for whom no extranodal disease was reported, no benefit has been shown at time of analysis 
([n = 85] [HR = 1.49, 95% CI (0.51, 4.31)]). The significance of this finding in stage IV HL patients 
with no extranodal disease is not established due to small patient numbers and low event rates 
(14 events). The efficacy in elderly patients with Stage IV disease in the A + AVD arm (patients ≥ 60 
years of age [n = 118] [HR = 0.80, 95% CI (0.42, 1.53)] and ≥ 65 years of age [n = 78] [HR = 0.78, 
95% CI (0.36, 1.67)]) showed better benefit compared with elderly patients in ITT population. 
 
In the ITT population, 33% fewer patients treated with ADCETRIS + AVD in the ITT population 
received subsequent salvage chemotherapy (n = 66) and high-dose chemotherapy and transplant 
(n = 36) compared with those treated with ABVD (n = 99 and n = 54, respectively). In the Stage IV 
population, 35% fewer patients treated with ADCETRIS + AVD received subsequent salvage 
chemotherapy (n = 45) compared with those treated with ABVD (n = 69) and 22% fewer patients 
treated with ADCETRIS + AVD received high-dose chemotherapy and transplant (n = 29) compared 
with those treated with ABVD (n = 37). 



23 

 
The European Organization for Research and Treatment of Cancer Quality of Life 30-Item 
Questionnaire (EORTC-QLQ-C30) showed no clinically meaningful difference between the two arms 
in both the ITT and Stage IV population. 
 
Study SGN35-005 
 
The efficacy and safety of ADCETRIS were evaluated in a randomised, double-blind, 
placebo-controlled, 2-arm multicenter trial in 329 patients with HL at risk of relapse or progression 
following ASCT. Patients with known cerebral/meningeal disease, including history of PML were 
excluded from the study. See Table 8 for patient characteristics. Of the 329 patients, 165 patients were 
randomised to the treatment arm and 164 patients were randomised to the placebo arm. In the study, 
patients were to receive their first dose after recovery from ASCT (between days 30-45 following 
ASCT). Patients were treated with 1.8 mg/kg of ADCETRIS or matching placebo intravenously over 
30 minutes every 3 weeks for up to 16 cycles. 
 
Eligible patients were required to have at least one of the following risk factors:  
• HL that was refractory to frontline treatment 
• Relapsed or progressive HL that occurred <12 months from the end of frontline treatment 
• Extranodal involvement at time of pre-ASCT relapse, including extranodal extension of nodal 

masses into adjacent vital organs. 
 



24 

Table 8: Summary of baseline patient and disease characteristics in the phase 3 HL post-ASCT 
Study 
 

Patient characteristics ADCETRIS 
n = 165 

Placebo 
n = 164 

Median age, years (range) 33 years (18-71) 32 years (18-76) 
Gender 76M (46%)/89F (54%) 97M (59%)/67F (41%) 
ECOG status   

0 87 (53%) 97 (59%) 
1 77 (47%) 67 (41%) 
2 1 (1%) 0 

Disease characteristics   
Median number of prior chemotherapy 
regimens (range) 

2 (2-8) 2 (2-7) 

Median time from HL diagnosis to first dose 
(range) 

18.7 mo (6.1-204.0) 18.8 mo (7.4-180.8) 

Disease stage at initial diagnosis of HL   
Stage I 1 (1%) 5 (3%) 
Stage II 73 (44%) 61 (37%) 
Stage III 48 (29%) 45 (27%) 
Stage IV 43 (26%) 51 (31%) 
Unknown 0 2 (1%) 

PET scan Status prior to ASCT   
FDG-AVID 64 (39%) 51 (31%) 
FDG-NEGATIVE 56 (34%) 57 (35%) 
NOT DONE 45 (27%) 56 (34%) 

Extranodal involvement at time of 
pre-ASCT relapse 

54 (33%) 53 (32%) 

B symptomsa 47 (28%) 40 (24%) 
Best response to salvage therapy pre-ASCTb   

Complete Response 61 (37%) 62 (38%) 
Partial Response 57 (35%) 56 (34%) 
Stable Disease 47 (28%) 46 (28%) 

HL Status after the end of frontline standard 
chemotherapyb 

  

Refractory 99 (60%) 97 (59%) 
Relapse occurred <12 months 53 (32%) 54 (33%) 
Relapse occurred ≥ 12 months 13 (8%) 13 (8%) 

a. For refractory disease, or upon progression or relapse after frontline therapy. 
b. Stratification factors at randomisation. 
 
 
The efficacy results are shown in Table 9. The primary endpoint of PFS was met and showed a 
difference in median PFS of 18.8 months in favour of the treatment arm. 
 



25 

Table 9: Efficacy results in HL patients at increased risk of relapse or progression following 
ASCT treated with 1.8 mg/kg of ADCETRIS every 3 weeks 
 

 
ADCETRIS 

n = 165 
Placebo 
n = 164 

Stratified Hazard 
Ratio 

Progression 
Free Survivala  
 

Median per IRF  

42.9 months 
(95% CI [30.4, 42.9]) 

24.1 months 
(95% CI [11.5, -]) 

0.57 
(95% CI [0.40, 0.81]) 
Stratified log-rank test 

p=0.001 
Median per Investigator   

Not reached 
(95% CI [26.4, -]) 

15.8 months 
(95% CI [8.5, -]) 

0.5 
(95% CI [0.36, 0.70])b 

Overall 
Survival 

Number of deaths (%)  

28 (17) 25 (15) 1.15 (95% CI [0.67, 1.97] 
a. At the time of the primary analysis, the median follow-up time for both arms was 30 months (range, 0 to 50).  
b. Stratified log-rank test was not performed for PFS per Investigator. 
 
 
Pre-specified subgroup analyses of PFS per IRF were performed by patients’ best response to 
pre-ASCT salvage therapy, HL status after frontline therapy, age, gender, baseline weight, baseline 
ECOG performance status, number of treatments pre-ASCT, geographic region, pre-ASCT PET 
status, B symptom status after failure of frontline therapy, and pre-ASCT extranodal disease status. 
The analyses showed a consistent trend towards benefit for patients who received ADCETRIS 
compared with patients who received placebo with the exception of patients ≥65 years of age (n = 8). 
 
No differences were observed in quality of life between the treatment and placebo arms. Medical 
resource utilization (MRU) analysis showed that hospitalizations and outpatient visits, as well as 
working days/other activities missed by patients and caregivers were lower with ADCETRIS 
compared with placebo in patients with HL at increased risk of relapse. 
 
An updated analysis conducted after 3 years of follow-up showed a sustained PFS improvement per 
IRF (HR = 0.58 [95% CI (0.41, 0.81)]). 
 
Post-hoc Risk Factor Analyses 
 
Post-hoc analyses were performed to evaluate the impact of increased risk (number of risk factors) on 
clinical benefit (Table 10). Representative risk factors for these analyses were: 
• HL that occurred <12 months or HL that was refractory to frontline therapy 
• Best response of PR or SD to most recent salvage therapy as determined by CT and/or PET 

scanning  
• Extranodal disease at pre-ASCT relapse 
• B symptoms at pre-ASCT relapse 
• Two or more prior salvage therapies.  

 
The results of these post-hoc analyses suggest increased clinical benefit for patients with two or more 
risk factors but no difference based on any of the individual risk factors. No benefit in terms of PFS or 
OS has been observed in patients with one risk factor for relapse or progression. 
 



26 

Table 10: Summary of PFS per IRF and OS by number of risk factors in the phase 3 HL 
post-ASCT Study  
 
   Progression Free Survival per IRF 
 Number of Risk 

Factors = 1 
Number of Risk 

Factors ≥ 2 
Number of Risk 

Factors ≥ 3 
ADCETRIS 

n = 21 
Placebo 
n = 28 

ADCETRIS 
n = 144 

Placebo 
n = 136 

ADCETRIS 
n = 82 

Placebo 
n = 84 

Number of 
patients with 
disease 
progression 
or deatha (%) 

9 (43) 7 (25) 51 (35) 68 (50) 32 (39) 49 (58) 

Stratified 
Hazard 
Ratio  

1.65 
 

(95% CI [0.60, 4.55])b 

0.49 
 

(95% CI [0.34, 0.71]) 

0.43  
 

(95% CI [0.27, 0.68]) 
Overall Survival  

 Number of Risk 
Factors = 1 

Number of Risk 
Factors ≥ 2 

Number of Risk 
Factors ≥ 3 

ADCETRIS 
n = 21 

Placebo 
n = 28 

ADCETRIS 
n = 144 

Placebo 
n = 136 

ADCETRIS 
n = 82 

Placebo 
n = 84 

Number of 
deathsc (%) 

5 (24) 1 (4) 23 (16) 24 (18) 15 (18) 16 (19) 

Stratified 
Hazard 
Ratio  

7.94 
 

(95% CI [0.93, 68.06])b 

0.94 
 

(95% CI [0.53, 1.67]) 

0.92 
 

(95% CI [0.45, 1.88]) 
a. Death without either prior progression or more than one missed assessment visit. 
b. Indicates results from non-stratified analysis. 
c. Events are death due to any cause. 
 
At the time of the updated analysis (3 years of follow-up) for patients with 2 or more risk factors, the 
hazard ratio for PFS per IRF was 0.49 (95% CI [0.34, 0.71]) and the hazard ratio for PFS per 
investigator was 0.41 (95% CI [0.29, 0.58]) (see Figures 3 and 4). 
 
Figure 3: Kaplan-Meier Plot of PFS per IRF in Patients with ≥ 2 Risk Factors 

 
 



27 

Figure 4: Kaplan-Meier Plot of PFS per Investigator in Patients with ≥ 2 Risk Factors 

 
 
 
Study SG035-0003 
 
The efficacy and safety of ADCETRIS as a single agent was evaluated in a pivotal open-label, 
single-arm, multicenter study in 102 patients with relapsed or refractory HL. See Table 11 below for a 
summary of baseline patient and disease characteristics.  
 
Table 11: Summary of baseline patient and disease characteristics in the phase 2 relapsed or 
refractory HL study 
 

Patient characteristics n = 102 
Median age, years (range) 31 years (15-77) 
Gender 48M (47%)/54F (53%) 
ECOG status  

0 42 (41%) 
1 60 (59%) 

Prior ASCT 102 (100%) 
Prior chemotherapy Regimens 3.5 (1-13) 
Time from ASCT to first post-transplant relapse 6.7 mo (0-131) 
Histologically confirmed CD30-expressing disease 102 (100%) 

Disease characteristics  
Primary Refractory to frontline therapya 72 (71%) 
Refractory to most recent therapy 43 (42%) 
Baseline B symptoms 35 (33%) 
Stage III at initial diagnosis 27 (26%) 
Stage IV at initial diagnosis 20 (20%) 

a. Primary refractory HL is defined as a failure to achieve a complete remission to, or progressed within 3 months of 
completing frontline therapy. 

