Approved Drug Label (PDF)
5
Warnings and Precautions
5.1
Skin Reactions
Additions
and/or revisions underlined:
.
. .
Skin
reactions occurred in 61% (all grades) of the 167 patients treated with PADCEV
in combination with intravenous pembrolizumab for the treatment of MIBC in
clinical trials. The majority of the skin reactions that occurred with
combination therapy included rash and maculo-papular rash. Grade 3-4 skin
reactions occurred in 10% of patients (Grade 3: 9%, Grade 4: 1.2%), including
rash, maculo-papular rash, toxic skin eruption, dermatitis exfoliative
generalized, erythema, exfoliative rash, skin toxicity, toxic epidermal
necrolysis, and toxic erythema of chemotherapy. A fatal reaction of toxic
epidermal necrolysis occurred in one patient (0.6%). The median time to onset
of severe skin reactions was 0.6 months (range: 0.2 to 8.8 months). Skin
reactions led to discontinuation of PADCEV in 10% of patients [see Adverse Reactions (6.1)]. Of the patients who experienced a
skin reaction and had data regarding resolution (n=102), 83% had complete
resolution and 17% had residual skin reactions at their last evaluation. Of the
patients with residual skin reactions at last evaluation, 29% (5/17) had Grade greater
than or equal to 2 skin reactions.
Skin
reactions occurred in 70% (all grades) of the 564 patients treated with PADCEV
in combination with intravenous pembrolizumab for the treatment of
locally advanced or mUC in clinical trials. When PADCEV was given in
combination with intravenous pembrolizumab, the incidence of skin
reactions, including severe events, occurred at a higher rate compared to
PADCEV as a single agent. The majority of the skin reactions that occurred with
combination therapy included maculo-papular rash, macular rash, and papular
rash. Grade 3-4 skin reactions occurred in 17% of patients (Grade 3: 16%, Grade
4: 1%), including maculo-papular rash, bullous dermatitis, dermatitis,
exfoliative dermatitis, pemphigoid, rash, erythematous rash, macular rash, and
papular rash. A fatal reaction of bullous dermatitis occurred in one patient
(0.2%). The median time to onset of severe skin reactions was 1.7 months
(range: 0.1 to 17.2 months). Skin reactions led to discontinuation of PADCEV in
6% of patients [see Adverse Reactions (6.1)]. Of the patients who experienced a
skin reaction and had data regarding resolution (n=391), 59% had complete
resolution and 41% had residual skin reactions at their last evaluation. Of the
patients with residual skin reactions at last evaluation, 27% (43/159) had
Grade greater than or equal to 2 skin reactions.
.
. .
5.3
Pneumonitis/Interstitial Lung Disease (ILD)
Additions
and/or revisions underlined:
.
. .
When
PADCEV was given in combination with intravenous pembrolizumab for
the treatment of MIBC, 4.2% of the 167 patients treated with combination
therapy had pneumonitis/ILD of any grade. All events were Grade 1-2. The median
time to onset of any grade pneumonitis/ILD was 2.5 months (range: 1.9 to 9.7
months).
When
PADCEV was given in combination with intravenous pembrolizumab for the
treatment of locally advanced or mUC,
10% of the 564 patients treated with combination therapy had pneumonitis/ILD of
any grade and 4% had Grade 3-4. A fatal event of pneumonitis/ILD occurred in
two patients (0.4%). The incidence of pneumonitis/ILD, including severe events,
occurred at a higher rate when PADCEV was given in combination with intravenous
pembrolizumab compared to PADCEV as a single agent. The median time to onset of
any grade pneumonitis/ILD was 4 months (range: 0.3 to 26 months).
.
. .
5.4
Peripheral Neuropathy
Additions
and/or revisions underlined:
When
PADCEV was given in combination with intravenous pembrolizumab for
the treatment of MIBC, 39% of the 167 patients treated with combination
therapy had peripheral neuropathy of any grade, 12% had Grade 2 neuropathy, and
3% had Grade 3 neuropathy. The median time to onset of Grade greater than or
equal to 2 peripheral neuropathy was 4.7 months (range: 0.2 to 11 months) [see Adverse Reactions (6.1)]. Of the patients who experienced
neuropathy and had data regarding resolution (n=65), 32% had complete
resolution, and 68% of patients had residual neuropathy at last evaluation. Of
the patients with residual neuropathy at last evaluation, 27% (12/44) had Grade
greater than or equal to 2 neuropathy.
