WARNING:
PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML)
JC virus
infection resulting in PML and death can occur in patients receiving
Adcetris [see Warnings and Precautions (5.9), Adverse Reactions (6.1)].
Indications and
Usage for Adcetris
Adcetris is
indicated for the treatment of:
Classical
Hodgkin lymphoma (cHL) Consolidation
Adult patients
with cHL at high risk of relapse or progression as post-autologous
hematopoietic stem cell transplantation (auto-HSCT) consolidation [see Clinical Studies
(14.1)].
Relapsed cHL
Adult patients
with cHL after failure of auto-HSCT or after failure of at least two prior
multi-agent chemotherapy regimens in patients who are not auto-HSCT
candidates [see Clinical Studies
(14.1)].
Adcetris is also
indicated for the treatment of:
Relapsed sALCL
Adult patients
with systemic anaplastic large cell lymphoma (sALCL) after failure of at least
one prior multi-agent chemotherapy regimen [see Clinical
Studies (14.2)]
The sALCL
indication is approved under accelerated approval based on overall response
rate. Continued approval for this indication may be contingent upon
verification and description of clinical benefit in confirmatory trials.
Relapsed pcALCL
or CD30-expressing MF
Adult patients
with pcALCL or CD30-expressing MF who have received prior systemic
therapy [see Clinical Studies
(14.2)].
Adcetris Dosage
and Administration
Recommended
Dosage
The recommended
Adcetris dosage is provided in Table 1.
The recommended
dose for patients with renal or hepatic impairment is provided in Table 2.
Table 1: Recommended Adcetris Dosage
|
|
*
The dose for
patients weighing greater than 100 kg should be calculated based on a weight
of 100 kg
|
|
Indication
|
Recommended
Dose*
|
Administration
|
Frequency and Duration
|
|
Classical Hodgkin Lymphoma
Consolidation
|
1.8 mg/kg up to a maximum of 180 mg
|
Intravenous infusion over 30 minutes
|
Initiate Adcetris treatment within 4–6 weeks
post-auto-HSCT or upon recovery from auto-HSCT.
Administer every 3 weeks until a maximum of 16 cycles, disease
progression, or unacceptable toxicity
|
|
Relapsed Classical Hodgkin
Lymphoma
|
1.8 mg/kg up to a maximum of 180 mg
|
Intravenous infusion over 30 minutes
|
Administer every 3 weeks until disease progression or
unacceptable toxicity
|
|
Relapsed Primary Cutaneous
Anaplastic Large Cell Lymphoma or CD30-expressing Mycosis Fungoides
|
1.8 mg/kg up to a maximum of 180 mg
|
Intravenous infusion over 30 minutes
|
Administer every 3 weeks until a maximum of
16 cycles, disease progression, or unacceptable toxicity
|
|
Relapsed Systemic Anaplastic
Large Cell Lymphoma
|
1.8 mg/kg up to a maximum of 180 mg
|
Intravenous infusion over 30 minutes
|
Administer every 3 weeks until disease progression or
unacceptable toxicity
|
Table 2: Recommended Dose for Patients with Renal or
Hepatic Impairment
|
|
CrCL: creatinine clearance
|
|
*
The dose
for patients weighing greater than 100 kg should be calculated based on a
weight of 100 kg
|
|
Impairment
|
Degree of Impairment
|
Recommended Dose
|
|
Renal
|
Normal
Mild (CrCL greater than
50–80 mL/min)
Moderate (CrCL 30–50 mL/min)
|
1.8 mg/kg up to a maximum of 180 mg*
|
|
Severe (CrCL less than 30 mL/min)
|
Avoid use [see Warnings and Precautions (5.6)]
|
|
Hepatic
|
Normal
|
1.8 mg/kg up to a maximum of 180 mg*
|
|
Mild (Child-Pugh A)
|
1.2 mg/kg up to a maximum of 120 mg*
|
|
|
Moderate (Child-Pugh B)
Severe (Child-Pugh C)
|
Avoid use [see Warnings and Precautions (5.7)]
|
|
|
|
|
|
|
Dose
Modification
Table 3: Dose Modifications for Peripheral
Neuropathy or Neutropenia
|
|
Toxicity
|
Severity
|
Dose Modification
|
|
Events were graded using the National Cancer Institute
Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0
|
|
*
The dose
for patients weighing greater than 100 kg should be calculated based on a
weight of 100 kg
|
|
Peripheral Neuropathy
|
New or worsening Grade 2 or 3
|
Hold dosing until improvement to baseline or Grade 1
Restart at 1.2 mg/kg up to a maximum of 120 mg*
|
|
Grade 4
|
Dosing should be discontinued
|
|
Neutropenia
|
Grade 3 or 4
|
Hold dosing until improvement to baseline or Grade 2 or
lower
Consider G-CSF prophylaxis for subsequent cycles
|
|
|
Recurrent Grade 4 despite G-CSF prophylaxis
|
Consider discontinuation or dose reduction to
1.2 mg/kg up to a maximum of 120 mg*
|
Instructions for
Preparation and Administration
Administration
Administer
Adcetris as an intravenous infusion only.Do not mix Adcetris with, or administer as an
infusion with, other medicinal products.
Reconstitution
Follow
procedures for proper handling and disposal of anticancer drugs [see References
(15)].Use
appropriate aseptic technique for reconstitution and preparation of dosing
solutions.Determine
the number of 50 mg vials needed based on the patient’s weight and the
prescribed dose [see Dosage and
Administration (2.1)]Reconstitute
each 50 mg vial of Adcetris with 10.5 mL of Sterile Water for Injection,
USP, to yield a single-use solution containing 5 mg/mL brentuximab
vedotin.Direct
the stream toward the wall of vial and not directly at the cake or powder.Gently
swirl the vial to aid dissolution. DO NOT SHAKE.Inspect
the reconstituted solution for particulates and discoloration. The
reconstituted solution should be clear to slightly opalescent, colorless,
and free of visible particulates.Following
reconstitution, dilute immediately into an infusion bag. If not diluted
immediately, store the solution at 2–8°C (36–46°F) and use within 24 hours
of reconstitution. DO NOT FREEZE.Discard
any unused portion left in the vial.
Dilution
Calculate
the required volume of 5 mg/mL reconstituted Adcetris solution needed.Withdraw
this amount from the vial and immediately add it to an infusion bag
containing a minimum volume of 100 mL of 0.9% Sodium Chloride Injection,
5% Dextrose Injection or Lactated Ringer's Injection to achieve a
final concentration of 0.4 mg/mL to 1.8 mg/mL brentuximab vedotin.Gently
invert the bag to mix the solution.Following
dilution, infuse the Adcetris solution immediately. If not used
immediately, store the solution at 2–8°C (36–46°F) and use within 24 hours
of reconstitution. DO NOT FREEZE.
Dosage Forms and
Strengths
For injection:
50 mg of brentuximab vedotin as a sterile, white to off-white lyophilized,
preservative-free cake or powder in a single-use vial for reconstitution.
Contraindications
Adcetris is
contraindicated with concomitant bleomycin due to pulmonary toxicity
(e.g., interstitial infiltration and/or inflammation) [see Adverse
Reactions (6.1)].
Warnings and
Precautions
Peripheral
Neuropathy
Adcetris
treatment causes a peripheral neuropathy that is predominantly sensory. Cases
of peripheral motor neuropathy have also been reported. Adcetris-induced
peripheral neuropathy is cumulative.
In studies of
Adcetris as monotherapy, 62% of patients experienced any grade of neuropathy.
The median time to onset of any grade was 13 weeks (range, 0–52). Of the
patients who experienced neuropathy, 62% had complete resolution, 24% had
partial improvement, and 14% had no improvement at the time of their last
evaluation. The median time from onset to resolution or improvement of any
grade was 21 weeks (range, 0–195). Of the patients who reported
neuropathy, 38% had residual neuropathy at the time of their last evaluation
[Grade 1 (27%), Grade 2 (9%), Grade 3 (2%)].
Monitor patients
for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia,
discomfort, a burning sensation, neuropathic pain, or weakness. Patients
experiencing new or worsening peripheral neuropathy may require a delay, change
in dose, or discontinuation of Adcetris [see Dosage and
Administration (2.2) and Adverse
Reactions (6.1)].
Anaphylaxis and
Infusion Reactions
Infusion-related
reactions, including anaphylaxis, have occurred with Adcetris. Monitor patients
during infusion. If anaphylaxis occurs, immediately and permanently discontinue
administration of Adcetris and administer appropriate medical therapy. If an
infusion-related reaction occurs, interrupt the infusion and institute
appropriate medical management. Patients who have experienced a prior
infusion-related reaction should be premedicated for subsequent infusions.
