Approved Drug Label (PDF)
6
Adverse Reactions
6.1
Clinical Trials Experience
Additions
and/or revisions underlined:
.
. .
Newly
Diagnosed Multiple Myeloma Ineligible for Autologous Stem Cell Transplant
In Combination with Bortezomib, Lenalidomide
and Dexamethasone
The
safety of DARZALEX FASPRO in combination with bortezomib, lenalidomide and
dexamethasone compared to bortezomib, lenalidomide and dexamethasone (VRd) was
evaluated in CEPHEUS in patients with newly diagnosed multiple myeloma who were
ineligible for ASCT or refused ASCT as initial therapy [see Clinical Studies (14.1)]. Patients received DARZALEX FASPRO
1,800 mg/30,000 units administered subcutaneously once weekly from weeks 1 to
6, once every 3 weeks from weeks 7 to 24 and once every 4 weeks starting with
week 25 until disease progression or unacceptable toxicity in combination with
VRd (n=197) or VRd alone (n=195).
The
median duration of treatment was 56.3 months (0.1 to 64.6 months) for DARZALEX
FASPRO-VRd and 34.3 months (0.5 to 63.8 months) for VRd.
Serious
adverse reactions occurred in 72% of patients who received DARZALEX FASPRO-VRd.
The most frequent serious adverse reactions in >5% of patients who received
DARZALEX FASPRO-VRd were pneumonia (19%), COVID-19 (12%), thromboembolism (7%),
and diarrhea (6%). Fatal adverse reactions occurred in 16.8% of patients who
received DARZALEX FASPRO- VRd. Fatal adverse reactions that occurred in more
than 1 patient included pneumonia (4%), COVID-19 (4%), and myocardial
infarction (2%).
Permanent
treatment discontinuation due to an adverse reaction occurred in 8% of patients
who received DARZALEX FASPRO-VRd. An adverse reaction which resulted in
permanent discontinuation of DARZALEX FASPRO-VRd in more than 1 patient
included pneumonia.
The
most common adverse reactions (greater than or equal to 20%) were upper
respiratory tract infection, sensory neuropathy, musculoskeletal pain,
diarrhea, fatigue, edema, rash, motor dysfunction, COVID-19, constipation,
sleep disorder, cough, pneumonia, renal impairment, dizziness, nausea, urinary
tract infection, pyrexia, abdominal pain, dyspnea, decreased appetite, and
bruising.
Table
11 summarized the adverse reactions in patients who received DARZALEX FASPRO in
CEPHEUS.
Table 11: Adverse Reactions
Reported in greater than or equal to 20% of Patients Who Received DARZALEX
FASPRO-VRd in CEPHEUS
Newly
added table; please refer to label for complete information.
Clinically
relevant adverse reactions in <20% of patients who received DARZALEX FASPRO with
bortezomib, lenalidomide and dexamethasone include:
- Infections: bronchitis, sepsis, herpes zoster,
hepatitis B reactivation
- Gastrointestinal disorders: vomiting, pancreatitis
- Metabolism and nutrition disorders:
hyperglycemia
- Vascular disorders: hypertension, hypotension,
thromboembolism, hemorrhage
- Nervous system disorders: headache, syncope
- General disorders and
administration site conditions: chills, infusion reactions, injection site reactions
- Cardiac disorders: atrial fibrillation
- Skin
and subcutaneous tissue disorders: pruritus
Table
12 summarizes the laboratory abnormalities in patients who received DARZALEX
FASPRO in CEPHEUS.
Table 12: Select Laboratory
Abnormalities (greater than or equal to 30%) That Worsened from Baseline in Patients
Who Received DARZALEX FASPRO-VRd in CEPHEUS
Newly
added table; please refer to label for complete information.
.
. .
8
Use in Specific Populations
8.1
Pregnancy
Additions
and/or revisions underlined:
.
. .
Data
Animal Data
DARZALEX FASPRO
for subcutaneous injection contains daratumumab and hyaluronidase. Mice that were genetically modified to
eliminate all CD38 expression (CD38 knockout mice) had reduced bone density at
birth that recovered by 5 months of age. Data from studies using CD38 knockout
animal models also suggest the involvement of CD38 in the regulation of humoral
immune responses (mice), feto-maternal immune tolerance (mice), and early
embryonic development (frogs).
No
systemic exposure of hyaluronidase was detected in monkeys given 220,000
U/kg subcutaneously (440 times higher than the human dose) and there
were no effects on embryo-fetal development in pregnant mice given 360,000
U/kg hyaluronidase subcutaneously daily during organogenesis, which is 720
times higher than the human dose.
There were
no effects on pre- and post-natal development through sexual maturity in
offspring of mice treated daily from implantation through lactation with 1,100,000
U/kg hyaluronidase subcutaneously, which is 2,200 times higher than the
human doses.
8.2
Lactation
Additions
and/or revisions underlined:
.
. .