 
Eighteen (18) patients (18%) received 16 cycles of ADCETRIS; and the median number of cycles 
received was 9 (ranging from 1 to 16).  
 
Response to treatment with ADCETRIS was assessed by Independent Review Facility (IRF) using the 
Revised Response Criteria for Malignant Lymphoma (Cheson, 2007). Treatment response was 
assessed by spiral CT of chest, neck, abdomen and pelvis; PET scans and clinical data. Response 
assessments were performed at cycles 2, 4, 7, 10, 13, and 16 with PET at cycles 4 and 7. 



28 

The objective response rate (ORR) per IRF assessment was 75% (76 of 102 patients in the 
intent-to-treat [ITT] set) and tumour reduction was achieved in 94% of patients. Complete remission 
(CR) was 33% (34 of 102 patients in the ITT set). The median overall survival (OS) is 40.5 months 
(the median observation time (time to death or last contact) from first dose was 35.1 months (range 
1.8 to 72.9+ months). The estimated overall survival rate at 5 years was 41% (95% CI [31%, 51%]). 
The investigator assessments were generally consistent with the independent review of the scans. Of 
the patients treated, 8 responding patients went on to receive an allogeneic SCT. For further efficacy 
results see Table 12.  
 
Table 12: Efficacy results in relapsed or refractory Hodgkin lymphoma patients treated with 
1.8 mg/kg of ADCETRIS every 3 weeks 
 
Best clinical response (n = 102 ) IRF n (%) 95% CI 
    Objective response rate (CR + PR) 76 (75) 64.9, 82.6 
          Complete remission (CR) 34 (33) 24.3, 43.4 
          Partial remission (PR) 42 (41) NA 
    Disease control rate (CR + PR + SD) 98 (96) 90.3, 98.9 
Duration of response  Median per IRF  95% CI 
    Objective response rate (CR + PR)a 6.7 months  3.6, 14.8 
    Complete remission (CR) 27.9 months 10.8, NEb  
Overall survival   95% CI 

Median 40.5 months  28.7, 61.9 
Estimated 5-year OS Rate 41% 31%, 51% 

a. The range of DOR was 1.2+ months to 43+ months and the median follow-up time from first dose for patients who 
achieved objective response (OR) per IRF was 9.0 months. 

b. Not estimable. 
 
An exploratory intra-patient analysis showed that approximately 64% of the HL patients treated with 
ADCETRIS as part of the SG035-0003 clinical study experienced an improvement in clinical benefit 
as measured by longer progression free survival (PFS) compared with their most recent prior line of 
therapy.  
 
Of the 35 patients (33%) who had B symptoms at baseline, 27 patients (77%) experienced resolution 
of all B symptoms at a median time of 0.7 months from initiation of ADCETRIS. 
 
Data in HL Patients Who Are Not Stem Cell Transplant (SCT) Candidates 
 
Study-C25007  
 
A phase 4 single-arm study was conducted in patients with relapsed or refractory HL (n = 60) who had 
received at least one prior chemotherapeutic regimen and at the time of treatment initiation with 
ADCETRIS were not considered candidates for SCT or multiagent chemotherapy. The median 
number of cycles was 7 (range 1 to 16 cycles). Patients were treated with 1.8 mg/kg of ADCETRIS 
every 3 weeks. Per IRF, the objective response rate (ORR) in the ITT population was 50% (95% CI, 
37; 63%). A best overall response of CR was reported for 7 patients (12%); PR was reported for 
23 patients (38%). Among these 30 patients, the median time to response, defined as the time from 
first dose to the soonest of PR or CR, was 6 weeks (range, 5 to 39 weeks). The median time to best 
overall response, defined as the time from first dose to the clinical best response of CR or PR, was 
11 weeks (range, 5 to 60 weeks). Twenty-eight patients (47%) went on to receive SCT after a median 
of 7 cycles (range, 4 to 16 cycles) of ADCETRIS treatment. The 32 patients (53%) who did not 
receive subsequent SCT also received ADCETRIS for a median of 7 cycles (range, 1 to 16 cycles).  
 
Of the study’s 60 patients, 49 patients (82%) received > 1 prior cancer-related treatment and 
11 patients (18%) received 1 prior cancer-related treatment. Per IRF, the ORR was 51% 
(95% CI [36%, 66%]) for the patients who had received > 1 prior cancer-related treatment and 45% 
(95% CI [17%, 77%]) for the patients who had received 1 prior cancer-related treatment. For the 



29 

patients who received > 1 prior cancer-related treatment, a best overall response of CR was reported 
for 6 patients (12%); PR was reported for 19 patients (39%). For the patients who received 1 prior 
cancer-related treatment, CR was reported for 1 patient (9%) and PR was reported for 4 patients 
(36%). Out of the 49 patients receiving > 1 line of prior treatment, 22 patients (45%) received 
subsequent SCT; of the 11 patients who had received 1 prior treatment, 6 patients (55%) received 
subsequent SCT. 
 
Data were also collected from patients (n = 15) in phase 1 dose escalation and clinical pharmacology 
studies, and from patients (n = 26) in a NPP, with relapsed or refractory HL who had not received an 
ASCT, and who were treated with 1.8 mg/kg of ADCETRIS every 3 weeks. 
 
Baseline patient characteristics showed failure from multiple prior chemotherapy regimens (median of 
3 with a range of 1 to 7) before first administration with ADCETRIS. Fifty nine percent (59%) of 
patients had advanced stage disease (Stage III or IV) at initial diagnosis.  
 
Results from these phase 1 studies and from the NPP experience showed, that in patients with relapsed 
or refractory HL without prior ASCT, clinically meaningful responses can be achieved as evidenced 
by an investigator-assessed, objective response rate of 54% and a complete remission rate of 22% after 
a median of 5 cycles of ADCETRIS.  
 
Study SGN35-006 (Retreatment Study) 
 
The efficacy of retreatment in patients who had previously responded (CR or PR) to treatment with 
ADCETRIS was evaluated in a phase 2, open-label, multicenter trial. Twenty patients with relapsed or 
refractory HL received a starting dose of 1.8 mg/kg and one patient received a starting dose of 
1.2 mg/kg of ADCETRIS administered intravenously over 30 minutes every 3 weeks. The median 
number of cycles was 7 (range, 2 to 37 cycles). Of the 20 evaluable patients with HL, 6 patients (30%) 
achieved a CR and 6 patients (30%) achieved a PR with ADCETRIS retreatment, for an ORR of 60%. 
The median duration of response was 9.2 and 9.4 months in patients who achieved OR (CR+PR) and 
CR, respectively. 
 
Systemic anaplastic large cell lymphoma 
 
Study SGN35-014 
 
The efficacy and safety of ADCETRIS were evaluated in a randomised, double-blind, double-dummy, 
active-controlled, multicenter trial of 452 patients with previously untreated CD30+ PTCL in 
combination with cyclophosphamide [C], doxorubicin [H] and prednisone [P] (CHP). For enrollment, 
the trial required CD30 expression ≥10% per immunohistochemistry. Only patients with CD30+ 
PTCLs who were eligible for a cyclophosphamide [C], doxorubicin [H], vincristine [O] and 
prednisone [P] (CHOP)-based regimen were included. The combination of ADCETRIS + CHP has not 
been studied in all PTCL subtypes. See Table 13 for enrolled PTCL subtypes. Of the 452 patients, 
226 were randomised to treatment with ADCETRIS + CHP and 226 patients were randomised to 
treatment with CHOP. Randomisation was stratified by ALK-positive sALCL versus all other 
subtypes and by the International Prognostic Index (IPI) score. Patients were treated with ADCETRIS 
administered as an intravenous infusion over 30 minutes on day 1 of each 21-day cycle for 6 to 
8 cycles + CHP. The median number of cycles received was 6 (range, 1 to 8 cycles); 70% of patients 
received 6 cycles of treatment, and 18% received 8 cycles of treatment. Table 13 provides a summary 
of baseline patient and disease characteristics. 
 



30 

Table 13: Summary of baseline patient and disease characteristics in the phase 3 previously 
untreated PTCL study (ITT and sALCL) 
 
 ITT Population  sALCL Populationb 
Patient characteristics ADCETRIS 

+ CHP 
n=226 

CHOP 
n=226 

ADCETRIS 
+ CHP 
n=162 

CHOP 
n=154 

Median age (range) 58.0 (18-85) 58.0 (18-83) 55.0 (18-85) 54.0 (18-83) 
Patients ≥ 65 years old (%) 69 (31) 70 (31) 38 (23) 36 (23) 
Male sex, n (%) 133 (59) 151 (67) 95 (59) 110 (71) 
ECOG status, n (%)     

0 84 (37) 93 (41) 58 (36) 53 (34) 
1 90 (40) 86 (38) 62 (38) 61 (40) 
2 51 (23) 47 (21) 41 (25) 40 (26) 

Disease characteristics     
Diagnosis, per local assessment, n 
(%)a 

    

sALCL 162 (72) 154 (68) 162 (100) 154 (100) 
ALK-positive 49 (22) 49 (22) 49 (30) 49 (32) 
ALK-negative 113 (50) 105 (46) 113 (70) 105 (68) 

Peripheral T-cell lymphoma (PTCL-
NOS) 

29 (13) 43 (19) NA NA 

Angioimmunoblastic T-cell 
lymphoma (AITL) 

30 (13) 24 (11) NA NA 

Adult T-cell leukemia/lymphoma 
(ATLL) 

4 (2) 3 (1) NA NA 

Enteropathy-associated T-cell 
lymphoma (EATL) 

1 (0) 2 (1) NA NA 

Median time from diagnosis to first 
dose, months (range) 

0.8 (0, 19) 0.9 (0, 10) 0.8 (0, 19) 0.9 (0, 10) 

Disease stage at initial diagnosis of 
PTCL, n (%) 

    

Stage I 12 (5) 9 (4) 12 (7) 7 (5) 
Stage II 30 (13) 37 (16) 22 (14) 27 (18) 
Stage III 57 (25) 67 (30) 29 (18) 46 (30) 
Stage IV 127 (56) 113 (50) 99 (61) 74 (48) 

IPI score      
0 8 (4) 16 (7) 7 (4) 14 (9) 
1 45 (20) 32 (14) 34 (21) 18 (12) 
2 74 (33) 78 (35) 58 (36) 60 (39) 
3 66 (29) 66 (29) 37 (23) 40 (26) 
4 29 (13) 25 (11) 22 (14) 16 (10) 
5 4 (2) 9 (4) 4 (2) 6 (4) 

Extranodal involvement at time of 
diagnosis, n (%) 

    

≤ 1 site 142 (63) 146 (65) 94 (58) 95 (62) 
>1 site 84 (37) 80 (35) 68 (42) 59 (38) 

Baseline bone marrow biopsy-
lymphoma involvement, n (%) 

    

Yes 30 (13) 34 (15) 15 (9) 13 (8) 
No 196 (87) 192 (85) 147 (91) 141 (92) 

a. As per the 2008 WHO classification. 
b. For patients with locally-diagnosed sALCL. 
 