Premedication may include acetaminophen, an antihistamine, and a
corticosteroid.
Hematologic
Toxicities
Prolonged (≥1
week) severe neutropenia and Grade 3 or Grade 4 thrombocytopenia or anemia can
occur with Adcetris. Febrile neutropenia has been reported with treatment with
Adcetris. Monitor complete blood counts prior to each dose of Adcetris. Monitor
more frequently for patients with Grade 3 or 4 neutropenia. Monitor patients
for fever. If Grade 3 or 4 neutropenia develops, consider dose delays,
reductions, discontinuation, or G-CSF prophylaxis with subsequent Adcetris
doses [see Dosage and
Administration (2.2)].
Serious Infections
and Opportunistic Infections
Serious
infections and opportunistic infections such as pneumonia, bacteremia, and
sepsis or septic shock (including fatal outcomes) have been reported in
patients treated with Adcetris. Monitor patients closely during treatment for
the emergence of possible bacterial, fungal, or viral infections.
Tumor Lysis
Syndrome
Patients with
rapidly proliferating tumor and high tumor burden may be at increased risk of
tumor lysis syndrome. Monitor closely and take appropriate measures.
Increased
Toxicity in the Presence of Severe Renal Impairment
The frequency of
≥Grade 3 adverse reactions and deaths was greater in patients with severe renal
impairment compared to patients with normal renal function. Due to higher MMAE
exposure, ≥Grade 3 adverse reactions may be more frequent in patients with
severe renal impairment compared to patients with normal renal function. Avoid
the use of Adcetris in patients with severe renal impairment [creatinine
clearance (CrCL) <30 mL/min] [see Use in Specific
Populations (8.6)].
Increased
Toxicity in the Presence of Moderate or Severe Hepatic Impairment
The frequency of
≥Grade 3 adverse reactions and deaths was greater in patients with moderate and
severe hepatic impairment compared to patients with normal hepatic function.
Avoid the use of Adcetris in patients with moderate (Child-Pugh B) or severe
(Child-Pugh C) hepatic impairment [see Use in Specific
Populations (8.7)].
Hepatotoxicity
Serious cases of
hepatotoxicity, including fatal outcomes, have occurred in patients receiving
Adcetris. Cases were consistent with hepatocellular injury, including
elevations of transaminases and/or bilirubin. Cases have occurred after the
first dose of Adcetris or after Adcetris rechallenge. Preexisting liver
disease, elevated baseline liver enzymes, and concomitant medications may also
increase the risk. Monitor liver enzymes and bilirubin. Patients experiencing
new, worsening, or recurrent hepatotoxicity may require a delay, change in
dose, or discontinuation of Adcetris.
Progressive
Multifocal Leukoencephalopathy
JC virus
infection resulting in PML and death has been reported in Adcetris-treated
patients. First onset of symptoms occurred at various times from initiation of
Adcetris therapy, with some cases occurring within 3 months of initial
exposure. In addition to Adcetris therapy, other possible contributory factors
include prior therapies and underlying disease that may cause
immunosuppression. Consider the diagnosis of PML in any patient presenting with
new-onset signs and symptoms of central nervous system abnormalities. Hold
Adcetris dosing for any suspected case of PML and discontinue Adcetris dosing
if a diagnosis of PML is confirmed.
Pulmonary
Toxicity
Events of
noninfectious pulmonary toxicity including pneumonitis, interstitial lung
disease, and acute respiratory distress syndrome (ARDS), some with fatal
outcomes, have been reported. Monitor patients for signs and symptoms of
pulmonary toxicity, including cough and dyspnea. In the event of new or
worsening pulmonary symptoms, hold Adcetris dosing during evaluation and until
symptomatic improvement.
Serious
Dermatologic Reactions
Stevens-Johnson
syndrome (SJS) and toxic epidermal necrolysis (TEN), including fatal outcomes,
have been reported with Adcetris. If SJS or TEN occurs, discontinue Adcetris
and administer appropriate medical therapy.
Gastrointestinal
Complications
Acute
pancreatitis, including fatal outcomes,has been reported. Other fatal and
serious gastrointestinal (GI) complications include perforation, hemorrhage,
erosion, ulcer, intestinal obstruction, enterocolitis, neutropenic colitis, and
ileus. Lymphoma with preexisting GI involvement may increase the risk of
perforation. In the event of new or worsening GI symptoms, including severe
abdominal pain, perform a prompt diagnostic evaluation and treat appropriately.
Embryo-Fetal
Toxicity
Based on the
mechanism of action and findings in animals, Adcetris can cause fetal harm when
administered to a pregnant woman. There are no adequate and well-controlled
studies of Adcetris in pregnant women. Brentuximab vedotin caused embryo-fetal
toxicities, including significantly decreased embryo viability and fetal
malformations, in animals at maternal exposures that were similar to the
clinical dose of 1.8 mg/kg every three weeks.
Advise females
of reproductive potential to avoid pregnancy during Adcetris treatment and for
at least 6 months after the final dose of Adcetris. If Adcetris is used during
pregnancy or if the patient becomes pregnant during Adcetris treatment, the
patient should be apprised of the potential risk to the fetus [see Use in Specific
Populations (8.1,8.3)].
Adverse
Reactions
The following
serious adverse reactions are described elsewhere in the labeling:
Peripheral
Neuropathy [see Warnings
and Precautions (5.1)]Anaphylaxis
and Infusion Reactions [see Warnings
and Precautions (5.2)]Hematologic
Toxicities [see Warnings
and Precautions (5.3)]Serious
Infections and Opportunistic Infections [see Warnings
and Precautions (5.4)]Tumor
Lysis Syndrome [see Warnings
and Precautions (5.5)]Increased
Toxicity in the Presence of Severe Renal Impairment [see Warnings
and Precautions (5.6)]Increased
Toxicity in the Presence of Moderate or Severe Hepatic Impairment [see Warnings
and Precautions (5.7)]Hepatotoxicity [see Warnings
and Precautions (5.8)]Progressive
Multifocal Leukoencephalopathy [see Warnings
and Precautions (5.9)]Pulmonary
Toxicity [see Warnings
and Precautions (5.10)]Serious
Dermatologic Reactions [see Warnings
and Precautions (5.11)] Gastrointestinal
Complications [see Warnings
and Precautions (5.12)]
Clinical Trial
Experience
Because clinical
trials are conducted under widely varying conditions, adverse reaction rates
observed in clinical trials of a drug cannot be directly compared to rates in
the clinical trials of another drug and may not reflect the rates observed in
practice.
The data below
reflect exposure to Adcetris as monotherapy in 393 patients, including
160 patients in two uncontrolled single-arm trials in cHL and systemic ALCL
(Studies 1 and 2) and 233 patients in two controlled randomized trials in
cHL, and pcALCL and CD30-expressing MF (Study 3: AETHERA and Study 4: ALCANZA).
In these trials, Adcetris was administered at 1.8 mg/kg every 3 weeks.
Across the
clinical trials of Adcetris as monotherapy (Studies 1-4), the most common
adverse reactions (≥20%) in Adcetris-treated patients were peripheral sensory
neuropathy, fatigue, nausea, diarrhea, neutropenia, upper respiratory tract
infection, and pyrexia.
Classical
Hodgkin Lymphoma Post-auto-HSCT Consolidation (Study 3: AETHERA)
Adcetris was
studied in 329 patients with cHL at high risk of relapse or progression
post-auto-HSCT in a randomized, double-blind, placebo-controlled clinical trial
in which the recommended starting dose and schedule was 1.8 mg/kg of Adcetris
administered intravenously over 30 minutes every 3 weeks or placebo for up
to 16 cycles. Of the 329 enrolled patients, 327 (167 Adcetris, 160
placebo) received at least one dose of study treatment. The median number of
treatment cycles in each study arm was 15 (range, 1–16) and 80 patients (48%)
in the Adcetris-treatment arm received 16 cycles [see Clinical Studies
(14.1)]
Standard
international guidelines were followed for infection prophylaxis for herpes
simplex virus (HSV), varicella-zoster virus (VZV), and Pneumocystis
jiroveci pneumonia
(PJP) post-auto-HSCT. Overall, 312 patients (95%) received HSV and VZV prophylaxis
with a median duration of 11.1 months (range, 0–20) and 319 patients (98%)
received PJP prophylaxis with a median duration of 6.5 months (range, 0–20).