When
PADCEV was given in combination with intravenous pembrolizumab for the
treatment of locally advanced or mUC,
67% of the 564 patients treated with combination therapy had peripheral
neuropathy of any grade, 36% had Grade 2 neuropathy, and 7% had Grade 3
neuropathy. The incidence of peripheral neuropathy occurred at a higher rate when
PADCEV was given in combination with intravenous pembrolizumab compared
to PADCEV as a single agent. The median time to onset of Grade greater than or
equal to 2 peripheral neuropathy was 6 months (range: 0.3 to 25 months) [see Adverse Reactions (6.1)]. Of the patients who experienced
neuropathy and had data regarding resolution (n=373), 13% had complete
resolution, and 87% of patients had residual neuropathy at last evaluation. Of
the patients with residual neuropathy at last evaluation, 45% (146/326) had
Grade greater than or equal to 2 neuropathy.
.
. .
6
Adverse Reactions
6.1
Clinical Trials Experience
Extensive
changes; please refer to label for complete information.
8
Use in Specific Populations
8.5
Geriatric Use
Additions
and/or revisions underlined:
Of
the 167 patients treated with PADCEV in combination with intravenous
pembrolizumab for the treatment of MIBC, 37% (n=61) were 65-74 years and 46%
(n=77) were 75 years or older.
Of the 564 patients treated with PADCEV in combination with intravenous
pembrolizumab for the treatment of locally advanced or mUC, 44% (n=247)
were 65-74 years and 26% (n=144) were 75 years or older. Of the 720 patients
treated with PADCEV as a single agent in clinical trials, 39% (n=282) were
65-74 years and 24% (n=170) were 75 years or older. No overall differences in
effectiveness were observed between patients 65 years of age or older and
younger patients.
Patients
75 years of age or older treated with PADCEV in combination with intravenous
pembrolizumab for the treatment of MIBC experienced a higher incidence
of fatal adverse reactions than younger patients. The incidence of fatal
adverse reactions was 4% in patients younger than 75 and 12% in patients
75 years or older.
Patients
75 years of age or older treated with PADCEV in combination with intravenous
pembrolizumab for the treatment of locally advanced or mUC experienced a
higher incidence of fatal adverse reactions than younger patients. The
incidence of fatal adverse reactions was 4% in patients younger than 75
and 7% in patients 75 years or older.
Patients
75 years of age or older treated with PADCEV as a single agent experienced a
higher incidence of fatal adverse reactions than younger patients. The
incidence of fatal adverse reactions was 6% in patients younger than 75 years,
and 11% in patients 75 years or older.
No
significant difference was observed in the pharmacokinetics of PADCEV between
patients 65 years and older and younger patients [see Clinical Pharmacology (12.3)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT
INFORMATION
Additions
and/or revisions underlined:
If your healthcare
provider prescribes PADCEV in combination with the medicines
pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph, also
read the Medication Guide that comes with these medicines for additional
important information.
.
. .
What is PADCEV?
PADCEV
is a prescription medicine used to treat adults with bladder cancer and cancers
of the urinary tract (renal pelvis, ureter, or urethra).
- PADCEV
may be used with pembrolizumab or pembrolizumab and berahyaluronidase
alfa-pmph before and after the surgical removal of your bladder when:
- your
bladder cancer has spread into the muscle layer of the bladder (muscle invasive
bladder cancer [MIBC]) but not to other parts of the body, and
- you
are not able to receive chemotherapy that contains the medicine cisplatin.
- PADCEV
may be used with pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph
when your bladder or urinary tract cancer has spread or cannot be removed by surgery (locally
advanced or metastatic).
- PADCEV
may be used alone when your bladder or urinary tract cancer has spread or
cannot be removed by surgery (locally advanced or metastatic) if you:
- have
received PD-1 or PD-L1 immunotherapy medicine and chemotherapy that contains platinum, or
- are
not able to receive a chemotherapy that contains cisplatin and you have received 1 or more prior therapies.
It
is not known if PADCEV is safe and effective in children.
.
. .
How will I receive
PADCEV?
- PADCEV
will be given to you by intravenous (IV) infusion into your vein over 30
minutes.