The primary endpoint in SGN35-014 was PFS per IRF, defined as the time from the date of 
randomisation to the date of first documentation of progressive disease, death due to any cause, or 
receipt of subsequent anticancer chemotherapy to treat residual or progressive disease, whichever 



31 

occurs first. Receipt of post-treatment consolidative radiotherapy, post-treatment chemotherapy for the 
purpose of mobilising peripheral blood stem cells, or consolidative autologous or allogeneic stem cell 
transplant were not considered as disease progression or as having started new anticancer therapy. 
 
Key secondary endpoints included PFS per IRF for patients with centrally-confirmed sALCL, CR rate 
per IRF following the completion of study treatment, OS and ORR per IRF following the completion 
of study treatment which were tested by a fixed sequence testing procedure following the statistical 
significance of PFS per IRF.  
 
The primary endpoint and alpha-protected, key secondary endpoints, which were evaluated 
hierarchically, were met. The median PFS per IRF for the ITT population was 48.2 months on the 
ADCETRIS + CHP arm versus 20.8 months on the CHOP arm. The stratified hazard ratio was 
0.71 (95% CI: 0.54; 0.93, p=0.011), indicating a 29% reduction in the risk of PFS events for 
ADCETRIS + CHP versus CHOP. For overall survival, the stratified hazard ratio was 
0.66 (95% CI: 0.46; 0.95, p=0.024), a 34% reduction in the risk of OS events for ADCETRIS + CHP 
versus CHOP.  
 
PFS per IRF for patients with centrally-confirmed sALCL was a pre-specified key secondary endpoint. 
The median PFS per IRF was 55.7 months on the ADCETRIS + CHP arm versus 54.2 months on the 
CHOP arm. The stratified hazard ratio was 0.59 (95% CI: 0.42; 0.84), compatible with a statistically 
significant 41% reduction in the risk of PFS events for ADCETRIS + CHP versus CHOP 
(p-value=0.003), see Figure 5 and Table 14. 
 
Subgroup analyses were performed for patients with locally-diagnosed sALCL. For overall survival, 
the stratified hazard ratio was 0.54 (95% CI: 0.34; 0.87), a 46% reduction in the risk of OS events for 
ADCETRIS + CHP versus CHOP, see Figure 6. At the end of treatment, the CR rate by IRF 
assessment was 71.0% for patients on the ADCETRIS + CHP arm compared with 53.2% for patients 
on the CHOP arm with a difference of 17.7% (95% CI: 7.2%; 28.3%). At the end of treatment, the 
ORR rate by IRF assessment was 87.7% for patients on the ADCETRIS + CHP arm compared with 
70.8% for patients on the CHOP arm with a difference of 16.9% (95% CI: 8.1%; 25.7%). In the 
subgroup of patients with ALK+ sALCL and ALK- sALCL the stratified hazard ratio for PFS per IRF 
was 0.29 (95% CI: 0.11; 0.79) and 0.65 (95% CI: 0.44; 0.95), respectively.  
 



32 

 
Table 14: Efficacy results in patients with previously untreated sALCL with 1.8 mg/kg of 
ADCETRIS on day 1 of a 3-week cycle  
 

 ADCETRIS + CHP 
n=162a 

CHOP 
n=154a 

PFS per IRF 
Number of patients with a PFS event, n (%) 56 (34) 73 (48) 
Median PFS, months (95% CI) 55.66 (48.20, NE) 54.18 (13.44, NE) 
Hazard ratio (95% CI)b 0.59 (0.42, 0.84) 
p-valuec 0.0031 

Estimated PFS (95% CI)d at:   
6 months 88.0%  

(81.8%, 92.2%) 
68.4%  

(60.3%, 75.2%) 
12 months 78.7%  

(71.4%, 84.4%) 
60.3%  

(51.9%, 67.6%) 
24 months 68.4%  

(60.4%, 75.2%) 
53.9%  

(45.5%, 61.5%) 
36 months 65.5%  

(57.1%, 72.7%) 
50.2%  

(41.6%, 58.1%) 

OSe 
Number of deaths (%) 29 (18) 44 (29) 
Median OS, months (95% CI) NE (NE, NE) NE (NE, NE) 
Hazard ratio (95% CI)b 0.54 (0.34, 0.87) 

p-valuec, f 0.0096 
CR Rateg 

% (95% CI) 71% (63.3%, 77.8%) 53% (45.0%, 61.3%) 
p-valuef, h 0.0004 

ORRg 
% (95% CI) 88% (81.6%, 92.3%) 71% (62.9%, 77.8%) 
p-valuef, h <0.0001 

CR=complete remission; IRF=Independent Review Facility; NE: Not estimable; ORR=objective response rate; 
PFS=progression-free survival. 
a PFS per IRF is calculated using patients with centrally-confirmed sALCL, with n=163 patients in A+CHP arm and 

n=151 in CHOP arm. OS, CR, and ORR are calculated using patients with locally-diagnosed sALCL 
b Hazard ratio (A+CHP/CHOP) and 95% confidence intervals are based on a stratified Cox’s proportional hazard 

regression model with stratification factors (ALK-positive sALCL versus all others and International Prognostic Index 
[IPI] score at baseline). Hazard ratio <1 favours A+CHP arm. 

c p-value is calculated using a stratified log-rank test. 
d PFS rate is estimated using Kaplan-Meier methods and 95% CI is calculated using the complementary log-log 

transformation method. 
e Median OS follow-up in the A+CHP arm was 38.5 months; in the CHOP arm was 41.0 months. 
f p-value is not adjusted for multiplicity.  
g Response per 2007 International Working Group Criteria at end of treatment. 
h p-value is calculated using a stratified Cochran-Mantel-Haenszel test. 
 



33 

Figure 5: Progression-free survival per IRF in the sALCL population (ADCETRIS + CHP vs. 
CHOP) 
 

  
 
Figure 6: Overall survival in the sALCL population (ADCETRIS + CHP vs. CHOP) 
 

 
*p-value for overall survival is not adjusted for multiplicity. 
 



34 

Study SG035-0004 
 
The efficacy and safety of ADCETRIS as a single agent was evaluated in an open-label, single-arm, 
multicenter study in 58 patients with relapsed or refractory sALCL. See Table 15 below for a 
summary of baseline patient and disease characteristics.  
 
Table 15: Summary of baseline patient and disease characteristics in the phase 2 relapsed or 
refractory sALCL study 
 

Patient characteristics n = 58 

Median age, years (range) 52 years (14-76) 
Gender 33M (57%)/25F (43%) 
ECOG statusa  

0 19 (33%) 
1 38 (66%) 

Prior ASCT 15 (26%) 
Prior chemotherapy Regimens (range) 2 (1-6) 
Histologically confirmed CD30-expressing disease 57 (98%) 
Anaplastic lymphoma kinase (ALK)-negative disease 42 (72%) 

Disease characteristics  
Primary Refractory to frontline therapyb 36 (62%) 
Refractory to most recent therapy 29 (50%) 
Relapsed to most recent therapy 29 (50%) 
Baseline B symptoms 17 (29%) 
Stage III at initial diagnosis 8 (14%) 
Stage IV at initial diagnosis 21 (36%) 

a. One patient had a baseline ECOG status of 2, which was prohibited by protocol and is captured as Inclusion Criteria Not 
Met. 

b. Primary refractory sALCL is defined as a failure to achieve a complete remission to, or progressed within 3 months of 
completing frontline therapy. 

 
The median time from initial sALCL diagnosis to first dose with ADCETRIS was 16.8 months.  
 
Ten (10) patients (17%) received 16 cycles of ADCETRIS; the median number of cycles received was 
7 (range, 1 to 16).  
 
Response to treatment with ADCETRIS was assessed by Independent Review Facility (IRF) using the 
Revised Response Criteria for Malignant Lymphoma (Cheson, 2007). Treatment response was 
assessed by spiral CT of chest, neck, abdomen and pelvis; PET scans and clinical data. Response 
assessments were performed at cycles 2, 4, 7, 10, 13 and 16 with PET at cycles 4 and 7.  
 
The ORR per IRF assessment was 86% (50 of 58 patients in the ITT set). CR was 59% (34 of 
58 patients in the ITT set) and tumour reduction (of any degree) was achieved in 97% of patients. The 
estimated overall survival at 5 years was 60% (95% CI [47%,73%]). The median observation time 
(time to death or last contact) from first dose was 71.4 months. The investigator assessments were 
generally consistent with the independent review of the scans. Of the patients treated, 9 responding 
patients went on to receive an allogeneic stem cell transplant (SCT) and 9 responding patients went on 
to autologous SCT. For further efficacy results, see Table 16 and Figure 7. 
 



35 

Table 16: Efficacy results in relapsed or refractory sALCL patients treated with 1.8 mg/kg of 
ADCETRIS every 3 weeks 
 
Best clinical response (n = 58 ) IRF n (%) 95% CI 
    Objective response rate (CR + PR) 50 (86) 74.6, 93.9 
          Complete remission (CR) 34 (59) 44.9, 71.4 
          Partial remission (PR) 16 (28) NA 
    Disease control rate (CR + PR + SD) 52 (90) 78.8, 96.1 
Duration of response  Median per IRF  95% CI 
    Objective response (CR + PR)a 13.2  5.7, 26.3  
    Complete remission (CR) 26.3 13.2, NEb 
Progression Free Survival Median per IRF 95% CI 

Median 14.6 6.9, 20.6 
Overall survival  Median 95% CI 

Median Not reached  21.3, NEb 
a. The range of DOR was 0.1 months to 39.1+ months and the median follow-up time from first dose for patients who 

achieved objective response (OR) per IRF was 15.5 months.  
b. Not estimable. 
 