Data
Animal Data
No
systemic exposure of hyaluronidase was detected in monkeys given 220,000
U/kg subcutaneously (440 times higher than the human dose) and there
were no effects on post-natal development through sexual maturity in offspring
of mice treated daily during lactation with 1,100,000 U/kg hyaluronidase
subcutaneously, which is 2,200 times higher than the human doses.
8.5
Geriatric Use
Additions
and/or revisions underlined:
.
. .
Of
the 197 patients with newly diagnosed multiple myeloma in CEPHEUS who received
DARZALEX FASPRO as combination therapy with bortezomib, lenalidomide and
dexamethasone, 61% were 65 to <75 years of age, and 21% were 75 years of age
and older. The clinical trial did not enroll patients over age 80 [see Clinical Studies (14.1)]. No
overall differences in effectiveness of DARZALEX FASPRO in combination with
bortezomib, lenalidomide and dexamethasone were observed between younger
patients and patients greater than or equal to 75 years. Adverse reactions
occurring at a higher frequency (greater than or equal to 5% difference) in
patients greater than or equal to 75 years of age included sensory neuropathy,
diarrhea, fatigue, constipation, renal impairment, dizziness, pyrexia, rash,
dyspnea, fracture, arrhythmia, decreased appetite, urinary tract infection,
injection site reaction, encephalopathy, vomiting, taste disorder, and herpes.
Serious adverse reactions occurring at a higher frequency (greater than or
equal to 5% difference) in patients greater than or equal to 75 years of age
included urinary tract infection, upper respiratory tract infection, diarrhea,
and encephalopathy.
.
. .
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT
INFORMATION
Additions
and/or revisions underlined:
.
. .
What is DARZALEX FASPRO?
DARZALEX
FASPRO is a prescription medicine used:
- to
treat adults with multiple myeloma:
- in
combination with the medicines bortezomib, lenalidomide, and dexamethasone in
newly diagnosed people who are eligible to receive a type of stem cell
transplant that uses their own stem cells (autologous stem cell transplant).
- in
combination with the medicines bortezomib, lenalidomide, and dexamethasone in
newly diagnosed people who cannot receive a type of stem cell transplant that
uses their own stem cells (autologous stem cell transplant).
.
. .
The most common side effects of
DARZALEX FASPRO when used in combination therapy include:
. . .
- kidney
problems
- movement
and balance problems,
muscle spasms, weakness, and tremors
- decreased
appetite
- urinary
tract infection
- stomach
pain
- cold-like
symptoms (upper respiratory tract infection)
- nerve
problems, including increased or decreased sensitivity to touch, temperature,
or pain; loss of smell; and numbness, tingling, or burning sensations
- feeling
dizzy
- bruising
- COVID-19
Approved Drug Label (PDF)
5
Warnings and Precautions
5.1 Hypersensitivity
and Other Administration Reactions
Additions and/or revisions underlined:
Both systemic administration-related reactions, including severe or life-threatening reactions, and local injection-site reactions can occur with DARZALEX
FASPRO. Fatal reactions have been reported with daratumumab-containing
products, including DARZALEX FASPRO [see
Adverse Reactions (6.2)].
Systemic Reactions
In a pooled
safety population of 1446 patients
with multiple myeloma (N=1253) or light chain (AL) amyloidosis (N=193)
who received DARZALEX FASPRO as monotherapy or as part of a combination therapy, 7% of patients experienced a
systemic administration-related reaction (Grade 2: 3%, Grade 3:
0.8%, Grade 4: 0.1%). In patients with high-risk smoldering multiple myeloma
(N=193), systemic administration-related reactions occurred in 17% of patients
in AQUILA (Grade 2: 7%, Grade 3: 1%).
In all patients (N=1639),
systemic administration-related reactions occurred in 7% of patients
with the first injection, 0.5% with the second injection, and cumulatively 1% with subsequent injections.
The median time to onset was 3.2
hours (range: 4 minutes
to 3.5 days). Of the 283 systemic administration-related reactions that
occurred in 135 patients, 240 (85%) occurred on the day of DARZALEX
FASPRO administration. Delayed systemic administration-related reactions have
occurred in 1% of the patients.
Severe
reactions include hypoxia, dyspnea, hypertension, and tachycardia, and ocular
adverse reactions, including choroidal effusion, acute myopia, and acute angle
closure glaucoma. Other signs and symptoms of systemic administration-related
reactions may include respiratory symptoms, such as bronchospasm, nasal
congestion, cough, throat irritation, allergic rhinitis, and wheezing, as well as anaphylactic reaction, pyrexia, chest pain,
pruritus, chills, vomiting, nausea, hypotension, and blurred vision.