- PADCEV
is given over periods of time called “cycles”.
- If
you receive PADCEV with pembrolizumab or pembrolizumab and berahyaluronidase
alfa-pmph:
- Each
cycle is 21 days.
- You
will receive PADCEV on days 1 and 8 of every cycle.
.
. .
What are the possible
side effects of PADCEV? PADCEV may cause serious side effects, including:
- See “What is the most important
information I should know about PADCEV?”
- High blood sugar (hyperglycemia). An increase in blood sugar is
common during treatment with PADCEV. Severe high blood sugar, a serious
condition called diabetic ketoacidosis (DKA), and death have happened in people
with and without diabetes, treated with PADCEV. Tell your healthcare provider
right away if you get any symptoms of high blood sugar, including:
.
. .
- Eye problems. Certain eye problems are common
during treatment with PADCEV. Tell your healthcare provider right away if you get
dry eyes, increased tearing, blurred vision, or any vision changes. You may use
artificial tear substitutes to help prevent or treat dry eyes.
.
. .
Your
healthcare provider may decrease your dose of PADCEV, or temporarily or
completely stop your treatment with PADCEV if you get severe side
effects.
Approved Drug Label (PDF)
6
Adverse Reactions
6.1 Clinical
Trials Experience
Additions and/or
revisions underlined:
Table 3. Adverse Reactions greater than or equal to 15%
(All Grades) in Patients Treated
with PADCEV in Combination with Pembrolizumab in EV-302
…
Clinically relevant adverse reactions
(<15%) include vomiting
(12%), pneumonitis/ILD (10%),
hypothyroidism (10%), blurred vision (6%), skin
hyperpigmentation (6%), infusion
site extravasation (2%), and myositis
(0.5%).
…
Table 5. Adverse Reactions greater than or equal to 20%
(All Grades) in Patients Treated
with PADCEV in Combination with Pembrolizumab in EV-103
…
Clinically relevant adverse reactions (<20%) include vomiting
(20%), pyrexia (18%),
hypothyroidism (11%), pneumonitis/ILD (10%),
skin hyperpigmentation (8%),
myasthenia gravis (2.5%),
myositis (3.3%), and infusion site
extravasation (0.8%).
…
Table 7. Adverse Reactions (greater than or equal to 15%)
in Patients Treated
with PADCEV in EV-301
…
Clinically
relevant adverse reactions (<15%) include vomiting (14%), increased
aspartate aminotransferase (12%), hyperglycemia (10%), increased alanine
aminotransferase (9%), skin
hyperpigmentation (8%), pneumonitis/ILD (3%) and infusion
site extravasation (0.7%).
…
Table 9. Adverse Reactions Reported in greater than or equal to 15% (All Grades) or greater
than or equal to 5% (Grade 3-4) of Patients
Treated with PADCEV in EV-201
Cohort 1
…
Clinically relevant
adverse reactions (<15%) include skin hyperpigmentation (14%), herpes zoster
(3%), pneumonitis/ILD (2%),
and infusion site extravasation (2%).
…
Table 11. Adverse Reactions greater than or equal to 15%
(All Grades) or greater
than or equal to 5% (Grades 3-4) in Patients
Treated with PADCEV in EV-201, Cohort 2
…
Clinically relevant
adverse reactions (<15%) include vomiting (13%), increased aspartate
aminotransferase (12%), increased lipase (11%), increased alanine
aminotransferase (10%), skin
hyperpigmentation (4%), pneumonitis/ILD (4%) and infusion site extravasation (1%).
…
8
Use in Specific Populations
8.6 Hepatic
Impairment
Additions and/or
revisions underlined:
Avoid
the use of PADCEV in patients with moderate or severe hepatic impairment (total
bilirubin >1.5 x ULN and any AST). PADCEV has only been studied in a limited
number of patients with moderate or severe hepatic impairment [see Clinical Pharmacology (12.3)]. In another ADC that contains
MMAE, the frequency of greater than or equal to Grade 3 adverse
reactions and deaths was
greater in patients with moderate (Child-Pugh B) or severe (Child-Pugh C)
hepatic impairment compared to patients with normal hepatic function.