Figure 7: Kaplan-Meier Plot of OS 
 

 
 
An exploratory intra-patient analysis showed that approximately 69% of the sALCL patients treated 
with ADCETRIS as part of the SG035-0004 clinical study experienced an improvement in clinical 
benefit as measured by longer progression free survival (PFS) compared with their most recent prior 
line of therapy. 
 
Of the 17 patients (29%) who had B symptoms at baseline, 14 patients (82%) experienced resolution 
of all B symptoms in a median time from initiation of ADCETRIS of 0.7 months. 
 
Study SGN35-006 (Retreatment study) 
 
The efficacy of retreatment in patients who had previously responded (CR or PR) to treatment with 
ADCETRIS was evaluated in a phase 2, open-label, multicenter trial. Seven patients with relapsed 
sALCL received a starting dose of 1.8 mg/kg and one patient received a starting dose of 1.2 mg/kg of 
ADCETRIS administered intravenously over 30 minutes every 3 weeks. The median number of cycles 
was 8.5 (range, 2 to 30 cycles). Of the 8 sALCL patients, 3 were retreated twice for a total of 
11 retreatment experiences. Retreatment with ADCETRIS resulted in 6 CRs (55%) and 4 PRs (36%), 



36 

for an ORR of 91%. The median duration of response was 8.8 and 12.3 months in patients who 
achieved OR (CR+PR) and CR, respectively. 
 
Cutaneous T-cell lymphoma 
 
Study C25001  
 
The efficacy and safety of ADCETRIS as a single agent was evaluated in a pivotal phase 3, open-
label, randomised, multicentre study in 128 patients with histologically confirmed CD30+ CTCL. 
CD30 positivity was defined as ≥10% target lymphoid cells demonstrating membrane, cytoplasmic, 
and/or Golgi staining pattern based on an immunohistochemistry assay (Ventana anti-CD30 
[Ber-H2]). Patients with a diagnosis of mycosis fungoides [MF] or primary cutaneous anaplastic large 
cell lymphoma [pcALCL] were considered eligible for the study. Patients were stratified by these 
disease types and randomised 1:1 to receive either ADCETRIS or the physician’s choice of either 
methotrexate or bexarotene. Patients with pcALCL received either prior radiation therapy or at least 1 
prior systemic therapy and patients with MF received at least 1 prior systemic therapy. Patients with a 
concurrent diagnosis of systemic ALCL, Sezary syndrome and other non-Hodgkin lymphoma (except 
for lymphomatoid papulosis [LyP]) were excluded from this study. Patients were treated with 
1.8 mg/kg of ADCETRIS intravenously over 30 minutes every 3 weeks for up to 16 cycles or 
physician’s choice for up to 48 weeks. The median number of cycles was approximately 12 cycles in 
the ADCETRIS arm. In the physician’s choice arm, the median duration of treatment (number of 
cycles) for patients receiving bexarotene was approximately 16 weeks (5.5 cycles) and 11 weeks 
(3 cycles) for patients receiving methotrexate. Table 17 provides a summary of the baseline patient 
and disease characteristics. 
 
Table 17: Summary of baseline patient and disease characteristics in the phase 3 CTCL Study 
(ITT Population) 
 
Patient characteristics ADCETRIS 

n = 64 
Physician’s Choice 
(Methotrexate or 

Bexarotene) 
n = 64 

Median age (range) 62 years (22-83) 58.5 years (22-83) 
Patients ≥ 65 years old n (%) 
Gender n (%) 

28 (44%) 
33M (52%)/31F (48%) 

24 (38%) 
37M (58%)/27F (42%) 

ECOG status n (%)   
0 43 (67) 46 (72) 
1 
2 

18 (28) 
3 (5) 

16 (25) 
2 (3) 

Disease characteristics   
Median number of prior therapies 
(range) 

4 (0-13) 3.5 (1-15) 

Median number of skin-directed 
therapies (range) 

1 (0-6) 1 (0-9) 

Median number of systemic 
therapies (range) 

2 (0-11) 2 (1-8) 

MF, n (%) 48 (75) 49 (77) 
Early (IA-IIA) 15 (31) 18 (37) 
Advanced (IIB-IVBa) 32 (67) 30 (61) 

pcALCL, n (%) 16 (25) 15 (23) 
Skin only  9 (56) 11 (73) 
Extracutaneous disease 7 (44) 4 (27) 

a One patient in each arm had incomplete staging data and are not included in the table. 
 



37 

The most common prior skin directed therapies in the ITT population were radiotherapy (64%), 
phototherapy (48%) and topical steroids (17%). The most common prior systemic therapies in the ITT 
population were chemotherapy (71%), immunotherapy (43%) and bexarotene (38%). 
 
The primary endpoint was objective response rate that lasts at least 4 months (ORR4) (duration from 
first response to last response ≥ 4 months), as determined by an independent review of the Global 
Response Score (GRS) consisting of skin evaluations (modified severity weighted assessment tool 
[mSWAT] as assessed per investigator), nodal and visceral radiographic assessment, and detection of 
circulating Sézary cells (Olsen 2011). Table 18 includes the results for ORR4 and other key secondary 
endpoints. 
 
Table 18: Efficacy results in CTCL patients treated with 1.8 mg/kg of ADCETRIS every 3 weeks 
(ITT population) 
 
 
 
 
 

ADCETRIS      
(n = 64) 

 Physician’s Choice 
(Methotrexate or 

Bexarotene)  
n = 64 

Objective Response Rate lasting at least 4 months (ORR4) per IRF 
n (%) 
Percent Difference (95% CI) 

36 (56.3)  
43.8 (29.1, 58.4) 

8 (12.5) 

p-value  <0.001  
Complete Response (CR) per IRF 
n (%) 
Percent Difference (95% CI) 

10 (15.6)  
14.1 (-4.0, 31.5) 

1 (1.6) 

Adjusted p-valuea  0.0046  
Progression Free Survival (PFS) per IRF 
Median (months) 16.7  3.5 
Hazard Ratio  0.270  
95% CI  (0.17, 0.43)  
Adjusted p-valuea  <0.001  
a   Calculated from a weighted Holm’s procedure. 
 
Pre-specified subgroup analyses of ORR4 per IRF were performed by patients’ CTCL subtype, 
physicians’ choice of treatment, baseline ECOG status, age, gender, and geographic region. The 
analyses showed a consistent trend towards benefit for patients who received ADCETRIS compared 
with patients who received physician’s choice. ORR4 was 50% and 75% in the ADCETRIS arm 
versus 10.2% and 20% in the physician’s choice arm for MF and pcALCL, respectively. 
 
No meaningful differences in quality of life (assessed by the EuroQol five dimensions questionnaire 
[EQ-5D] and Functional Assessment of Cancer Therapy-General [FACT-G]) were observed between 
the treatment arms. 
 
The efficacy and safety of ADCETRIS were evaluated in two additional open-label studies in 
108 patients with relapsed CD30+ CTCL (including MF and pcALCL as well as SS, LyP and mixed 
CTCL histology), regardless of CD30 expression level. Patients were treated with ADCETRIS 
1.8 mg/kg intravenously over 30 minutes every 3 weeks for up to 16 cycles. The safety and efficacy 
results in these studies were consistent with results in Study C25001. Overall response rates for MF 
were 54-66%; pcALCL, 67%; SS, 50%; LyP, 92%; and mixed CTCL histology, 82-85%. 
 
Paediatric population 
 
The safety, pharmacokinetics and anti-tumour activity of ADCETRIS in 36 paediatric patients 
(7-17 years of age) with r/r HL and sALCL (children aged 7-11 years, n = 12 and adolescents aged 
12 to 17 years, n = 24) were evaluated in a phase 1/2 open-label, single-agent, multicentre dose-
escalation study (C25002). Phase 1 of the study assessed the safety profile (see section 4.8), 
determined the paediatric maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D), 



38 

and assessed the pharmacokinetics of ADCETRIS (see section 5.2). Phase 1 included 3 r/r HL patients 
treated at 1.4 mg/kg and 9 patients (7 r/r HL and 2 sALCL) treated at 1.8 mg/kg. The MTD was not 
reached. The RP2D was determined to be 1.8 mg/kg. Across the study, a total of 16 patients with r/r 
HL and 17 patients with r/r sALCL, of whom 10 were in first relapse, were treated with 1.8 mg/kg of 
ADCETRIS. The best overall response rate (ORR) per independent review facility (IRF) was analysed 
across both study phases at the RP2D. Of these 33 patients who received the RP2D, 32 were evaluable 
for response. The ORR was 47% in response-evaluable patients with r/r HL, 53% in patients with r/r 
sALCL and 60% in sALCL patients in first relapse. Eight HL patients and 9 sALCL patients went on 
to receive SCT following treatment with ADCETRIS.  
 
The European Medicines Agency has deferred the obligation to submit the results of studies with 
ADCETRIS in one or more subsets of the paediatric population in the treatment of Hodgkin 
lymphoma and treatment of anaplastic large cell lymphoma (see section 4.2 for information on 
paediatric use). 
 
This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. This 
means that further evidence on this medicinal product is awaited. 
The European Medicines Agency will review new information on this medicinal product at least every 
year and this SmPC will be updated as necessary. 
 
5.2 Pharmacokinetic properties 
 
Monotherapy 
 
The pharmacokinetics of brentuximab vedotin were evaluated in phase 1 studies and in a population 
pharmacokinetic analysis of data from 314 patients. In all clinical trials, brentuximab vedotin was 
administered as an intravenous infusion.  
 
Maximum concentrations of brentuximab vedotin ADC were typically observed at the end of infusion 
or the sampling timepoint closest to the end of infusion. A multiexponential decline in ADC serum 
concentrations was observed with a terminal half-life of approximately 4 to 6 days. Exposures were 
approximately dose proportional. Minimal to no accumulation of ADC was observed with multiple 
doses at the every 3-week schedule, consistent with the terminal half-life estimate. Typical Cmax and 
AUC of ADC after a single 1.8 mg/kg in a phase 1 study was approximately 31.98 μg/ mL and 
79.41 μg/ mL x day respectively. 
 