Adverse
reactions that led to dose delays in more than 5% of Adcetris-treated patients
were neutropenia (22%), peripheral sensory neuropathy (16%), upper respiratory
tract infection (6%), and peripheral motor neuropathy (6%) [see Dosage and
Administration (2.2)]. Adverse reactions led to treatment
discontinuation in 32% of Adcetris-treated patients. Adverse reactions that led
to treatment discontinuation in 2 or more patients were peripheral sensory
neuropathy (14%), peripheral motor neuropathy (7%), acute respiratory distress
syndrome (1%), paraesthesia (1%), and vomiting (1%). Serious adverse reactions,
were reported in 25% of Adcetris-treated patients. The most common serious
adverse reactions were pneumonia (4%), pyrexia (4%), vomiting (3%), nausea (2%),
hepatotoxicity (2%), and peripheral sensory neuropathy (2%).
Table 4: Adverse Reactions Reported in ≥10% in
Adcetris-treated Patients with Classical Hodgkin Lymphoma Post-auto-HSCT
Consolidation (Study 3: AETHERA)
|
|
|
Adcetris
Total N
= 167
% of
patients
|
Placebo
Total N
= 160
% of
patients
|
|
Adverse Reaction
|
Any
Grade
|
Grade 3
|
Grade 4
|
Any
Grade
|
Grade 3
|
Grade 4
|
|
Events were graded using the NCI CTCAE Version 4
|
|
*
Derived from
laboratory values and adverse reaction data
|
|
Blood and lymphatic system
disorders
|
|
|
|
|
|
|
|
Neutropenia*
|
78
|
30
|
9
|
34
|
6
|
4
|
|
Thrombocytopenia*
|
41
|
2
|
4
|
20
|
3
|
2
|
|
Anemia*
|
27
|
4
|
-
|
19
|
2
|
-
|
|
Nervous system disorders
|
|
|
|
|
|
|
|
Peripheral sensory neuropathy
|
56
|
10
|
-
|
16
|
1
|
-
|
|
Peripheral motor neuropathy
|
23
|
6
|
-
|
2
|
1
|
-
|
|
Headache
|
11
|
2
|
-
|
8
|
1
|
-
|
|
Infections and infestations
|
|
|
|
|
|
|
|
Upper respiratory tract
infection
|
26
|
-
|
-
|
23
|
1
|
-
|
|
General disorders and
administration site conditions
|
|
|
|
|
|
|
|
Fatigue
|
24
|
2
|
-
|
18
|
3
|
-
|
|
Pyrexia
|
19
|
2
|
-
|
16
|
-
|
-
|
|
Chills
|
10
|
-
|
-
|
5
|
-
|
-
|
|
Gastrointestinal disorders
|
|
|
|
|
|
|
|
Nausea
|
22
|
3
|
-
|
8
|
-
|
-
|
|
Diarrhea
|
20
|
2
|
-
|
10
|
1
|
-
|
|
Vomiting
|
16
|
2
|
-
|
7
|
-
|
-
|
|
Abdominal pain
|
14
|
2
|
-
|
3
|
-
|
-
|
|
Constipation
|
13
|
2
|
-
|
3
|
-
|
-
|
|
Respiratory, thoracic and
mediastinal disorders
|
|
|
|
|
|
|
|
Cough
|
21
|
-
|
-
|
16
|
-
|
-
|
|
Dyspnea
|
13
|
-
|
-
|
6
|
-
|
1
|
|
Investigations
|
|
|
|
|
|
|
|
Weight decreased
|
19
|
1
|
-
|
6
|
-
|
-
|
|
Musculoskeletal and
connective tissue disorders
|
|
|
|
|
|
|
|
Arthralgia
|
18
|
1
|
-
|
9
|
-
|
-
|
|
Muscle spasms
|
11
|
-
|
-
|
6
|
-
|
-
|
|
Myalgia
|
11
|
1
|
-
|
4
|
-
|
-
|
|
Skin and subcutaneous tissue
disorders
|
|
|
|
|
|
|
|
Pruritus
|
12
|
1
|
-
|
8
|
-
|
-
|
|
Metabolism and nutrition
disorders
|
|
|
|
|
|
|
|
Decreased appetite
|
12
|
1
|
-
|
6
|
-
|
-
|
Relapsed Classical
Hodgkin Lymphoma (Study 1)
Adcetris was
studied in 102 patients with cHL in a single arm clinical trial in which the
recommended starting dose and schedule was 1.8 mg/kg intravenously every 3
weeks. Median duration of treatment was 9 cycles (range, 1–16) [see Clinical Studies
(14.1)].
Adverse
reactions that led to dose delays in more than 5% of Adcetris-treated patients
were neutropenia (16%) and peripheral sensory neuropathy (13%) [see Dosage and
Administration (2.2)]. Adverse reactions led to treatment
discontinuation in 20% of Adcetris-treated patients. Adverse reactions that led
to treatment discontinuation in 2 or more patients were peripheral sensory
neuropathy (6%) and peripheral motor neuropathy (3%). Serious adverse
reactions, were reported in 25% of Adcetris-treated patients. The most common
serious adverse reactions were peripheral motor neuropathy (4%), abdominal pain
(3%), pulmonary embolism (2%), pneumonitis (2%), pneumothorax (2%),
pyelonephritis (2%), and pyrexia (2%).
Table 5: Adverse Reactions Reported in ≥10% of
Patients with Relapsed Classical Hodgkin Lymphoma (Study 1)
|
|
|
|
cHL
|
|
|
Total N
= 102
% of
patients
|
|
|
Adverse Reaction
|
Any
Grade
|
Grade 3
|
Grade 4
|
|
|
Events were graded using the NCI CTCAE Version
3.0
|
|
|
*
Derived from
laboratory values and adverse reaction data
|
|
|
Blood and lymphatic system disorders
|
|
|
|
|
|
Neutropenia*
|
54
|
15
|
6
|
|
|
Anemia*
|
33
|
8
|
2
|
|
|
Thrombocytopenia*
|
28
|
7
|
2
|
|
|
Lymphadenopathy
|
11
|
-
|
-
|
|
|
Nervous system disorders
|
|
|
|
|
|
Peripheral sensory neuropathy
|
52
|
8
|
-
|
|
|
Peripheral motor neuropathy
|
16
|
4
|
-
|
|
|
Headache
|
19
|
-
|
-
|
|
|
Dizziness
|
11
|
-
|
-
|
|
|
General disorders and administration site conditions
|
|
|
|
|
|
Fatigue
|
49
|
3
|
-
|
|
|
Pyrexia
|
29
|
2
|
-
|
|
|
Chills
|
13
|
-
|
-
|
|
|
Infections and infestations
|
|
|
|
|
|
Upper respiratory tract infection
|
47
|
-
|
-
|
|
|
Gastrointestinal disorders
|
|
|
|
|
|
Nausea
|
42
|
-
|
-
|
|
|
Diarrhea
|
36
|
1
|
-
|
|
|
Abdominal pain
|
25
|
2
|
1
|
|
|
Vomiting
|
22
|
-
|
-
|
|
|
Constipation
|
16
|
-
|
-
|
|
|
Skin and subcutaneous tissue disorders
|
|
|
|
|
|
Rash
|
27
|
-
|
-
|
|
|
Pruritus
|
17
|
-
|
-
|
|
|
Alopecia
|
13
|
-
|
-
|
|
|
Night sweats
|
12
|
-
|
-
|
|
|
Respiratory, thoracic and mediastinal disorders
|
|
|
|
|
|
Cough
|
25
|
-
|
-
|
|
|
Dyspnea
|
13
|
1
|
-
|
|
|
Oropharyngeal pain
|
11
|
-
|
-
|
|
|
Musculoskeletal and connective tissue disorders
|
|
|
|
|
|
Arthralgia
|
19
|
-
|
-
|
|
|
Myalgia
|
17
|
-
|
-
|
|
|
Back pain
|
14
|
-
|
-
|
|
|
Pain in extremity
|
10
|
-
|
-
|
|
|
Psychiatric disorders
|
|
|
|
|
|
Insomnia
|
14
|
-
|
-
|
|
|
Anxiety
|
11
|
2
|
-
|
|
|
Metabolism and nutrition disorders
|
|
|
|
|
|
Decreased appetite
|
11
|
-
|
-
|
|
Relapsed
Systemic Anaplastic Large Cell Lymphoma (Study 2)
Adcetris was
studied in 58 patients with sALCL in a single arm clinical trial in which the
recommended starting dose and schedule was 1.8 mg/kg intravenously every 3 weeks.