Approved Drug Label (PDF)
5
Warnings and Precautions
5.1 Skin Reactions
Additions and/or
revisions underlined:
…
Skin reactions occurred in 56% (all grades)
of the 753 patients treated with PADCEV as a single agent in
clinical trials. Twenty-four percent (24%) of patients had
maculo-papular rash and 33% had pruritus. Grade 3-4 skin reactions occurred in 12%
of patients, including maculo-papular rash, erythematous rash, rash or drug
eruption, symmetrical drug-related intertriginous and flexural exanthema
(SDRIFE), bullous dermatitis, exfoliative dermatitis, and palmar-plantar
erythrodysesthesia. The median time to onset of severe skin reactions was 0.7
months (range: 0.1 to 6 months). Among patients experiencing a skin reaction
leading to dose interruption who then restarted PADCEV (n=59), 24% of patients
restarting at the same dose and 16% of patients restarting at a reduced dose
experienced recurrent severe skin reactions. Skin reactions led to
discontinuation of PADCEV in 2.6% of patients [see Adverse Reactions (6.1)].
When PADCEV was given in combination with
pembrolizumab, the incidence of skin reactions, including severe events,
occurred at a higher rate. Skin reactions occurred in 72% (all grades) of the
121 patients treated with PADCEV in combination with pembrolizumab in clinical
trials. The majority of the skin reactions that occurred with combination
therapy included maculo-papular rash, macular rash and papular rash. Grade 3-4
skin reactions occurred in 20% of patients (Grade 3: 19%, Grade 4: 0.8%),
including maculo-papular rash, bullous dermatitis, dermatitis, exfoliative
dermatitis, pemphigoid, rash, erythematous rash, macular rash, and papular
rash. A fatal reaction of bullous dermatitis occurred in one patient (0.8%).
The median time to onset of severe skin reactions was 2.6 months (range: 0.3 to
16 months). Skin reactions led to discontinuation of PADCEV in 6% of patients [see
Adverse Reactions (6.1)].
…
5.2 Hyperglycemia
![]()
Additions and/or revisions underlined:
…
In clinical trials of PADCEV as a single agent,
14% of the 753 patients treated with PADCEV developed hyperglycemia; 7%
of patients developed Grade 3-4 hyperglycemia. Fatal events of hyperglycemia
and diabetic ketoacidosis occurred in one patient each (0.1%).
…
5.3 Pneumonitis/Interstitial Lung Disease (ILD)
Additions and/or
revisions underlined:
Severe, life-threatening or fatal pneumonitis/ILD
occurred in patients treated with PADCEV.
![]()
In clinical trials of PADCEV as a single agent, 2.9% of the 753
patients treated with PADCEV had pneumonitis/ILD of any grade and 0.8%
had Grade 3-4. The median time to onset of pneumonitis/ILD was 2.7 months
(range: 0.6 to 6 months).
The incidence of pneumonitis/ILD, including severe
events occurred at a higher rate when PADCEV was given in combination with
pembrolizumab. When PADCEV was given in combination with pembrolizumab, 9% of
the 121 patients treated with combination therapy had pneumonitis/ILD of any
grade and 3.3% had Grade 3. A fatal event of pneumonitis occurred in one
patient (0.8%). The median time to onset of pneumonitis/ILD was 6 months
(range: 0.6 to 26 months).
Monitor patients for signs and symptoms indicative
of pneumonitis/ILD such as hypoxia, cough, dyspnea or interstitial
infiltrates on radiologic exams. Evaluate and exclude infectious, neoplastic
and other causes for such signs and symptoms through appropriate
investigations.
Withhold PADCEV for patients who develop Grade 2
pneumonitis/ILD and consider dose reduction. Permanently discontinue
PADCEV in all patients with Grade 3 or 4
pneumonitis/ILD [see Dosage and
Administration (2.2)].
5.4 Peripheral Neuropathy
![]()
Additions and/or revisions underlined:
Peripheral neuropathy occurred in 53% of the
753 patients treated with PADCEV as a single agent in clinical
trials including 40% with sensory neuropathy, 7% with muscular weakness
and 7% with motor neuropathy. Thirty percent of patients experienced Grade 2
reactions and 5% experienced Grade 3-4 reactions. Peripheral neuropathy
occurred in patients treated with PADCEV with or without preexisting peripheral
neuropathy. The median time to onset of Grade greater than or equal to 2
peripheral neuropathy was 4.9 months (range: 0.1 to 20 months).