MMAE is the major metabolite of brentuximab vedotin. Median Cmax, AUC and Tmax of MMAE after 
a single 1.8 mg/kg of the ADC in a phase 1 study was approximately 4.97 ng/ mL, 37.03 ng/ mL x day 
and 2.09 days respectively. MMAE exposures decreased after multiple doses of brentuximab vedotin 
with approximately 50% to 80% of the exposure of the first dose being observed at subsequent doses. 
MMAE is further metabolised mainly to an equally potent metabolite; however, its exposure is an 
order of magnitude lower than that of MMAE. Thus, it is not likely to have any substantial 
contribution to the systemic effects of MMAE. 
 
In the first cycle, higher MMAE exposure was associated with an absolute decrease in neutrophil 
count. 
 
Combination therapy 
 
The pharmacokinetics of ADCETRIS in combination with AVD were evaluated in a single phase 3 
study in 661 patients. Population pharmacokinetic analysis indicated that the pharmacokinetics of 
ADCETRIS in combination with AVD were consistent to that in monotherapy.  
 
After multiple-dose, IV infusion of 1.2 mg/kg brentuximab vedotin every two weeks, maximal serum 
concentrations of ADC were observed near the end of the infusion and elimination exhibited a 
multi-exponential decline with a t1/2z of approximately 4 to 5 days. Maximal plasma concentrations of 



39 

MMAE were observed approximately 2 days after the end of infusion, and exhibited a 
mono-exponential decline with a t1/2z of approximately 3 to 4 days. 
 
After multiple-dose, IV infusion of 1.2 mg/kg brentuximab vedotin every two weeks, steady-state 
trough concentrations of ADC and MMAE were achieved by Cycle 3. Once steady-state was achieved, 
the PK of ADC did not appear to change with time. ADC accumulation (as assessed by AUC14D 
between Cycle 1 and Cycle 3) was 1.27-fold. The exposure of MMAE (as assessed by AUC14D 
between Cycle 1 and Cycle 3) appeared to decrease with time by approximately 50%. 
 
The pharmacokinetics of ADCETRIS in combination with CHP were evaluated in a single phase 
3 study in 223 patients (SGN35-014). After multiple-dose IV infusion of 1.8 mg/kg ADCETRIS every 
3 weeks, the pharmacokinetics of ADC and MMAE were similar to those of monotherapy. 
 
Distribution 
 
In vitro, the binding of MMAE to human serum plasma proteins ranged from 68-82%. MMAE is not 
likely to displace or to be displaced by highly protein-bound medicines. In vitro, MMAE was a 
substrate of P-gp and was not an inhibitor of P-gp at clinical concentrations. 
 
In humans, the mean steady state volume of distribution was approximately 6-10 L for ADC. Based on 
population PK estimation the typical apparent central volume of distribution of MMAE was 35.5 L. 
 
Metabolism 
 
The ADC is expected to be catabolised as a protein with component amino acids recycled or 
eliminated. 
 
In vivo data in animals and humans suggest that only a small fraction of MMAE released from 
brentuximab vedotin is metabolised. The levels of MMAE metabolites have not been measured in 
human plasma. At least one metabolite of MMAE has been shown to be active in vitro.  
 
MMAE is a substrate of CYP3A4 and possibly CYP2D6. In vitro data indicate that the MMAE 
metabolism that occurs is primarily via oxidation by CYP3A4/5. In vitro studies using human liver 
microsomes indicate that MMAE inhibits only CYP3A4/5 at concentrations much higher than was 
achieved during clinical application. MMAE does not inhibit other isoforms.  
 
MMAE did not induce any major CYP450 enzymes in primary cultures of human hepatocytes. 
 
Elimination 
 
The ADC is eliminated by catabolism with a typical estimated CL and half life of 1.5 L/day and 
4-6 days respectively.  
 
The elimination of MMAE was limited by its rate of release from ADC, typical apparent CL and half 
life of MMAE was 19.99 L/day and 3-4 days respectively.  
 
An excretion study was undertaken in patients who received a dose of 1.8 mg/kg of brentuximab 
vedotin. Approximately 24% of the total MMAE administered as part of the ADC during a 
brentuximab vedotin infusion was recovered in both urine and faeces over a 1-week period. Of the 
recovered MMAE, approximately 72% was recovered in the faeces. A lesser amount of MMAE (28%) 
was excreted in the urine. 
 
Pharmacokinetics in special populations 
 
Population PK analysis showed that baseline serum albumin concentration was a significant covariate 
of MMAE clearance. The analysis indicated that MMAE clearance was 2-fold lower in patients with 



40 

low serum albumin concentrations <3.0 g/dL compared with patients with serum albumin 
concentrations within the normal range. 
 
Hepatic impairment 
 
A study evaluated the PK of brentuximab vedotin and MMAE after the administration of 1.2 mg/kg of 
ADCETRIS to patients with mild (Child-Pugh A; n = 1), moderate (Child-Pugh B; n = 5) and severe 
(Child-Pugh C; n = 1) hepatic impairment. Compared to patients with normal hepatic function, 
MMAE exposure increased approximately 2.3-fold (90% CI 1.27-4.12-fold) in patients with hepatic 
impairment. 
 
Renal impairment 
 
A study evaluated the PK of brentuximab vedotin and MMAE after the administration of 1.2 mg/kg of 
ADCETRIS to patients with mild (n = 4), moderate (n = 3) and severe (n = 3) renal impairment. 
Compared to patients with normal renal function, MMAE exposure increased approximately 1.9-fold 
(90% CI 0.85-4.21-fold) in patients with severe renal impairment (creatinine clearance < 30 mL/min). 
No effect was observed in patients with mild or moderate renal impairment. 
 
Elderly 
 
The population pharmacokinetics of brentuximab vedotin were examined from several studies, 
including data from 380 patients up to 87 years old (34 patients ≥65-< 75 and 17 patients ≥75 years of 
age). Additionally, the population pharmacokinetics of brentuximab vedotin in combination with AVD 
were examined, including data from 661 patients up to 82 years old (42 patients ≥ 65-< 75 and 
17 patients ≥ 75 years of age). The influence of age on pharmacokinetics was investigated in each 
analysis and it was not a significant covariate. 
 
Paediatric population 
 
The pharmacokinetics of brentuximab vedotin ADC and MMAE following a 30-minute intravenous 
infusion of BV administered at 1.4 mg/kg or 1.8 mg/kg given every 3 weeks were evaluated in a phase 
1/2 clinical trial of 36 paediatric patients (7-17 years of age) with r/r HL and sALCL (children aged 
7-11 years, n = 12 and adolescents aged 12 to 17 years, n = 24) (see section 5.1). The Cmax of ADC 
was typically observed at the end of infusion or the sampling closest to the end of infusion. A multi-
exponential decline in ADC serum concentrations was observed with a terminal half-life of 
approximately 4 to 5 days. Exposures were approximately dose proportional with a trend observed for 
lower ADC exposures at lower ages/ body weights in the study population.  
Median ADC AUC in children and adolescents from this study was approx. 14% and 3% lower than in 
adult patients, respectively, while MMAE exposures were 53% lower and 13% higher, respectively, 
than in adult patients. Median Cmax and AUC of ADC after a single 1.8 mg/kg dose were 29.8 µg/ mL 
and 67.9 µg*day/ mL, respectively, in patients < 12 years of age and 34.4 µg/mL and 
77.8 µg*day/mL, respectively, in patients ≥ 12 years of age. Median Cmax, AUC, and Tmax of MMAE 
after a single 1.8 mg/kg dose were 3.73 ng/mL, 17.3 ng*day/mL, and 1.92 days, respectively, in 
patients < 12 years of age and 6.33 ng/mL, 42.3 ng*day/mL, and 1.82 days, respectively, in patients 
≥ 12 years of age. 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. 
 
5.3 Preclinical safety data 
 
MMAE has been shown to have aneugenic properties in an in vivo rat bone marrow micronucleus 
study. These results were consistent with the pharmacological effect of MMAE on the mitotic 
apparatus (disruption of the microtubule network) in cells. 
 
The effects of brentuximab vedotin on human male and female fertility have not been studied. 
However, results of repeat-dose toxicity studies in rats indicate the potential for brentuximab vedotin 



41 

to impair male reproductive function and fertility. Testicular atrophy and degeneration were partially 
reversible following a 16-week treatment-free period. 
 
Brentuximab vedotin caused embryo-foetal lethality in pregnant female rats.  
 
In nonclinical studies, lymphoid depletion and reduced thymic weight were observed, consistent with 
the pharmacologic disruption of microtubules caused by MMAE derived from brentuximab vedotin. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Citric acid monohydrate (for pH-adjustment) 
Sodium citrate dihydrate (for pH-adjustment) 
α,α-Trehalose dihydrate 
Polysorbate 80 
 
6.2 Incompatibilities 
 
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal 
products except those mentioned in section 6.6. 
 
6.3 Shelf life 
 
4 years. 
 
After reconstitution/dilution, from a microbiological point of view, the product should be used 
immediately. However, chemical and physical in-use stability has been demonstrated for 24 hours at 
2 °C-8 °C. 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2 °C-8 °C).  
 
Do not freeze.  
 
Keep the vial in the original carton in order to protect from light. 
 
For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3. 
 
6.5 Nature and contents of container  
 
Type I glass vial with a butyl rubber stopper and an aluminium/plastic flip-off seal, containing 50 mg 
powder. 
 
Pack of 1 vial.  
 
6.6 Special precautions for disposal and other handling 
 
General precautions 
 
Procedures for proper handling and disposal of anticancer medicinal products should be considered.  
 
Proper aseptic technique throughout the handling of this medicinal product should be followed. 
 



42 

Instructions for reconstitution  
 
Each single use vial must be reconstituted with 10.5 mL of water for injections to a final concentration 
of 5 mg/ mL. Each vial contains a 10% overfill giving 55 mg of ADCETRIS per vial and a total 
reconstituted volume of 11 mL. 
 
1. Direct the stream toward the wall of the vial and not directly at the cake or powder.  
2. Gently swirl the vial to aid dissolution. DO NOT SHAKE. 
3. The reconstituted solution in the vial is a clear to slightly opalescent, colourless solution with a 

final pH of 6.6.  
4. The reconstituted solution should be inspected visually for any foreign particulate matter and/or 

discolouration. In the event of either being observed, discard the medicinal product.  
 
Preparation of infusion solution 
 
The appropriate amount of reconstituted ADCETRIS must be withdrawn from the vial(s) and added to 
an infusion bag containing sodium chloride 9 mg/ mL (0.9%) solution for injection in order to achieve 
a final concentration of 0.4-1.2 mg/ mL ADCETRIS. The recommended diluent volume is 150 mL. 
The already reconstituted ADCETRIS can also be diluted into 5% dextrose for injection or Lactated 
Ringer's for injection.  
 