Median duration of treatment was 7 cycles (range, 1–16) [see Clinical Studies
(14.2)]
Adverse
reactions that led to dose delays in more than 5% of Adcetris-treated patients
were neutropenia (12%) and peripheral sensory neuropathy (7%) [see Dosage and
Administration (2.2)]. Adverse reactions led to treatment
discontinuation in 19% of Adcetris-treated patients. The adverse reaction that
led to treatment discontinuation in 2 or more patients was peripheral sensory
neuropathy (5%). Serious adverse reactions were reported in 41% of
Adcetris-treated patients. The most common serious adverse reactions were
septic shock (3%), supraventricular arrhythmia (3%), pain in extremity (3%),
and urinary tract infection (3%).
Table 6: Adverse Reactions Reported in ≥10% of
Patients with Relapsed Systemic Anaplastic Large Cell Lymphoma (Study 2)
|
|
|
|
sALCL
|
|
|
Total N
= 58
% of
patients
|
|
|
Adverse Reaction
|
Any
Grade
|
Grade 3
|
Grade 4
|
|
|
Events were graded using the NCI CTCAE Version 3.0
|
|
|
*
Derived from laboratory
values and adverse reaction data
|
|
|
Blood and lymphatic system disorders
|
|
|
|
|
|
Neutropenia*
|
55
|
12
|
9
|
|
|
Anemia*
|
52
|
2
|
-
|
|
|
Thrombocytopenia*
|
16
|
5
|
5
|
|
|
Lymphadenopathy
|
10
|
-
|
-
|
|
|
Nervous system disorders
|
|
|
|
|
|
Peripheral sensory neuropathy
|
53
|
10
|
-
|
|
|
Headache
|
16
|
2
|
-
|
|
|
Dizziness
|
16
|
-
|
-
|
|
|
General disorders and administration site conditions
|
|
|
|
|
|
Fatigue
|
41
|
2
|
2
|
|
|
Pyrexia
|
38
|
2
|
-
|
|
|
Chills
|
12
|
-
|
-
|
|
|
Pain
|
28
|
-
|
5
|
|
|
Edema peripheral
|
16
|
-
|
-
|
|
|
Infections and infestations
|
|
|
|
|
|
Upper respiratory tract infection
|
12
|
-
|
-
|
|
|
Gastrointestinal disorders
|
|
|
|
|
|
Nausea
|
38
|
2
|
-
|
|
|
Diarrhea
|
29
|
3
|
-
|
|
|
Vomiting
|
17
|
3
|
-
|
|
|
Constipation
|
19
|
2
|
-
|
|
|
Skin and subcutaneous tissue disorders
|
|
|
|
|
|
Rash
|
31
|
-
|
-
|
|
|
Pruritus
|
19
|
-
|
-
|
|
|
Alopecia
|
14
|
-
|
-
|
|
|
Dry skin
|
10
|
-
|
-
|
|
|
Respiratory, thoracic and mediastinal disorders
|
|
|
|
|
|
Cough
|
17
|
-
|
-
|
|
|
Dyspnea
|
19
|
2
|
-
|
|
|
Musculoskeletal and connective tissue disorders
|
|
|
|
|
|
Myalgia
|
16
|
2
|
-
|
|
|
Back pain
|
10
|
2
|
-
|
|
|
Pain in extremity
|
10
|
2
|
2
|
|
|
Muscle spasms
|
10
|
2
|
-
|
|
|
Psychiatric disorders
|
|
|
|
|
|
Insomnia
|
16
|
-
|
-
|
|
|
Metabolism and nutrition disorders
|
|
|
|
|
|
Decreased appetite
|
16
|
2
|
-
|
|
|
Investigations
|
|
|
|
|
|
Weight decreased
|
12
|
3
|
-
|
|
Primary
Cutaneous Anaplastic Large Cell Lymphoma and CD30-expressing Mycosis Fungoides
(Study 4: ALCANZA)
Adcetris was
studied in 131 patients with pcALCL or CD30-expressing MF requiring systemic
therapy in a randomized, open-label, multicenter clinical trial in which the
recommended starting dose and schedule was Adcetris 1.8 mg/kg intravenously
over 30 minutes every 3 weeks or physician’s choice of either methotrexate 5 to
50 mg orally weekly or bexarotene 300 mg/m2 orally
daily.
Of the 131
enrolled patients, 128 (66 brentuximab vedotin, 62 physician’s choice) received
at least one dose of study treatment. The median number of treatment cycles in
the Adcetris-treatment arm was 12 (range, 1–16) compared to 3 (range, 1–16) and
6 (range, 1–16) in the methotrexate and bexarotene arms, respectively.
Twenty-four (24) patients (36%) in the Adcetris-treatment arm received
16 cycles compared to 5 patients (8%) in the physician’s choice arm [see Clinical Studies
(14)].
Adverse
reactions that led to dose delays in more than 5% of Adcetris-treated patients
were peripheral sensory neuropathy (15%) and neutropenia (6%) [see Dosage and
Administration (2.2)]. Adverse reactions led to treatment
discontinuation in 24% of Adcetris-treated patients. The most common adverse
reaction that led to treatment discontinuation was peripheral neuropathy (12%).
Serious adverse reactions were reported in 29% of Adcetris-treated patients.
The most common serious adverse reactions were cellulitis (3%) and pyrexia
(3%).
Table 7: Adverse Reactions Reported in ≥10%
Adcetris-treated Patients with pcALCL or CD30-expressing MF (Study 4:
ALCANZA)
|
|
|
Adcetris
Total N
= 66
% of
patients
|
Physician’s
Choicea
Total N
= 62
% of
patients
|
|
Adverse Reaction
|
Any
Grade
|
Grade 3
|
Grade 4
|
Any
Grade
|
Grade 3
|
Grade 4
|
|
a Physician’s choice of either methotrexate or bexarotene
Events were graded using the NCI CTCAE Version
4.03
|
|
*
Derived from
laboratory values and adverse reaction data
|
|
Blood and lymphatic system
disorders
|
|
|
|
|
|
|
|
Anemia*
|
62
|
-
|
-
|
65
|
5
|
-
|
|
Neutropenia*
|
21
|
3
|
2
|
24
|
5
|
-
|
|
Thrombocytopenia*
|
15
|
2
|
2
|
2
|
-
|
-
|
|
Nervous system disorders
|
|
|
|
|
|
|
|
Peripheral sensory neuropathy
|
45
|
5
|
-
|
2
|
-
|
-
|
|
Gastrointestinal disorders
|
|
|
|
|
|
|
|
Nausea
|
36
|
2
|
-
|
13
|
-
|
-
|
|
Diarrhea
|
29
|
3
|
-
|
6
|
-
|
-
|
|
Vomiting
|
17
|
2
|
-
|
5
|
-
|
-
|
|
General disorders and
administration site conditions
|
|
|
|
|
|
|
|
Fatigue
|
29
|
5
|
-
|
27
|
2
|
-
|
|
Pyrexia
|
17
|
-
|
-
|
18
|
2
|
-
|
|
Edema peripheral
|
11
|
-
|
-
|
10
|
-
|
-
|
|
Asthenia
|
11
|
2
|
-
|
8
|
-
|
2
|
|
Skin and subcutaneous tissue
disorders
|
|
|
|
|
|
|
|
Pruritus
|
17
|
2
|
-
|
13
|
3
|
-
|
|
Alopecia
|
15
|
-
|
-
|
3
|
-
|
-
|
|
Rash maculo-papular
|
11
|
2
|
-
|
5
|
-
|
-
|
|
Pruritus generalized
|
11
|
2
|
-
|
2
|
-
|
-
|
|
Metabolism and nutrition
disorders
|
|
|
|
|
|
|
|
Decreased appetite
|
15
|
-
|
-
|
5
|
-
|
-
|
|
Musculoskeletal and
connective tissue disorders
|
|
|
|
|
|
|
|
Arthralgia
|
12
|
-
|
-
|
6
|
-
|
-
|
|
Myalgia
|
12
|
-
|
-
|
3
|
-
|
-
|
|
Respiratory, thoracic and
mediastinal disorders
|
|
|
|
|
|
|
|
Dyspnea
|
11
|
-
|
-
|
-
|
-
|
-
|
Additional
Important Adverse Reactions
Infusion
reactions
In studies of
Adcetris as monotherapy (Studies 1–4), 13% of Adcetris-treated patients
experienced infusion-related reactions. The most common adverse reactions in
Studies 1–4 (≥3% in any study) associated with infusion-related reactions were
chills (4%), nausea (3–4%), dyspnea (2–3%), pruritus (2–5%), pyrexia (2%), and
cough (2%). Grade 3 events were reported in 5 of the 51 Adcetris-treated
patients who experienced infusion-related reactions.