Neuropathy led to treatment discontinuation in 7% of patients [see
Adverse Reactions (6.1)]. Of the patients who experienced neuropathy who had data regarding
resolution (N = 319) 14% had complete resolution, 46% had partial improvement,
and 40% had no improvement at the time of their last evaluation. Of the 86% of
patients with residual neuropathy at last evaluation, 51% had Grade 2 or
greater neuropathy
at the time of their last evaluation.
The incidence of peripheral neuropathy occurred at
a higher rate when PADCEV was given in combination with pembrolizumab. When
PADCEV was given in combination with pembrolizumab, 65% of the 121 patients
treated with combination therapy had peripheral neuropathy of any grade, 45%
had Grade 2 neuropathy, and 3.3% had Grade 3 neuropathy. The median time to
onset of Grade greater than or equal to 2 peripheral neuropathy was 6 months
(range: 0.3 to 25 months).
…
5.5 Ocular Disorders
Additions
and/or revisions underlined:
Ocular
disorders were reported in 40% of the 384 patients treated with PADCEV as a
single agent in clinical trials in which ophthalmologic exams were
scheduled. The majority of these events involved the cornea and included events
associated with dry eye such as keratitis, blurred vision, increased
lacrimation, conjunctivitis, limbal stem cell deficiency, and keratopathy.
…
5.6 Infusion Site Extravasation
![]()
Additions and/or
revisions underlined:
Skin
and soft tissue reactions secondary to extravasation have been observed after
administration of PADCEV. Of the 753 patients treated with PADCEV as
a single agent in clinical trials, 1.5% of patients experienced skin
and soft tissue reactions, including 0.3% who experienced Grade 3-4 reactions.
Reactions may be delayed. Erythema, swelling, increased temperature, and pain
worsened until 2-7 days after extravasation and resolved within 1-4 weeks of
peak. Two patients (0.3%) developed extravasation reactions with secondary
cellulitis, bullae, or exfoliation. Ensure adequate venous access prior to
starting PADCEV and monitor for possible extravasation during administration.
If extravasation occurs, stop the infusion and monitor for adverse reactions.
6
Adverse Reactions
Additions and/or
revisions underlined:
…
Pneumonitis/Interstitial Lung Disease (ILD) [see
Warnings and Precautions (5.3)]
…
6.1 Clinical
Trials Experience
Extensive additions and/or revisions, please refer
to label.
8
Use in Specific Populations
8.5 Geriatric Use
Additions
and/or revisions underlined
Of the 753
patients treated with PADCEV as a single agent in clinical trials, 40%
(n=300) were 65-74 years and 27% (n=202) were 75 years or older.
Of the 121 patients treated with PADCEV in combination with
pembrolizumab, 43% (n=52) were 65-74 years and 33% (n=40) were 75 years or
older. No overall differences in effectiveness were observed between patients
65 years of age or older and younger patients.
Patients
65 years of age or older treated with PADCEV as a single agent experienced a
higher incidence of serious and fatal adverse reactions than younger patients.
In clinical trials, the incidence of serious adverse reactions was 42% in
patients younger than 65 years, 45% in patients ages 65-74 years, and 49% in
patients 75 years or older. The incidence of fatal adverse reactions was 4.4%
in patients younger than 65 years, 6% in patients ages 65-74 years, and 11% in
patients 75 years or older. The incidence of treatment discontinuations of
PADCEV due to adverse reactions was 17% in patients younger than 65 years, 20%
in patients ages 65-74 years, and 26% in patients 75 years or older.
There
were an insufficient number of patients treated with PADCEV in combination with
pembrolizumab in clinical trials to accurately characterize safety by age.
No significant difference was observed in the
pharmacokinetics of PADCEV between patients 65 years and older and younger patients [see Clinical Pharmacology (12.3)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
Additions
and/or revisions underlined
…
Pneumonitis/Interstitial
Lung Disease
Advise
patients to immediately report new or worsening respiratory symptoms [see Warnings and Precautions (5.3)].
…
Approved Drug Label (PDF)
5
Warnings and Precautions
5.1 Skin Reactions
(Additions and/or revisions underlined)
Severe cutaneous adverse reactions, including fatal cases of
SJS or TEN occurred in patients treated with PADCEV. SJS and TEN occurred predominantly during the first cycle
of treatment but may
occur later.