Gently invert the bag to mix the solution containing ADCETRIS. DO NOT SHAKE.  
 
Any portion left in the vial, after withdrawal of the volume to be diluted, must be disposed of in 
accordance with local requirements.  
 
Do not add other medicinal products to the prepared ADCETRIS infusion solution or intravenous 
infusion set. The infusion line should be flushed following administration with sodium chloride 
9 mg/ mL (0.9%) solution for injection, 5% dextrose for injection, or Lactated Ringer's for injection.  
 
Following dilution, infuse the ADCETRIS solution immediately at the recommended infusion rate.  
 
Total storage time of the solution from reconstitution to infusion should not exceed 24 hours.  
 
Determining dosage amount: 
 
Calculation to determine the total ADCETRIS dose (mL) to be further diluted (see section 4.2):  
 

ADCETRIS dose (mg/kg) x patient’s body weight (kg)  = Total ADCETRIS dose (mL) to be further diluted Reconstituted vial concentration (5 mg/mL) 
 
Note: If patient’s weight is more than 100 kg, the dose calculation should use 100 kg. The maximal 
recommended dose is 180 mg.  
 
Calculation to determine the total number of ADCETRIS vials needed:  
 

Total ADCETRIS dose (mL) to be administered  = Number of ADCETRIS vials needed Total volume per vial (10 mL/vial) 
 



43 

Table 19: Sample calculations for patients receiving the recommended dose of 1.8 mg/kg of 
ADCETRIS for weights ranging from 60 kg to 120 kg 
 
Patient 
weight 
(kg) 

Total dose =  
patient weight 
multiplied by 
recommended dose 
[1.8 mg/kga]) 

Total volume to be dilutedb = 
total dose divided by 
reconstituted vial 
concentration [5 mg/ mL]) 

Number of vials needed =  
total volume to be diluted 
divided by total volume 
per vial [10 mL/vial]) 

60 kg 108 mg 21.6 mL 2.16 vials 
80 kg 144 mg 28.8 mL 2.88 vials 
100 kg 180 mg 36 mL 3.6 vials 
120 kgc 180 mg d 36 mL 3.6 vials 

a. For a reduced dose, use 1.2 mg/kg for the calculation. 
b. To be diluted in 150 mL of diluent and administered by intravenous infusion over 30 minutes every 3 weeks. 
c. If patient’s weight is more than 100 kg, the dose calculation should use 100 kg. 
d. The maximal recommended dose is 180 mg. 
 
Table 20: Sample calculations for patients receiving the recommended dose of 1.2 mg/kg of 
ADCETRIS for weights ranging from 60 kg to 120 kg as combination therapy or when a 
reduced dose is required 
 
Patient 
weight 
(kg) 

Total dose =  
patient weight 
multiplied by 
recommended dose 
[1.2 mg/kga]) 

Total volume to be dilutedb = 
total dose divided by 
reconstituted vial 
concentration [5 mg/mL]) 

Number of vials needed =  
total volume to be diluted 
divided by total volume 
per vial [10 mL/vial]) 

60 kg 72 mg 14.4 mL 1.44 vials 
80 kg 96 mg 19.2 mL 1.92 vials 
100 kg 120 mg 24 mL 2.4 vials 

120 kgc 120 mg d 24 mL 2.4 vials 
a. For a reduced dose, use 0.9 mg/kg for the calculation. 
b. To be diluted in 150 mL of diluent and administered by intravenous infusion over 30 minutes every 2 weeks as 

combination therapy or every 3 weeks when a reduced dose of the monotherapy is required. 
c. If patient’s weight is more than 100 kg, the dose calculation should use 100 kg. 
d. The maximal recommended dose for combination therapy is 120 mg. 
 
Disposal 
 
ADCETRIS is for single use only.  
Any unused product or waste material should be disposed of in accordance with local requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Takeda Pharma A/S 
Dybendal Alle 10 
2630 Taastrup 
Denmark  
 
 
8. MARKETING AUTHORISATION NUMBER  
 
EU/1/12/794/001 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 25 October 2012 



44 

Date of latest renewal: 19 September 2019 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu 

http://www.ema.europa.eu/


45 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 
A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 

MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE  
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT  
 
E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES 

FOR THE CONDITIONAL MARKETING AUTHORISATION 
 
 
 



46 

A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 
MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE 

 
Name and address of the manufacturers of the biological active substance  
 
Piramal Healthcare UK Ltd. 
Earls Road, Grangemouth 
Stirlingshire, Scotland FK3 8XG 
United Kingdom 
 
Lonza AG 
Lonzastrasse 
3930 Visp 
Switzerland 
 
Name and address of the manufacturers responsible for batch release 
 
Takeda Austria GmbH 
St. Peter-Straβe 25 
A-4020 Linz 
Austria 
 
Delpharm Novara S.r.l. 
Via Crosa, 86 
28065 Cerano (NO) 
Italy 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
• Periodic safety update reports (PSURs)  

 
The requirements for submission of PSURs for this medicinal product are set out in the list of Union 
reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any 
subsequent updates published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk management plan (RMP) 
 
The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities 
and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation 
and any agreed subsequent updates of the RMP. 
 



47 

An updated RMP should be submitted: 
• At the request of the European Medicines Agency;  
• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached 

 
 
E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION 

MEASURES FOR THE CONDITIONAL MARKETING AUTHORISATION  
 
This being a conditional marketing authorisation and pursuant to Article 14a(4) of Regulation (EC) No 
726/2004, the MAH shall complete, within the stated timeframe, the following measure: 
 
Description Due date 
To perform a single-arm study in a similar patient 
population as the sALCL population investigating 
response rate, duration of response, rate of (second) 
ASCT and data in subpopulations (including but not 
necessarily restricted to ALK status and age) based on 
a CHMP agreed protocol (Study C25006). 

 
Final Study Report by: Q1 2021 

 



48 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



49 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



50 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
ADCETRIS 50 mg powder for concentrate for solution for infusion 
brentuximab vedotin 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each vial contains 50 mg of brentuximab vedotin 
 
After reconstitution each vial contains 5 mg/ml of brentuximab vedotin 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: Citric acid monohydrate, sodium citrate dihydrate, α,α-trehalose dihydrate, polysorbate 80 
See package leaflet for further information 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder for concentrate for solution for infusion 
1 vial 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous use after reconstitution and dilution  
Read the package leaflet 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 



51 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator  
Do not freeze 
Keep the vial in the outer carton in order to protect from light. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
For single use only 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda Pharma A/S 
Dybendal Alle 10 
2630 Taastrup 
Denmark  
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/12/794/001 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN: 



52 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
ADCETRIS 50 mg powder for concentrate for solution for infusion 
brentuximab vedotin 
IV use 
 
 
2. METHOD OF ADMINISTRATION 
 
For intravenous use after reconstitution and dilution  
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
50 mg 
 
 
6. OTHER 
 
 



53 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



54 

 
Package leaflet: Information for the patient 

 
Adcetris 50 mg powder for concentrate for solution for infusion 

brentuximab vedotin 
 

This medicine is subject to additional monitoring. This will allow quick identification of new 
safety information. You can help by reporting any side effects you may get. See the end of section 4 
for how to report side effects. 
 
Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor. 
- If you get any side effects, talk to your doctor. This includes any possible side effects not listed 
 in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Adcetris is and what it is used for 
2. What you need to know before you are given Adcetris 
3. How Adcetris will be given 
4. Possible side effects 
5. How to store Adcetris 
6. Contents of the pack and other information 
 
 
1. What Adcetris is and what it is used for 
 
Adcetris contains the active substance brentuximab vedotin, an anti-cancer agent, which is made up 
of a monoclonal antibody linked to a substance intended to kill cancer cells. This substance is 
delivered to cancer cells by the monoclonal antibody. A monoclonal antibody is a protein which 
recognises certain cancer cells.  
 
Hodgkin lymphoma, systemic anaplastic large cell lymphoma and cutaneous T-cell lymphoma are 
types of cancer of the white blood cells. 
 
Classical Hodgkin lymphoma expresses specific proteins on the cell surface that are different from 
non-classical Hodgkin lymphoma.  
 
Adcetris is used to treat patients with advanced classical Hodgkin lymphoma who have not had 
treatment before. Adcetris will be given to you together with doxorubicin, vinblastine and dacarbazine 
which are other chemotherapy medicines used to treat Hodgkin lymphoma.  
 
Adcetris is used alone to lower the likelihood of classical Hodgkin lymphoma coming back after an 
autologous stem cell transplant in patients with certain risk factors. 
 
Adcetris is also used alone to treat classical Hodgkin lymphoma that has: 
- come back after or not responded to an infusion of your own healthy stem cells into your body 

(autologous stem cell transplant), or 
- come back after or never responded to at least two previous therapies, and where you cannot 

receive additional combination anti-cancer treatments or have an autologous stem cell 
transplant. 

 
Systemic anaplastic large cell lymphoma is a type of non-Hodgkin lymphoma found in your lymph 
nodes and/or throughout other parts of your body. 
 



55 

Adcetris is used to treat patients with systemic anaplastic large cell lymphoma who have not had 
treatment before. Adcetris will be given to you together with cyclophosphamide, doxorubicin and 
prednisone which are other chemotherapy medicines used to treat these conditions. 
 
Adcetris is also used to treat systemic anaplastic large cell lymphoma that has: 
- not responded to other types of anti-cancer treatments, or  
- come back after previous anti-cancer treatment. 
 
Cutaneous T-cell lymphoma is a cancer of a certain type of white blood cell called a ‘T-cell’ that 
mainly affects the skin. Adcetris is used to treat cutaneous T-cell lymphoma where a specific type of 
protein is present on the cells’ surface. 
 
Adcetris is used to treat cutaneous T-cell lymphoma in patients who have previously received at least 
one anti-cancer medicine that travels through the bloodstream. 
 
 
2. What you need to know before you are given Adcetris 
 
Do NOT use Adcetris if you 
 
- are allergic to brentuximab vedotin or any of the other ingredients of this medicine (listed in 

section 6).  
- are currently using bleomycin, an anti-cancer agent.  
 