Pulmonary
toxicity
In a trial in
patients with cHL that studied Adcetris with bleomycin as part of a combination
regimen, the rate of non-infectious pulmonary toxicity was higher than the
historical incidence reported with ABVD (adriamycin, bleomycin, vinblastine,
dacarbazine). Patients typically reported cough and dyspnea. Interstitial
infiltration and/or inflammation were observed on radiographs and computed
tomographic imaging of the chest. Most patients responded to corticosteroids.
The concomitant use of Adcetris with bleomycin is contraindicated [see Contraindications
(4)].
Cases of
pulmonary toxicity have also been reported in patients receiving Adcetris. In
Study 3 (AETHERA), pulmonary toxicity was reported in 8 patients (5%) in
the Adcetris-treated arm and 5 patients (3%) in the placebo arm.
Post Marketing
Experience
The following
adverse reactions have been identified during post-approval use of Adcetris.
Because these reactions are reported voluntarily from a population of uncertain
size, it is not always possible to reliably estimate their frequency or
establish a causal relationship to drug exposure.
Blood and
lymphatic system disorders: febrile neutropenia [see Warnings and
Precautions (5.3)].
Gastrointestinal
disorders: acute
pancreatitis and gastrointestinal complications (including fatal
outcomes) [see Warnings and
Precautions (5.12)].
Hepatobiliary
disorders:
hepatotoxicity [see Warnings and
Precautions (5.8)].
Infections: PML [see Boxed Warning, Warnings and
Precautions (5.9)], serious infections and opportunistic
infections [see Warnings and
Precautions (5.4)].
Metabolism and
nutrition disorders: hyperglycemia.
Respiratory,
thoracic and mediastinal disorders: noninfectious pulmonary toxicity including pneumonitis,
interstitial lung disease, and ARDS (some with fatal outcomes) [see Warnings and
Precautions (5.10) and Adverse
Reactions (6.1)].
Skin and
subcutaneous tissue disorders: Toxic epidermal necrolysis, including fatal
outcomes [see Warnings and
Precautions (5.11)].
Immunogenicity
As with all
therapeutic proteins, there is potential for immunogenicity. The detection of
antibody formation is highly dependent on the sensitivity and specificity of
the assay. Additionally, the observed incidence of antibody (including
neutralizing antibody) positivity in an assay may be influenced by several
factors including assay methodology, sample handling, timing of sample
collection, concomitant medications, and underlying disease. For these reasons,
comparison of the incidence of antibodies to Adcetris in the studies described
below with the incidence of antibodies in other studies or to other products
may be misleading.
Patients with
cHL and sALCL in Studies 1 and 2 [see Clinical Studies
(14)] were
tested for antibodies to brentuximab vedotin every 3 weeks using a sensitive
electrochemiluminescent immunoassay. Approximately 7% of patients in these
trials developed persistently positive antibodies (positive test at more than 2
timepoints) and 30% developed transiently positive antibodies (positive in 1 or
2 post-baseline timepoints). The anti-brentuximab antibodies were directed
against the antibody component of brentuximab vedotin in all patients with
transiently or persistently positive antibodies. Two of the patients (1%) with
persistently positive antibodies experienced adverse reactions consistent with
infusion reactions that led to discontinuation of treatment. Overall, a higher
incidence of infusion related reactions was observed in patients who developed
persistently positive antibodies.
A total of 58
patient samples that were either transiently or persistently positive for
anti-brentuximab vedotin antibodies were tested for the presence of
neutralizing antibodies. Sixty-two percent (62%) of these patients had at least
one sample that was positive for the presence of neutralizing antibodies. The effect
of anti-brentuximab vedotin antibodies on safety and efficacy is not known.
Drug
Interactions
Effect of Other
Drugs on Adcetris
CYP3A4
Inhibitors: Co-administration of Adcetris with ketoconazole, a potent
CYP3A4 inhibitor, increased exposure to MMAE [see Clinical
Pharmacology (12.3)] which may increase the risk of
adverse reaction. Closely monitor adverse reactions when Adcetris is given
concomitantly with strong CYP3A4 inhibitors.
P-gp Inhibitors: Co-administration
of Adcetris with P-gp inhibitors may increase exposure to MMAE. Closely monitor
adverse reactions when Adcetris is given concomitantly with P-gp inhibitors.
USE IN SPECIFIC
POPULATIONS
Pregnancy
Risk Summary
Adcetris can
cause fetal harm based on the findings from animal studies and the drug’s
mechanism of action [see Clinical
Pharmacology (12.1)]. In
animal reproduction studies, administration of brentuximab vedotin to pregnant
rats during organogenesis at doses similar to the clinical dose of 1.8 mg/kg
every three weeks caused embryo-fetal toxicities, including congenital
malformations (see Data). Consider
the benefits and risks of Adcetris and possible risks to the fetus when
prescribing Adcetris to a pregnant woman.
The estimated
background risk of major birth defects and miscarriage for the indicated
population is unknown. All pregnancies have a background risk of birth defect,
loss, or other adverse outcomes. In the U.S. general population, the estimated
background risk of major birth defects and miscarriage in clinically recognized
pregnancies is 2–4% and 15–20%, respectively.
Data
Animal Data
In
an embryo-fetal developmental study, pregnant rats received 2 intravenous doses
of 0.3,
1, 3, or 10 mg/kg brentuximab vedotin
during the period of organogenesis (once each on
Pregnancy Days 6 and 13).
Drug-induced embryo-fetal toxicities were seen mainly in
animals treated with 3 and 10
mg/kg of the drug and included increased early resorption
(≥99%), post-implantation loss
(≥99%), decreased numbers of live fetuses, and external
malformations (i.e., umbilical
hernias and malrotated hindlimbs). Systemic exposure in
animals at the brentuximab vedotin
dose of 3 mg/kg is approximately the same exposure in
patients with cHL or sALCL who received
the recommended dose of 1.8 mg/kg every three weeks.
Lactation
Risk Summary
There is no
information regarding the presence of brentuximab vedotin in human milk, the
effects on the breastfed child, or the effects on milk production. Because of
the potential for serious adverse reactions in a breastfed child from Adcetris,
including cytopenias and neurologic or gastrointestinal toxicities, advise
patients that breastfeeding is not recommended during Adcetris treatment.
Females and
Males of Reproductive Potential
Adcetris can
cause fetal harm based on the findings from animal studies and the drug’s
mechanism of action [see Use in Specific
Populations (8.1), Clinical
Pharmacology (12.1)].
Pregnancy
Testing
Verify the
pregnancy status of females of reproductive potential prior to initiating
Adcetris therapy.
Contraception
Females
Advise
females of reproductive potential to avoid pregnancy during Adcetris treatment
and for at least 6 months after the
final dose of Adcetris. Advise females to immediately
report pregnancy [see Use in Specific
Populations (8.1)].
Males
Adcetris
may damage spermatozoa and testicular tissue, resulting in possible genetic
abnormalities. Males with female
sexual partners of reproductive potential should use
effective contraception during
Adcetris treatment and for at least 6 months after the final
dose of Adcetris [see Nonclinical
Toxicology (13.1)].
Infertility
Males
Based
on findings in rats, male fertility may be compromised by treatment with
Adcetris
[see Nonclinical
Toxicology (13.1)].
Pediatric Use
Safety and
effectiveness of Adcetris have not been established in pediatric patients.
Geriatric Use
Clinical trials
of Adcetris in cHL (Studies 1 and 3: AETHERA) and sALCL (Study 2) did not
include sufficient numbers of patients aged 65 and over to determine whether
they respond differently from younger patients.
In the clinical
trial of Adcetris in pcALCL or CD30-expressingMF (Study 4: ALCANZA), 42% of
Adcetris-treated patients were aged 65 or older. No meaningful differences in
safety or efficacy were observed between these patients and younger patients.
Renal Impairment
Avoid the use of
Adcetris in patients with severe renal impairment (CrCL <30 mL/min) [See Warnings and
Precautions (5.6) and Clinical
Pharmacology (12.3)]. No dosage adjustment is required
for mild (CLcr >50–80 mL/min) or moderate (CrCL 30–50 mL/min) renal
impairment.
Hepatic
Impairment
Avoid the use of
Adcetris in patients with moderate (Child-Pugh B) or severe (Child-Pugh C)
hepatic impairment [See Warnings and
Precautions (5.7) and Clinical
Pharmacology (12.3)]. Dosage reduction is required in
patients with mild (Child-Pugh A) hepatic impairment [See Dosage and
Administration (2.1)].
Overdosage
There is no
known antidote for overdosage of Adcetris. In case of overdosage, the patient
should be closely monitored for adverse reactions, particularly neutropenia,
and supportive treatment should be administered.