Skin reactions occurred in 55% of the 680 patients treated with PADCEV in clinical trials.
Twenty-three percent (23%)
of patients had maculopapular
rash and 33% had
pruritus. Grade 3-4 skin reactions occurred in 13% of
patients, including
maculo-papular rash, rash erythematous, rash or drug eruption,
symmetrical drug- related intertriginous
and
flexural exanthema (SDRIFE), dermatitis bullous, dermatitis exfoliative, and palmar- plantar erythrodysesthesia. In
clinical trials, the median time to onset of severe skin reactions was 0.6
months (range: 0.1 to 6.4 months).
Among patients experiencing
a skin reaction leading to dose
interruption who then restarted PADCEV (n=59), 24% of patients
restarting at the same dose and 16% of
patients restarting at a reduced dose experienced recurrent
severe skin reactions. Skin reactions led to discontinuation of PADCEV in 2.6% of patients [see Adverse Reactions (6.1)].
Monitor patients closely throughout treatment for skin reactions. Consider topical corticosteroids and antihistamines, as clinically indicated.
Withhold PADCEV
and refer for specialized care for suspected
SJS, TEN or for severe (Grade 3)
skin reactions.
Permanently discontinue PADCEV
in patients with confirmed
SJS or TEN; or Grade 4 or recurrent Grade 3 skin reactions [see Dosage and Administration (2.2)].
5.2 Hyperglycemia
(Additions and/or revisions underlined)
Hyperglycemia and diabetic ketoacidosis (DKA), including fatal events, occurred in patients with and
without pre-existing diabetes mellitus, treated with
PADCEV.
Patients with baseline hemoglobin
A1C > or equal to 8% were excluded from
clinical trials. In clinical trials,
14% of the 680 patients treated
with PADCEV developed hyperglycemia; 7% of patients developed Grade 3-4 hyperglycemia.
The incidence of Grade
3-4 hyperglycemia increased
consistently in patients with higher
body mass index and in patients with higher baseline A1C.
Five percent (5%) of patients
required initiation of insulin therapy
for treatment of hyperglycemia.
The median time to onset
of hyperglycemia was 0.6 months (range: 0.1 to 20.3 months). Hyperglycemia led to discontinuation of PADCEV in 0.6% of patients. [see Adverse Reactions (6.1)].
Closely monitor blood glucose levels
in patients with, or at risk
for, diabetes mellitus or hyperglycemia. If blood glucose is elevated (>250 mg/dL), withhold PADCEV [see Dosage and Administration
(2.2)].
5.3 Pneumonitis
(Newly
added section)
Severe, life-threatening
or
fatal pneumonitis occurred in patients treated with PADCEV.
In clinical trials, 3.1% of the 680 patients
treated with PADCEV had pneumonitis of
any grade and 0.7% had Grade
3-4. In clinical
trials, the median time to onset of pneumonitis was 2.9 months (range:
0.6 to 6 months).
Monitor patients for signs and
symptoms indicative of pneumonitis such as hypoxia,
cough, dyspnea or interstitial
infiltrates on radiologic exams. Evaluate and exclude
infectious, neoplastic and other causes for
such signs and symptoms through appropriate investigations.
Withhold PADCEV
for patients who develop persistent
or recurrent Grade 2 pneumonitis and consider dose reduction.
Permanently discontinue PADCEV in all
patients with Grade 3 or 4
pneumonitis [see Dosage and Administration
(2.2)].
5.4 Peripheral Neuropathy
(Additions and/or revisions underlined)
Peripheral neuropathy occurred
in 52% of the 680 patients
treated with PADCEV in clinical trials
including 39% with sensory neuropathy,
7% with muscular weakness
and 6% with motor neuropathy;
4% experienced Grade 3-4
reactions. Peripheral neuropathy
occurred in patients treated with
PADCEV with or without
preexisting peripheral neuropathy. The median
time to onset of Grade > or equal to 2 peripheral neuropathy was 4.6 months (range:
0.1 to 15.8 months). Neuropathy led to treatment
discontinuation in 5% of patients. [see Adverse
Reactions (6.1)].
Monitor patients for symptoms of new or worsening peripheral neuropathy and
consider dose interruption or dose reduction of PADCEV when peripheral neuropathy occurs.