Warnings and precautions 
 
When you first receive this medicine and during the course of treatment, tell your doctor if you: 
- have confusion, trouble thinking, memory loss, blurred or loss of vision, decreased strength, 

decreased control or sensation in one arm or leg, a change in the way of walking, or loss of 
balance, as these may be symptoms of a serious and potentially fatal brain condition known as 
progressive multifocal leukoencephalopathy (PML). If you have these symptoms prior to 
treatment with this medicine, tell your doctor immediately about any changes in these 
symptoms. You should also inform your partner or caregivers about your treatment, since they 
may notice symptoms that you are not aware of 

- have severe and persistent stomach pain, with or without nausea and vomiting, as these may be 
symptoms of a serious and potentially fatal condition known as pancreatitis (inflammation of 
the pancreas) 

- have new or worsening shortness of breath or cough as these may be symptoms of a serious and 
potentially fatal lung complication (pulmonary toxicity) 

- are taking, or have previously taken, medicines which may affect your immune system, such as 
chemotherapy or immunosuppressive agents  

- have, or think you have, an infection. Some infections may be serious and can be due to viruses, 
bacteria, or other causes that may be life-threatening 

- experience a whistling sound during breathing (wheezing)/difficulty breathing, hives, itching, or 
swelling (signs of an infusion reaction). For more detailed information, see “Infusion reactions” 
in section 4 

- have any problems with a change in the sensitivity of the skin, especially in the hands or feet, 
such as numbness, tingling, a burning sensation, pain, discomfort or weakness (neuropathy) 

- have headaches, feel tired, experience dizziness, look pale (anaemia), or have unusual bleeding 
or bruising under the skin, longer than usual bleeding after your blood has been drawn, or 
bleeding from your gums (thrombocytopenia)  

- develop chills or shivering, or feel warm; you should take your temperature as you may have a 
fever. A fever with a low white blood cell count may be a sign of serious infection  

- experience dizziness, decreased urination, confusion, vomiting, nausea, swelling, shortness of 
breath, or heart rhythm disturbances (this may be a potentially life-threatening complication 
known as tumour lysis syndrome) 



56 

- experience flu-like symptoms followed by a painful red or purplish rash that spreads and blisters 
including extensive detachment of the skin that may be life-threatening (this may be a serious 
skin reaction known as Stevens-Johnson syndrome and toxic epidermal necrolysis) 

- have new or worsening stomach pain, nausea, vomiting, constipation as these may be symptoms 
of a serious and potentially fatal stomach or intestinal complication (gastrointestinal 
complications) 

- have abnormal liver test results as this may be related to a serious and potentially fatal liver 
injury (hepatotoxicity). Liver disease and other medical conditions that may have been present 
before you start taking Adcetris and some medications that you are currently taking might 
increase the risk of liver injury 

- feel tired, have frequent urination, increased thirst, increased appetite with unintended weight 
loss, or irritability (hyperglycaemia) 

- have kidney or liver problems 
 

Your doctor will perform regular blood tests to make sure that it is safe for you to receive this 
medicine. 
 
Other medicines and Adcetris 
 
Tell your doctor if you are taking any other medicines, if you have taken any recently, or if you start 
taking new ones. This includes herbal medicines and other medicines you can obtain without a 
prescription.  
 
Pregnancy, breast-feeding and fertility 
 
You and your partner must use two methods of effective contraception during your treatment with this 
medicine. Women must continue using contraception for 6 months following the last dose of Adcetris. 
 
You should not use this medicine if you are pregnant unless you and your doctor decide that the 
benefit to you outweighs the potential risk to the unborn baby.  
 
It is important to tell your doctor before and during treatment if you are pregnant, think you may be 
pregnant, or are planning to get pregnant. 
 
If you are breast-feeding, you should discuss with your doctor whether you should receive this 
medicine. 
 
Men being treated with this medicine are advised to have sperm samples frozen and stored before 
treatment. Men are advised not to father a child during treatment with this medicine and for up to 
6 months following the last dose of this medicine.  
 
Driving and using machines 
 
Your treatment may influence your ability to drive or operate machines. If you feel unwell during 
treatment then do not drive or operate machines. 
 
Adcetris contains sodium 
 
This medicine contains 13.2 mg sodium (main component of cooking/table salt) in each vial. This is 
equivalent to 0.7% of the recommended maximum daily dietary intake of sodium for an adult. 
 
 
3. How Adcetris will be given 
 
If you have any questions on the use of this medicine, ask the doctor or nurse who is giving you the 
infusion.  
 



57 

Dose and frequency 
 
The dose of this medicine depends on your body weight.  
 
• The usual dose of Adcetris given in combination with doxorubicin, vinblastine and dacarbazine is 

1.2 mg/kg given every 2 weeks for 6 months.  
 

• The usual dose of Adcetris given in combination with cyclophosphamide, doxorubicin and 
prednisone is 1.8 mg/kg given every 3 weeks for approximately 4-6 months.  

 
See the package leaflets for these medicines given in combination with Adcetris for additional 
information on their use and effects. After the first dose of Adcetris in combination with chemotherapy, 
your doctor may also give you a medicine that will help prevent development or reduce the severity of 
neutropenia (decrease of white blood cell count) which can increase the risk of infection. Tell your 
doctor if you have kidney or liver problems as your doctor may lower your starting dose or may not 
recommend Adcetris. 
 
• The usual dose of Adcetris given alone is 1.8 mg/kg, given once every 3 weeks for no more than 

one year. Your doctor may lower your starting dose to 1.2 mg/kg if you have kidney or liver 
problems. 

 
Adcetris is to be given to adults only. It is not for use in children.  
 
How Adcetris is given 
 
This medicine is given to you into a vein (intravenously) as an infusion. It is given by your doctor or 
nurse over 30 minutes. Your doctor or nurse will also monitor you during and after the infusion.  
 
If you have any other questions on the use of this medicine, ask your doctor. 
 
 
4. Possible side effects  
 
Like all medicines, this medicine may cause side effects, although not everybody gets them.  
 
Infusion reactions 
 
Medicines of this type (monoclonal antibodies) can cause infusion reactions such as: 
- a rash  
- shortness of breath 
- difficulty breathing 
- cough 
- a tight chest  
- fever 
- back pain 
- chills 
- headache 
- feeling sick (nausea) or being sick (vomiting). 
 
Infusion reactions to this medicine may affect more than 1 in 10 people.  
 
In general, these types of reactions occur within minutes to several hours following completion of the 
infusion. However, they may develop more than several hours after completion of the infusion but this 
is uncommon. These infusion reactions can be serious or even fatal (known as an anaphylactic 
reaction). It is not known how frequently infusion-related reactions to this medicine are serious or 
fatal.  
 



58 

You may be given other medicines such as  
- anti-histamines, corticosteroids or paracetamol  
to help reduce any of the reactions above if you have already experienced these when receiving this 
type of medicine.  
 
If you think you have previously had a similar reaction, tell your doctor BEFORE you are given this 
medicine.  
If you develop infusion reactions (as stated previously), your doctor may stop giving this medicine and 
start support treatment. 
If your infusion is restarted, your doctor may increase the time over which your infusion is given so 
that you may be able to tolerate it better.  
 
Tell your doctor straight away if you notice any of the following symptoms because some of them 
may be signs of a serious or possibly fatal condition: 
- progressive multifocal leukoencephalopathy (PML) symptoms such as confusion, trouble 

thinking, memory loss, blurred or loss of vision, decreased strength, decreased control or 
sensation in one arm or leg, a change in the way of walking, or loss of balance (for more 
detailed information, see section 2) (affects less than 1 in 100 people) 

- symptoms of inflammation of the pancreas (pancreatitis) such as severe and persistent stomach 
pain, with or without nausea and vomiting (may affect up to 1 in 100 people). 

- shortness of breath or cough (may affect more than 1 in 10 people) 
- flu-like symptoms followed by a painful red or purplish rash that spreads and blisters including 

extensive detachment of the skin (may affect up to 1 in 100 people) 
- a change in feeling or sensitivity, especially in the skin, numbness, tingling, discomfort, a 

burning sensation, weakness, or pain in the hands or feet (neuropathy; may affect more than 1 in 
10 people) 

- a feeling of weakness (may affect more than 1 in 10 people) 
- constipation (may affect more than 1 in 10 people) 
- diarrhoea, vomiting (may affect more than 1 in 10 people) 
- chills or shivering (may affect up to 1 in 10 people) 
- feeling tired, frequent urination, increased thirst, increased appetite with unintended weight loss, 

and irritability (these may be signs of hyperglycaemia, which may affect up to 1 in 10 people) 
- unusual bleeding or bruising under the skin, longer than usual bleeding after your blood has 

been drawn, or bleeding from your gums (these may be signs of thrombocyopenia which may 
affect up to 1 in 10 people) 

- headaches, experience dizziness, look pale (these may be signs of anaemia, which may affect 
more than 1 in 10 people) 

 
You may experience the following side effects: 
 
The following side effects have been reported with Adcetris alone: 
 

Very common side effects (may affect more than 1 in 10 people) 
- decreased level of white blood cells 
- upper respiratory tract infection 
- decrease in weight 
- infection 
- nausea 
- abdominal pain 
- itching 
- muscle pain 
- joint pain or painful, swollen joints 
 

Common side effects (may affect up to 1 in 10 people) 
- pneumonia 
- sore, creamy-yellow, raised patches in the mouth (thrush) 
- decreased level of blood platelets 



59 

- dizziness 
- blisters which may crust or scab 
- increased level of blood sugar 
- increased liver enzyme levels  
- unusual hair loss or thinning 
 

Uncommon side effects (may affect up to 1 in 100 people) 
- Tumour lysis syndrome – a potentially-life threatening condition in which you may experience 

dizziness, decreased urination, confusion, vomiting, nausea, swelling, shortness of breath, or 
heart rhythm disturbances.  