Adcetris
Description
Adcetris
(brentuximab vedotin) is a CD30-directed antibody-drug conjugate (ADC)
consisting of three components: 1) the chimeric IgG1 antibody cAC10, specific
for human CD30, 2) the microtubule disrupting agent MMAE, and 3) a
protease-cleavable linker that covalently attaches MMAE to cAC10.
Brentuximab
vedotin has an approximate molecular weight of 153 kDa. Approximately
4 molecules of MMAE are attached to each antibody molecule. Brentuximab
vedotin is produced by chemical conjugation of the antibody and small molecule
components. The antibody is produced by mammalian (Chinese hamster ovary)
cells, and the small molecule components are produced by chemical synthesis.
Adcetris
(brentuximab vedotin) for Injection is supplied as a sterile, white to
off-white, preservative-free lyophilized cake or powder in single-dose vials.
Following reconstitution with 10.5 mL Sterile Water for Injection, USP, a
solution containing 5 mg/mL brentuximab vedotin is produced. The reconstituted
product contains 70 mg/mL trehalose dihydrate, 5.6 mg/mL sodium citrate
dihydrate, 0.21 mg/mL citric acid monohydrate, and 0.20 mg/mL polysorbate 80
and water for injection. The pH is approximately 6.6.
Adcetris -
Clinical Pharmacology
Mechanism of
Action
CD30 is a member
of the tumor necrosis factor receptor family. CD30 is expressed on the surface
of sALCL cells and on Hodgkin Reed-Sternberg (HRS) cells in cHL, and has
limited expression on healthy tissue and cells. In vitro data suggest that
signaling through CD30-CD30L binding may affect cell survival and proliferation.
Brentuximab
vedotin is an ADC. The antibody is a chimeric IgG1 directed against CD30. The
small molecule, MMAE, is a microtubule-disrupting agent. MMAE is covalently
attached to the antibody via a linker. Nonclinical data suggest that the anticancer
activity of Adcetris is due to the binding of the ADC to CD30-expressing cells,
followed by internalization of the ADC‑CD30 complex, and the release of MMAE
via proteolytic cleavage. Binding of MMAE to tubulin disrupts the microtubule
network within the cell, subsequently inducing cell cycle arrest and apoptotic
death of the cells. Additionally, in vitro data provide evidence for
antibody-dependent cellular phagocytosis (ADCP).
Pharmacodynamics
Cardiac
Electrophysiology
The effect of
brentuximab vedotin (1.8 mg/kg) on the QTc interval was evaluated in an
open-label, single-arm study in 46 evaluable patients with CD30-expressing
hematologic malignancies. Administration of brentuximab vedotin did not prolong
the mean QTc interval >10 ms from baseline. Small increases in the mean
QTc interval (<10 ms) cannot be excluded because this study did not include
a placebo arm and a positive control arm.
Pharmacokinetics
The
pharmacokinetics of brentuximab vedotin were evaluated in early development
trials, including dose-finding trials, and in a population pharmacokinetic
analysis of data from 314 patients. The pharmacokinetics of three analytes
were determined: the ADC, MMAE, and total antibody. Total antibody had the
greatest exposure and had a similar PK profile as the ADC. Hence, data on the
PK of the ADC and MMAE have been summarized.
Maximum
concentrations of ADC were typically observed close to the end of infusion.
Exposures were approximately dose proportional from 1.2 to 2.7 mg/kg.
Steady-state of the ADC was achieved within 21 days with every 3-week dosing of
Adcetris, consistent with the terminal half-life estimate. Minimal to no
accumulation of ADC was observed with multiple doses at the every 3-week
schedule.
The time to
maximum concentration for MMAE ranged from approximately 1 to 3 days. Similar
to the ADC, steady‑state of MMAE was achieved within 21 days with every 3 week
dosing of Adcetris. MMAE exposures decreased with continued administration of
Adcetris with approximately 50% to 80% of the exposure of the first dose being
observed at subsequent doses.
Distribution
In humans, the
mean steady state volume of distribution was approximately 6–10 L for ADC.
In vitro, the
binding of MMAE to human plasma proteins ranged from 68–82%. MMAE is not likely
to displace or to be displaced by highly protein-bound drugs. In vitro, MMAE was a
substrate of P-gp and was not a potent inhibitor of P-gp.
Elimination
MMAE appeared to
follow metabolite kinetics, with the elimination of MMAE appearing to be
limited by its rate of release from ADC.
In
pharmacokinetic analyses, a multiexponential decline in ADC serum
concentrations was observed with a terminal half-life of approximately 4 to 6
days.
Metabolism
In vivo data in animals and humans suggest that only a small fraction of MMAE
released
from brentuximab vedotin is
metabolized. 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 CYP3A4/5 but not other CYP isoforms. MMAE did
not induce any major CYP450 enzymes
in primary cultures of human hepatocytes.
Excretion
An excretion study was undertaken in
patients who received a dose of 1.8 mg/kg of
Adcetris. Approximately 24% of the
total MMAE administered as part of the ADC during
an Adcetris infusion was recovered in
both urine and feces over a 1-week period. Of the
recovered MMAE, approximately 72% was
recovered in the feces and the majority of the
excreted MMAE was unchanged.
Specific
Populations
Renal Impairment: The
pharmacokinetics and safety of brentuximab vedotin and MMAE
were evaluated after the
administration of 1.2 mg/kg of Adcetris to patients with mild
(CrCL >50–80 mL/min; n=4),
moderate (CrCL 30–50 mL/min; n=3) and severe (CrCL
<30 mL/min; n=3) renal
impairment. In patients with severe renal impairment, the rate of
≥Grade 3 adverse reactions was 3/3
(100%) compared to 3/8 (38%) in patients with normal
renal function. Additionally, the AUC
of MMAE (component of Adcetris) was
approximately 2-fold higher in
patients with severe renal impairment compared to patients
with normal renal function.
Hepatic Impairment: The
pharmacokinetics and safety of brentuximab vedotin and MMAE
were evaluated 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. In patients with moderate
and severe hepatic impairment, the rate of ≥Grade 3
adverse reactions was 6/6 (100%)
compared to 3/8 (38%) in patients with normal hepatic
function. Additionally, the AUC of
MMAE was approximately 2.2-fold higher in patients with
hepatic impairment compared to
patients with normal hepatic function.
Effects of
Gender, Age, and Race: Based on the population pharmacokinetic analysis,
gender, age, and race do not have a
meaningful effect on the pharmacokinetics of
brentuximab vedotin.
Drug Interaction
Studies
CYP3A4
Inhibitors/Inducers: In vitro data indicate that
monomethyl auristatin E (MMAE) is a
substrate of CYP3A4/5. MMAE is
primarily metabolized by CYP3A. Co-administration of
Adcetris with ketoconazole, a potent
CYP3A4 inhibitor, increased exposure to MMAE by
approximately 34%.
Co-administration
of Adcetris with rifampin, a potent CYP3A4 inducer, reduced exposure
to MMAE by approximately 46%.
P-gp Inhibitors: In vitro
data indicate that MMAE is a substrate of the efflux transporter
P‑glycoprotein (P-gp).
Co-administration of Adcetris with P-gp inhibitors may increase
exposure to MMAE.
Effects of
Adcetris on Other Drugs
Co-administration of Adcetris did not affect exposure to midazolam, a CYP3A4
substrate.
MMAE does not inhibit other CYP
enzymes at relevant clinical concentrations. Adcetris is
not expected to alter the exposure
to drugs that are metabolized by CYP3A4 enzymes.
Nonclinical
Toxicology
Carcinogenesis,
Mutagenesis, Impairment of Fertility
Carcinogenicity
studies with brentuximab vedotin or the small molecule (MMAE) have not been
conducted.
MMAE was
genotoxic in the rat bone marrow micronucleus study through an aneugenic
mechanism. This effect is consistent with the pharmacological effect of MMAE as
a microtubule-disrupting agent. MMAE was not mutagenic in the bacterial reverse
mutation assay (Ames test) or the L5178Y mouse lymphoma forward mutation assay.
Fertility
studies with brentuximab vedotin or MMAE have not been conducted. However,
results of repeat-dose toxicity studies in rats indicate the potential for
brentuximab vedotin to impair male reproductive function and fertility. In a
4-week repeat-dose toxicity study in rats with weekly dosing at 0.5, 5, or 10
mg/kg brentuximab vedotin, seminiferous tubule degeneration, Sertoli cell
vacuolation, reduced spermatogenesis, and aspermia were observed. Effects in
animals were seen mainly at 5 and 10 mg/kg of brentuximab vedotin. These doses
are approximately 3 and 6-fold the human recommended dose of 1.8 mg/kg,
respectively, based on body weight.