Permanently discontinue PADCEV
in patients who develop
Grade >3 peripheral neuropathy [see Dosage and Administration (2.2)].
5.5 Ocular Disorders
(Additions and/or revisions underlined)
Ocular disorders were reported in 40% of the 384
patients treated with
PADCEV in clinical trials in which ophthalmologic exams were scheduled. The majority of these events involved
the cornea and included events
associated with dry
eye such as keratitis, blurred vision, increased lacrimation,
conjunctivitis, limbal stem cell deficiency, and
keratopathy.
Dry eye
symptoms occurred in 34% of patients,
and blurred vision occurred in 13% of
patients, during treatment with PADCEV. The median time to onset to symptomatic ocular disorder was 1.6
months (range: 0 to
19.1 months). Monitor patients for ocular disorders. Consider
artificial tears for prophylaxis
of dry eyes and ophthalmologic
evaluation if ocular symptoms
occur or do not resolve.
Consider treatment with ophthalmic topical steroids, if indicated after an ophthalmic exam. Consider dose interruption
or dose reduction of PADCEV
for symptomatic ocular disorders.
5.6 Infusion Site Extravasation
(Additions and/or revisions underlined)
Skin and soft
tissue reactions secondary to extravasation have been
observed after administration
of PADCEV. Of the 680 patients, 1.6% of patients experienced skin and soft tissue reactions, including
0.3% who experienced Grade 3-4 reactions. Reactions may be delayed. Erythema, swelling, increased
temperature, and pain worsened
until 2-7 days after extravasation and resolved within 1-4 weeks
of peak. Two patients (0.3%) developed extravasation reactions with secondary
cellulitis, bullae, or exfoliation. Ensure adequate venous access
prior to starting PADCEV and
monitor for possible extravasation
during administration. If extravasation occurs, stop the infusion
and monitor for adverse reactions.
6
Adverse Reactions
(Newly
added information)
6.1 Clinical Trials Experience
(Extensive
changes; please refer to label)
6.3 Immunogenicity
(Additions and/or revisions underlined)
As with
all therapeutic proteins, there is
a 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
in the trials described below with the
incidence of antibodies
in other trials or other enfortumab vedotin-ejfv products may
be misleading.
Following administration of PADCEV
1.25 mg/kg; 16/590 (2.7%) patients
tested positive for anti-therapeutic antibody
(ATA) against enfortumab vedotin-ejfv at one
or more post-baseline time points. Due to the limited number of patients
with ATA against enfortumab vedotin-ejfv, no
conclusions can be drawn concerning a potential effect of
immunogenicity on efficacy,
safety or pharmacokinetics.
7
Drug Interactions
7.1 Effects of Other Drugs on PADCEV
(Additions and/or revisions underlined)
Dual P-gp and
Strong CYP3A4 Inhibitors
Concomitant use with dual P-gp
and strong CYP3A4 inhibitors may increase unconjugated
MMAE exposure
[see
Clinical Pharmacology (12.3)], which
may increase the incidence or severity of PADCEV toxicities. Closely monitor patients
for signs of toxicity when PADCEV is given concomitantly with dual P-gp and
strong CYP3A4 inhibitors.
8
Use in Specific Populations
8.5 Geriatric Use
(Additions and/or revisions underlined)
Of the
680 patients treated with PADCEV
in clinical trials, 440 (65%) were 65
years or older and
168 (25%) were 75 years
or
older. No overall differences in safety or effectiveness were observed between
these patients and
younger patients [see
Clinical Pharmacology (12.3)].
8.6 Hepatic Impairment
(Additions and/or revisions underlined)
Avoid the
use of PADCEV in patients with
moderate or severe hepatic impairment
(total bilirubin >1.5 x ULN and AST
any). PADCEV has
only been studied in a limited number of patients with moderate hepatic impairment (n=3) and has not been evaluated in patients with severe hepatic impairment [see
Clinical Pharmacology (12.3)]. In another
ADC that contains MMAE, the
frequency of > or equal to Grade 3 adverse
reactions and deaths was
greater in patients with moderate (Child-Pugh B) or
severe (Child-Pugh C) hepatic
impairment compared to patients with normal hepatic function. No adjustment in the starting dose is required when administering
PADCEV to patients with mild hepatic impairment (total bilirubin
1 to 1.5 × ULN and AST any,
or total bilirubin < or equal to ULN and AST >ULN).