- new or recurring cytomegalovirus (CMV) infection 
- an infection in the blood (sepsis) and/or septic shock (a life-threatening form of sepsis) 
- Stevens-Johnson syndrome and toxic epidermal necrolysis - a rare, serious disorder in which 

you may experience flu-like symptoms followed by a painful red or purplish rash that spreads 
and blisters including extensive detachment of the skin  

- decreased level of white blood cells with a fever 
- damage to the nerves and nerve coverings (demyelinating polyneuropathy) 
 
The following side effects have been reported with Adcetris in combination with chemotherapy 
medicines: 
 

Very common side effects (may affect more than 1 in 10 people) 
- decreased level of white blood cells 
- decreased level of blood platelets 
- decreased level of white blood cells with a fever 
- upper respiratory tract infection 
- decrease in weight 
- infection 
- nausea 
- abdominal pain 
- unusual hair loss or thinning 
- muscle pain 
- joint pain or painful, swollen joints 
- dizziness 
- decreased appetite 
- not being able to sleep 
- bone pain 
- blisters which may crust or scab 

 
Common side effects (may affect up to 1 in 10 people) 

- an infection in the blood (sepsis) and/or septic shock (a life-threatening form of sepsis); 
pneumonia 

- sore or inflammation in the mouth 
- sore, creamy-yellow, raised patches in the mouth (thrush) 
- itching 
- increased level of blood sugar 
- increased liver enzyme levels 
 

Uncommon side effects (may affect up to 1 in 100 people) 
- Tumour lysis syndrome – a potentially-life threatening condition in which you may experience 

dizziness, decreased urination, confusion, vomiting, nausea, swelling, shortness of breath, or 
heart rhythm disturbances  

- Stevens-Johnson syndrome - a rare, serious disorder in which you may experience flu-like 
symptoms followed by a painful red or purplish rash that spreads and blisters including 
extensive detachment of the skin  

- new or recurring cytomegalovirus (CMV) infection 
 



60 

If you are an older patient (≥ 65 years of age) you may experience serious adverse events more 
frequently.  
 
Reporting of side effects 
 
If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this 
leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. 
By reporting side effects you can help provide more information on the safety of this medicine. 
 
 
5. How to store Adcetris  
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the vial label and the carton after 
EXP. The expiry date refers to the last day of that month.  
 
Unopened vial: Store in a refrigerator (2 °C-8 °C). Do not freeze. 
Keep the vial in the original carton in order to protect from light.  
 
Reconstituted/diluted solution: Use immediately or store in a refrigerator (2 °C-8 °C) and use within 
24 hours. 
 
Do not use this medicine if you notice any particulate matter or discolouration prior to administration.  
 
Do not throw away any medicines via wastewater or household waste. The doctor or nurse will 
dispose of this medicine. These measures will help protect the environment.  
 
 
6. Contents of the pack and other information 
 
What Adcetris contains 
 
- The active substance is brentuximab vedotin. Each vial contains 50 mg of brentuximab vedotin. 

After reconstitution each mL of solution contains 5 mg of Adcetris.  
- The other ingredients are citric acid monohydrate, sodium citrate dihydrate, α,α-trehalose 

dihydrate, and polysorbate 80 See section 2 for further information about sodium.  
 
What Adcetris looks like and contents of the pack 
 
Adcetris is a white to off-white cake or powder for concentrate for solution for infusion provided in a 
glass vial.  
 
Each pack of Adcetris consists of one vial.  
 
Marketing Authorisation Holder 
 
Takeda Pharma A/S 
Dybendal Alle 10 
2630 Taastrup 
Denmark  
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


61 

Manufacturer 
 
Takeda Austria GmbH 
St. Peter-Straβe 25 
A-4020 Linz 
Austria 
 
Delpharm Novara S.r.l. 
Via Crosa, 86 
28065 Cerano (NO)  
Italy 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Takeda Belgium 
Tél/Tel: +32 2 464 06 11 
takeda-belgium@takeda.com  
 

Lietuva 
Takeda, UAB 
Tel: +370 521 09 070 
lt-info@takeda.com 
 

България 
Такеда България 
Тел.: + 359 2 958 27 36 
 

Luxembourg/Luxemburg 
Takeda Belgium 
Tél:/Tel: +32 2 464 06 11 
takeda-belgium@takeda.com  
 

Česká republika 
Takeda Pharmaceuticals  
Czech Republic s.r.o. 
Tel: + 420 234 722 722  
 

Magyarország 
Takeda Pharma Kft. 
Tel.: +361 2707030 
 

Danmark 
Takeda Pharma A/S 
Tlf: +45 46 77 11 11 
 

Malta 
Takeda Italia S.p.A. 
Tel: +39 06 502601 
 

Deutschland 
Takeda GmbH 
Tel: +49 (0) 800 825 3325 
medinfo@takeda.de 
 

Nederland 
Takeda Nederland bv 
Tel: +31 23 56 68 777 
nl.medical.info@takeda.com 
 

Eesti 
Takeda Pharma AS 
Tel: +372 6177 669 
 

Norge 
Takeda AS 
Tlf: +47 6676 3030 
infonorge@takeda.com 
 

Ελλάδα 
TAKEDA ΕΛΛΑΣ Α.Ε 
Tηλ: +30 210 6387800 
gr.info@takeda.com 
 

Österreich 
Takeda Pharma Ges.m.b.H.  
Tel: +43 (0) 800 20 80 50  
 

España 
Takeda Farmacéutica España S.A 
Tel: +34 917 90 42 22 
spain@takeda.com 
 

Polska 
Takeda Pharma sp. z o.o. 
Tel.: + 48 22 608 13 00 
 

France 
Takeda France  
Tél: +33 1 46 25 16 16 

Portugal 
Takeda Farmacêuticos Portugal, Lda. 
Tel: + 351 21 120 1457 



62 

  
Hrvatska 
Takeda Pharmaceuticals Croatia d.o.o. 
Tel: +385 1 377 88 96 
 

România  
Takeda Pharmaceuticals SRL 
Tel: +40 21 335 03 91 

 
Ireland 
Takeda Products Ireland Limited 
Tel: +44 (0)1628 537 900 
 

Slovenija 
Takeda GmbH, Podružnica Slovenija 
Tel: + 386 (0) 59 082 480 

Ísland 
Vistor hf.  
Sími: +354 535 7000 
vistor@vistor.is 

 

Slovenská republika 
Takeda Pharmaceuticals Slovakia s.r.o. 
Tel: +421 (2) 20 602 600 
 
 

Italia  
Takeda Italia S.p.A. 
Tel: +39 06 502601 

Suomi/Finland 
Takeda Oy 
Puh/Tel: +358 20 746 5000 
infoposti@takeda.com 
 

Κύπρος 
A. POTAMITIS MEDICARE LTD 
Tηλ: +357 22583333 
info@potamitismedicare.com 
 
 

Sverige 
Takeda Pharma AB 
Tel: +46 8 731 28 00 
infosweden@takeda.com 

 

Latvija 
Takeda Latvia SIA 
Tel: +371 67840082 

 

United Kingdom 
Takeda UK Ltd 
Tel: +44 (0)1628 537 900 
 

 
This leaflet was last revised in 
 
This medicine has been given ‘conditional approval’. This means that there is more evidence to come 
about this medicine. 
The European Medicines Agency will review new information on this medicine at least every year and 
this leaflet will be updated as necessary. 
 
Detailed information on this medicine is available on the European Medicines Agency website: 
http://www.ema.europa.eu/ 
 
 
---------------------------------------------------------------------------------------------------------------------- 
The following information is intended for healthcare professionals only: 
 
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. 
 
Disposal  
 
Adcetris is for single use only.  
 
Any unused product or waste material should be disposed of in accordance with local requirements. 
 



63 

Instructions for reconstitution  
 
Each single use vial must be reconstituted with 10.5 mL of water for injections to a final concentration 
of 5 mg/mL. Each vial contains a 10% overfill giving 55 mg of Adcetris per vial and a total 
reconstituted volume of 11 mL. 
1. Direct the stream toward the wall of the vial and not directly at the cake or powder.  
2. Gently swirl the vial to aid dissolution. DO NOT SHAKE.  
3. The reconstituted solution in the vial is a clear to slightly opalescent, colourless solution with a 

final pH of 6.6.  
4. The reconstituted solution should be inspected visually for any foreign particulate matter and/or 

discolouration. In the event of either being observed, discard the medicinal product. 
 
Preparation of Infusion Solution 
 
The appropriate amount of reconstituted Adcetris must be withdrawn from the vial(s) and added to an 
infusion bag containing sodium chloride 9 mg/mL (0.9%) solution for injection in order to achieve a 
final concentration of 0.4-1.2 mg/mL Adcetris. The recommended diluent volume is 150 mL. The 
already reconstituted Adcetris can also be diluted into 5% dextrose for injection or Lactated Ringer's 
for injection.  
 
Gently invert the bag to mix the solution containing Adcetris. DO NOT SHAKE.  
 
Any portion left in the vial, after withdrawal of the volume to be diluted, must be disposed of in 
accordance with local requirements.  
 
Do not add other medicinal products to the prepared Adcetris infusion solution or intravenous infusion 
set. The infusion line should be flushed following administration with sodium chloride 9 mg/mL 
(0.9%) solution for injection, 5% dextrose for injection, or Lactated Ringer's for injection.  
 
Following dilution, infuse the Adcetris solution immediately at the recommended infusion rate.  
 
Total storage time of the solution from reconstitution to infusion should not exceed 24 hours.  



64 

 

 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX IV 
 

SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION TO THE TERMS 
OF THE MARKETING AUTHORISATION(S) 

 
 
 
 
 



65 

Scientific conclusions 
 
Taking into account the PRAC Assessment Report for the non-interventional imposed PASS final 
study report for the medicinal product(s) mentioned above, the scientific conclusions of CHMP are as 
follows:  
Currently, the following is described regarding the safety profile in elderly treated with brentuximab 
vedotin monotherapy in SmPC section 4.8: “The safety profile in elderly patients was consistent with 
that of adult patients”. Based on the information provided by the MAH, this statement is not 
considered adequate. The incidences of pneumonia, febrile neutropenia and neutropenia were shown 
to be considerable different for patients ≥ 65 years as compared to patients < 65 years. Furthermore, as 
also mentioned by the MAH older age is an important risk factor for, among others, the occurrence of 
neutropenia and febrile neutropenia.  
Therefore, in view of available data regarding the PASS final study report, the PRAC considered that 
changes to the product information were warranted. 
 
The CHMP agrees with the scientific conclusions made by the PRAC. 
 
Grounds for the variation to the terms of the marketing authorisation(s) 
 
On the basis of the scientific conclusions for the results of the study for the medicinal product(s) 
mentioned above, the CHMP is of the opinion that the benefit-risk balance of this/these medicinal 
product(s) is unchanged, subject to the proposed changes to the product information. 
The CHMP is of the opinion that the terms of the marketing authorisation(s) of the medicinal 
product(s) mentioned above should be varied. 
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES FOR THE CONDITIONAL MARKETING AUTHORISATION 
	A. LABELLING
	B. PACKAGE LEAFLET
	SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION TO THE TERMS OF THE MARKETING AUTHORISATION(S)