Clinical Studies
Classical
Hodgkin Lymphoma
Randomized
Placebo-controlled Clinical Trial in Classical Hodgkin Lymphoma Post-auto-HSCT
Consolidation (Study 3: AETHERA)
The efficacy of
Adcetris in patients with cHL at high risk of relapse or disease progression
post-auto-HSCT was studied in a randomized, double-blind, placebo-controlled
clinical trial. Three hundred twenty-nine (329) patients were randomized 1:1 to
receive placebo or Adcetris 1.8 mg/kg intravenously over 30 minutes every 3
weeks for up to 16 cycles, beginning 30–45 days post-auto-HSCT. Patients in the
placebo arm with progressive disease per investigator could receive Adcetris as
part of a separate trial. The primary endpoint was progression-free survival
(PFS) determined by independent review facility (IRF). Standard international
guidelines were followed for infection prophylaxis for HSV, VZV, and PJP
post-auto-HSCT [see Clinical Trial
Experience (6.1)].
High risk of
post-auto-HSCT relapse or progression was defined according to status following
frontline therapy: refractory, relapse within 12 months, or relapse ≥12 months
with extranodal disease. Patients were required to have obtained a complete
response (CR), partial response (PR), or stable disease (SD) to most recent
pre-auto-HSCT salvage therapy.
A total of 329
patients were enrolled and randomized (165 Adcetris, 164 placebo);
327 patients received study treatment. Patient demographics and baseline
characteristics were generally balanced between treatment arms. The 329
patients ranged in age from 18–76 years (median, 32 years) and most were male
(53%) and white (94%). Patients had received a median of 2 prior systemic
therapies (range, 2–8) excluding autologous hematopoietic stem cell
transplantation.
The efficacy
results are summarized in Table 8. PFS is calculated from randomization to date
of disease progression or death (due to any cause). The median PFS
follow-up time from randomization was 22 months (range, 0–49). Study 3
(AETHERA) demonstrated a statistically significant improvement in IRF-assessed
PFS and increase in median PFS in the Adcetris arm compared with the placebo
arm. At the time of the PFS analysis, an interim overall survival analysis
demonstrated no difference.
Table 8: Efficacy Results in Patients with Classical
Hodgkin Lymphoma Post-auto-HSCT Consolidation (Study 3: AETHERA)
|
|
+ Estimates are unreliable
|
|
*
Not estimable
|
|
|
|
Progression-free Survival
|
Adcetris
N = 165
|
Placebo
N = 164
|
|
|
Independent Review Facility
|
|
|
Number
of events (%)
|
60 (36)
|
75 (46)
|
|
|
Median
months (95% CI)
|
42.9+ (30.4, 42.9+)
|
24.1 (11.5, NE*)
|
|
|
Stratified Hazard Ratio (95% CI)
|
0.57 (0.40, 0.81)
|
|
|
Stratified Log-Rank Test p-value
|
P=0.001
|
|
Clinical Trial
in Relapsed Classical Hodgkin Lymphoma (Study 1)
The efficacy of
Adcetris in patients with cHL who relapsed after autologous hematopoietic stem
cell transplantation was evaluated in one open-label, single-arm, multicenter
trial. One hundred two (102) patients were treated with 1.8 mg/kg of Adcetris
intravenously over 30 minutes every 3 weeks. An independent review facility
(IRF) performed efficacy evaluations which included overall response rate (ORR
= complete remission [CR] + partial remission [PR]) and duration of response as
defined by clinical and radiographic measures including computed tomography
(CT) and positron-emission tomography (PET) as defined in the 2007 Revised
Response Criteria for Malignant Lymphoma (modified).
The 102 patients
ranged in age from 15–77 years (median, 31 years) and most were female (53%)
and white (87%). Patients had received a median of 5 prior therapies including
autologous hematopoietic stem cell transplantation.
The efficacy
results are summarized in Table 9. Duration of response is calculated from date
of first response to date of progression or data cutoff date.
Table 9: Efficacy Results in Patients with
Classical Hodgkin Lymphoma (Study 1)
|
|
+Follow up was ongoing at the time of data submission
|
|
*
Not estimable
|
|
|
N = 102
|
|
Percent (95% CI)
|
Duration of Response, in
months
|
|
Median (95% CI)
|
Range
|
|
CR
|
32 (23, 42)
|
20.5 (12.0, NE*)
|
1.4 to 21.9+
|
|
PR
|
40 (32, 49)
|
3.5 (2.2, 4.1)
|
1.3 to 18.7
|
|
ORR
|
73 (65, 83)
|
6.7 (4.0, 14.8)
|
1.3 to 21.9+
|
Systemic
Anaplastic Large Cell Lymphoma
Clinical Trial
in Relapsed sALCL (Study 2)
The efficacy of
Adcetris in patients with relapsed sALCL was evaluated in one open-label,
single-arm, multicenter trial. This trial included patients who had sALCL that
was relapsed after prior therapy. Fifty-eight (58) patients were treated with
1.8 mg/kg of Adcetris administered intravenously over 30 minutes every 3 weeks.
An IRF performed efficacy evaluations which included overall response rate (ORR
= complete remission [CR] + partial remission [PR]) and duration of response as
defined by clinical and radiographic measures including computed tomography
(CT) and positron-emission tomography (PET) as defined in the 2007 Revised
Response Criteria for Malignant Lymphoma (modified).
The 58 patients
ranged in age from 14–76 years (median, 52 years) and most were male (57%) and
white (83%). Patients had received a median of 2 prior therapies; 26% of
patients had received prior autologous hematopoietic stem cell transplantation.
Fifty percent (50%) of patients were relapsed and 50% of patients were
refractory to their most recent prior therapy. Seventy-two percent (72%) were
anaplastic lymphoma kinase (ALK)-negative.
The efficacy
results are summarized in Table 10. Duration of response is calculated from
date of first response to date of progression or data cutoff date.
Table 10: Efficacy Results in Patients with Systemic
Anaplastic Large Cell Lymphoma (Study 2)
|
|
|
|
N = 58
|
|
|
Percent
(95% CI)
|
Duration
of Response, in months
|
|
|
Median
(95% CI)
|
Range
|
|
|
+ Follow up was ongoing at the time of data submission
|
|
|
*
Not estimable
|
|
|
CR
|
57 (44, 70)
|
13.2 (10.8, NE*)
|
0.7 to 15.9+
|
|
|
PR
|
29 (18, 41)
|
2.1 (1.3, 5.7)
|
0.1 to 15.8+
|
|
|
ORR
|
86 (77, 95)
|
12.6 (5.7, NE*)
|
0.1 to 15.9+
|
|
Primary
Cutaneous Anaplastic Large Cell Lymphoma and CD30-expressing Mycosis Fungoides
Randomized
Clinical Trial in Primary Cutaneous Anaplastic Large Cell Lymphoma and
CD30-expressing Mycosis Fungoides (Study 4: ALCANZA)
The efficacy of
Adcetris in patients with primary cutaneous anaplastic large cell lymphoma
(pcALCL) or mycosis fungoides (MF) requiring systemic therapy was studied in
ALCANZA, a randomized, open-label, multicenter clinical trial. In ALCANZA, one
hundred thirty-one (131) patients were randomized 1:1 to receive Adcetris 1.8
mg/kg intravenously over 30 minutes every 3 weeks or physician’s choice of
methotrexate (5 to 50 mg orally weekly) or bexarotene (300 mg/m2 orally
daily). The randomization was stratified by baseline disease diagnosis (MF or
pcALCL). Patients could receive a maximum of 16 cycles (21-day cycle) of therapy
every 3 weeks for those receiving brentuximab vedotin or 48 weeks of therapy
for those in the control arm.
Patients with
pcALCL must have received prior radiation or systemic therapy, and must have at
least 1 biopsy with CD30-expression of ≥10%. Patients with MF must have
received prior systemic therapy and have had skin biopsies from at least 2
separate lesions, with CD30-expression of ≥10% in at least 1 biopsy.
A total of 131
patients were randomized (66 Adcetris, 65 physician’s choice). The efficacy
results were based on 128 patients (64 patients in each arm with
CD30-expression of ≥10% in at least one biopsy). Among 128 patients, the
patients’ age ranged from 22–83 years (median, 60 years) and 55% of them were
male and 85% of them were white. Patients had received a median of 4 prior
systemic therapies (range, 0–15), including a median of 1 prior skin-directed
therapy (range, 0–9) and 2 systemic therapies (range, 0–11). At study entry,
patients were diagnosed as Stage 1 (25%), Stage 2 (38%), Stage 3 (5%), or Stage
4 (13%).