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Patient Counseling Information
(Newly
added information)
Pneumonitis
Advise patients to immediately report new or worsening respiratory symptoms [see Warnings and Precautions (5.3)].
Patient Information
(Extensive
changes; please refer to label)
Approved Drug Label (PDF)
5
Warnings and Precautions
5.1 Skin Reactions
(Newly
added section)
Severe cutaneous
adverse reactions, including fatal cases of
Stevens-Johnson syndrome
(SJS) or toxic
epidermal necrolysis (TEN) occurred in patients
treated with PADCEV. SJS
and TEN occurred predominantly during the
first cycle of treatment
but may occur later.
Skin reactions occurred in 54% of the
310 patients treated with PADCEV
in clinical trials.
Twenty-six percent (26%) of patients
had maculopapular rash and 30% had
pruritus. Grade 3-4 skin reactions occurred in 10% of patients and included symmetrical drug-related intertriginous and flexural
exanthema (SDRIFE),
dermatitis bullous, dermatitis exfoliative, and palmar-plantar erythrodysesthesia. In study
EV-201, the median time to
onset of severe skin reactions
was 0.8
months (range: 0.2 to
5.3). Of the patients who
experienced rash, 65% had complete resolution and 22% had
partial improvement. [see
Adverse Reactions (6.2)].
Monitor
patients closely
throughout treatment for skin reactions.
Consider topical corticosteroids and antihistamines, as clinically indicated. Withhold
PADCEV and consider referral
for specialized care for severe (Grade
3) skin
reactions, suspected SJS or TEN.
Permanently discontinue PADCEV in patients
with confirmed SJS or TEN; or Grade 4 or recurrent
Grade 3 skin reactions
[see
Dosage and Administration (2.2)].
6
Adverse Reactions
(Additions and/or revisions underlined)
The following serious
adverse reactions are described
elsewhere in the labeling:
6.2 Post Marketing Experience
(Newly
added section)
The following
adverse reactions have been
identified during post-approval use of PADCEV.
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.
Skin and subcutaneous tissue disorders: Epidermal necrosis, Stevens-Johnson syndrome, toxic
epidermal necrolysis [see Warnings
and Precautions (5.1)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Patient Counseling Information
(Newly
added information)
Skin Reactions
Inform patients
that severe skin reactions
including SJS and
TEN with fatal outcomes
have occurred after administration of PADCEV, predominantly
during the first cycle of treatment but may occur later.
Advise patients to contact their healthcare provider immediately
if they develop new
target lesions, progressively worsening
skin reactions, severe
blistering or peeling
of the skin [see
Warnings and Precautions (5.1)].
Patient Information
(Additions and/or revisions underlined)
• Skin reactions. Severe skin reactions have happened
after treatment with PADCEV, in some cases severe skin
reactions have caused death. Most severe skin reactions
occurred during the first cycle (28 days) of treatment but
may happen later. Tell your healthcare provider right
away if you develop any of these signs of a new or worsening
skin reaction:
o target lesions (skin reactions that look like rings)
o rash or itching that continues to get worse
o blistering or peeling of the skin
o painful sores or ulcers in mouth or nose, throat, or
genital area
o fever or flu-like symptoms
o swollen lymph nodes
Peripheral neuropathy. You may develop nerve problems
called peripheral neuropathy during treatment with
PADCEV. Tell your healthcare provider right away if
you get new or worsening numbness or tingling in your hands or
feet or muscle weakness.
• Eye problems. You can develop certain eye problems during
treatment with PADCEV. Tell your healthcare provider
right away if you have dry eyes, or blurred vision. You
may use artificial tear substitutes to help prevent or treat dry
eyes.
• Leakage of PADCEV out of your vein into the tissues around
your infusion site (extravasation). If PADCEV
leaks from the injection site or the vein into the
nearby skin and tissues, it could cause an infusion site reaction. These
reactions can happen right after you receive an
infusion, but sometimes may happen days after your infusion. Tell
your healthcare provider or get medical help right
away if you notice any redness, swelling, itching, or discomfort at
the infusion site.
The most common side effects of PADCEV include:
• tiredness (fatigue)
Get Email Alerts |
Guide