Efficacy was
established based on the proportion of patients achieving an objective response
(CR +PR) that lasts at least 4 months (ORR4). ORR4 was determined by
independent review facility (IRF) using the global response score (GRS),
consisting of skin evaluations per modified severity-weighted assessment tool
(mSWAT), nodal and visceral radiographic assessment, and detection of
circulating Sézary cells (MF patients only). Additional efficacy outcome
measures included proportion of patients achieving a complete response (CR) per
IRF, and progression-free survival (PFS) per IRF.
The efficacy
results are summarized in Table 11 below and the Kaplan-Meier curves of
IRF-Assessed Progression-free Survival are shown in Figure 2.
Table 11: Efficacy
Results in Patients with Relapsed pcALCL or CD30-expressing MF (Study 4:
ALCANZA)
|
|
a physician’s choice of either methotrexate or bexarotene.
b ORR4 is defined as proportion of patients
achieving an objective response (CR +PR) that lasts at least 4 months
c CI=Confidence Interval ;
d test of the treatment difference was stratified
by baseline disease diagnosis (MF or pcALCL)
e adjusted for multiplicity
|
|
|
Adcetris
N = 64
|
Physician’s Choicea
N = 64
|
|
ORR4b
|
|
Percent (95% CIc)
|
56.3 (44.1, 68.4)
|
12.5 (4.4, 20.6)
|
|
P-valued
|
<0.001
|
|
ORR
|
67.2 (55.7, 78.7)
|
20.3 (10.5, 30.2)
|
|
CR
|
|
Percent (95% CIc)
|
15.6 (7.8, 26.9)
|
1.6 (0, 8.4)
|
|
P-valued,e
|
0.0066
|
|
PR
|
51.6 (39.3, 63.8)
|
18.8 (9.2, 28.3)
|
|
PFS
|
|
Number of events (%)
|
36 (56.3)
|
50 (78.1)
|
|
Median months (95% CIc)
|
16.7 (14.9, 22.8)
|
3.5 (2.4, 4.6)
|
|
Hazard Ratioc (95% CIc)
|
0.27 (0.17, 0.43)
|
|
Log-Rank Test p-valued,e
|
p<0.001
|
Supportive
trials include 2 single-arm trials which enrolled patients with MF and were
treated with Adcetris 1.8 mg/kg intravenously over 30 minutes every 3 weeks.
Out of 73 patients with MF from the 2 pooled supportive trials, 34% (25/73)
achieved ORR4. Among these 73 patients, 35 had 1% to 9% CD30-expression and 31%
(11/35) achieved ORR4.
REFERENCES
1. OSHA Hazardous
Drugs. OSHA. [Accessed on 30 July 2013, from
http://www.osha.gov/SLTC/hazardousdrugs/index.html]
How
Supplied/Storage and Handling
How Supplied
Adcetris
(brentuximab vedotin) for Injection is supplied as a sterile, white to
off-white preservative-free lyophilized cake or powder in individually-boxed
single-dose vials:
NDC
(51144-050-01), 50 mg brentuximab vedotin.
Storage
Store vial at
2–8°C (36–46°F) in the original carton to protect from light.
Special Handling
Adcetris is an
antineoplastic product. Follow special handling and disposal procedures1.
Patient
Counseling Information
Peripheral
Neuropathy
Advise patients that Adcetris can cause a peripheral neuropathy. They should be
advised to report to their health care provider any numbness or tingling of the
hands or feet or any muscle weakness [see Warnings and
Precautions (5.1)].
Fever/Neutropenia
Advise patients to contact their health care provider if a fever of 100.5°F or
greater or other evidence of potential infection such as chills, cough, or pain
on urination develops [see Warnings and
Precautions (5.3)].
Infusion Reactions
Advise patients to contact their health care provider if they experience signs
and symptoms of infusion reactions including fever, chills, rash, or breathing
problems within 24 hours of infusion [see Warnings and
Precautions (5.2)].
Hepatotoxicity
Advise patients to report symptoms that may indicate liver injury, including
fatigue, anorexia, right upper abdominal discomfort, dark urine, or
jaundice [see Warnings and
Precautions (5.8)].
Progressive Multifocal Leukoencephalopathy
Instruct patients receiving Adcetris to immediately report if they have any of
the following neurological, cognitive, or behavioral signs and symptoms or if
anyone close to them notices these signs and symptoms [see Boxed Warning, Warnings and
Precautions (5.9)]:
• changes in mood or usual behavior
• confusion, thinking problems, loss of
memory
• changes in vision, speech, or walking
• decreased strength or weakness on one
side of the body
Pulmonary Toxicity
Instruct patients to report symptoms that may indicate pulmonary toxicity,
including cough or shortness of breath [see Warnings and
Precautions (5.10)].
Acute Pancreatitis
Advise patients to contact their health care provider if they develop severe
abdominal pain [seeWarnings and
Precautions (5.12)].
Gastrointestinal Complications
Advise patients to contact their health care provider if they develop severe
abdominal pain, chills, fever, nausea, vomiting, or diarrhea [see Warnings and
Precautions (5.12)].
Females and Males of Reproductive Potential
Adcetris can cause fetal harm. Advise women receiving Adcetris to avoid
pregnancy during Adcetris treatment and for at least 6 months after the final
dose of Adcetris.
Advise males with female sexual partners of reproductive potential to use
effective contraception during Adcetris treatment and for at least 6 months
after the final dose of Adcetris [see Use
in Specific
Populations (8.3)].
Advise patients to report pregnancy immediately [see Warnings and
Precautions (5.13)].
Lactation
Advise patients to avoid breastfeeding while receiving Adcetris [see Use in Specific
Populations (8.2)].
Manufactured by:
Seattle Genetics, Inc.
Bothell, WA 98021
1-855-473-2436
U.S. License 1853
Adcetris, Seattle
Genetics and are US registered trademarks of Seattle Genetics, Inc.
© 2017 Seattle Genetics, Inc., Bothell, WA 98021. All rights
reserved.
PACKAGE LABEL
NDC 51144-050-01
Adcetris®
(brentuximab
vedotin)
FOR INJECTION
50 mg/vial
Single-use vial.
Discard unused
portion.
Reconstitution
and dilution required
For intravenous
use only
Rx Only
SeattleGenetics®
|
Adcetris
brentuximab vedotin injection, powder, lyophilized, for solution
|
|
Product Information
|
|
Product Type
|
HUMAN PRESCRIPTION DRUG LABEL
|
Item Code (Source)
|
NDC:51144-050
|
|
Route of Administration
|
INTRAVENOUS
|
DEA Schedule
|
|
|
|
Active Ingredient/Active Moiety
|
|
Ingredient Name
|
Basis of Strength
|
Strength
|
|
Brentuximab Vedotin (Brentuximab Vedotin)
|
Brentuximab Vedotin
|
50 mg in 10.5 mL
|
|
|
Inactive Ingredients
|
|
Ingredient Name
|
Strength
|
|
Trehalose Dihydrate
|
|
|
Trisodium Citrate
Dihydrate
|
|
|
Citric Acid Monohydrate
|
|
|
Polysorbate 80
|
|
|
|
Product Characteristics
|
|
Color
|
WHITE (off-white)
|
Score
|
|
|
Shape
|
|
Size
|
|
|
Flavor
|
|
Imprint Code
|
|
|
Contains
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package Description
|
|
|
1
|
NDC:51144-050-01
|
1 VIAL, SINGLE-DOSE in 1 BOX
|
|
|
1
|
|
10.5 mL in 1 VIAL, SINGLE-DOSE
|
|
|
|
|
|
Marketing Information
|
|
Marketing Category
|
Application Number or Monograph Citation
|
Marketing Start Date
|
Marketing End Date
|
|
BLA
|
BLA125388
|
08/25/2011
|
|
|
|
Labeler - Seattle Genetics, Inc. (028484371)
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
PIERRE FABRE MEDICAMENT PRODUCTION
|
|
504638276
|
analysis(51144-050), manufacture(51144-050)
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
BSP Pharmaceuticals Srl
|
|
857007830
|
analysis(51144-050), manufacture(51144-050)
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
Seattle Genetics, Inc.
|
|
028484371
|
analysis(51144-050)
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
Covance Laboratories
|
|
213137276
|
analysis(51144-050)
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
Baxter Oncology GmbH
|
|
344276063
|
manufacture(51144-050), analysis(51144-050)
|
Revised: 11/2017
Seattle
Genetics, Inc.