Pre-medicate
patients with histamine-1 receptor antagonist, acetaminophen and
corticosteroids [see Dosage and
Administration (2.6)]. Monitor patients for systemic administration-related
reactions, especially following the first and second injections. For
anaphylactic reaction or life- threatening (Grade
4) administration-related reactions,
immediately and permanently
discontinue DARZALEX FASPRO. Consider administering corticosteroids and other
medications after the administration of DARZALEX FASPRO depending on dosing
regimen and medical history to minimize the risk of delayed (defined as
occurring the day after administration) systemic administration-related
reactions [see Dosage and Administration
(2.6)].
Ocular adverse
reactions, including acute myopia and narrowing of the anterior
chamber angle due to ciliochoroidal effusions with
potential for increased intraocular pressure or glaucoma, have occurred with
daratumumab-containing products. If ocular symptoms occur, interrupt DARZALEX
FASPRO and seek immediate ophthalmologic evaluation prior to restarting
DARZALEX FASPRO.
Local
Reactions
In this pooled
safety population of 1446 patients
with multiple myeloma (N=1253) or light chain (AL) amyloidosis (N=193), injection-site reactions occurred in 8% of patients, including
Grade 2 reactions in 1.1%.
The most frequent (>1%) injection-site reactions were injection site
erythema and injection site rash. In patients with high-risk smoldering multiple myeloma (N=193),
injection- site reactions occurred
in 28% of patients, including Grade 2 reactions
in 3%. These local reactions occurred a median of 6 minutes (range: 0 minutes to 6.5 days)
after starting administration of DARZALEX FASPRO. Monitor for local reactions
and consider symptomatic management.
5.3 Infections
Newly added
subsection:
DARZALEX FASPRO can cause serious, life-threatening, or
fatal infections. In patients who received DARZALEX FASPRO in a pooled safety population including
patients with smoldering multiple myeloma and light
chain (AL) amyloidosis (N=1639), serious infections, including opportunistic infections, occurred in 24% of patients,
Grade 3 or 4 infections occurred in 22%, and
fatal infections occurred in 2.5%. The most common type of serious infection
reported was pneumonia (8.5%).
Monitor patients
for signs and symptoms of infection prior to and during treatment with DARZALEX FASPRO
and treat appropriately. Administer prophylactic antimicrobials according to guidelines [see
Dosage and Administration (2.6)].
6
Adverse Reactions
Addition of the
following to the bulleted line listing:
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 291 patients
who received DARZALEX FASPRO as monotherapy for relapsed and refractory multiple
myeloma, 37% were 65 to <75 years of age, and 19% were 75 years of age and older. No overall differences
in effectiveness of DARZALEX FASPRO have been observed between patients
greater than or equal to 65 years of age and younger patients. Adverse reactions that occurred at a higher frequency (greater than or equal to 5% difference) in patients ?65 years of age included
upper respiratory tract infection,
urinary tract infection, dizziness, cough,
dyspnea, diarrhea, nausea,
fatigue, and peripheral edema. Serious adverse reactions that occurred at a higher
frequency (greater than or
equal to 2% difference) in patients greater than or equal to 65 years of age included
pneumonia.
Of the 214 patients who received DARZALEX FASPRO as
combination therapy with pomalidomide and dexamethasone or DARZALEX FASPRO as
combination therapy with lenalidomide and low-dose dexamethasone for relapsed
and refractory multiple myeloma, 43% were 65 to <75 years of age, and 18% were 75
years of age and older. No overall differences in effectiveness
were observed between patients greater than or equal to 65 years (n=131) and
<65 years (n=85). Adverse reactions occurring at a higher frequency (greater
than or equal to 5% difference) in patients greater than or equal to 65 years of age included fatigue, pyrexia,
peripheral edema, urinary tract infection, diarrhea, constipation, vomiting,
dyspnea, cough, and hyperglycemia. Serious adverse reactions occurring at a
higher frequency (greater than or equal to 2% difference) in patients greater
than or equal to 65 years of age
included neutropenia, thrombocytopenia, diarrhea, anemia, COVID-19,
ischemic colitis, deep vein thrombosis, general physical health deterioration,
pulmonary embolism, and urinary tract infection.
…
Of the 193 patients
who received DARZALEX
FASPRO as monotherapy for high-risk smoldering multiple myeloma,
35% (n=67) were 65 to <75 years of age, and 11% (n=21) were 75 years of age and older. No overall difference in
effectiveness were observed between patients 65 to 75 years (n=67) and <65 years
(n=105); there were too few patients 75 years of age and older to assess for a difference in effectiveness.
Adverse reactions that occurred at a higher frequency (greater than or equal to
5% difference) in patients greater than or equal to 65 years of age were
pneumonia, dizziness, arrhythmia, hemorrhage, arthritis, and cataract. Serious
adverse reactions occurring at a higher
frequency (greater than or
equal to 5% difference) in patients greater
than or equal to 65 years of age included pneumonia and fracture.
Of the 193 patients
who received DARZALEX
FASPRO as part of a combination therapy
for light chain (AL) amyloidosis,
35% were 65 to <75 years of age, and
10% were 75 years of age and older. Clinical
studies of DARZALEX
FASPRO as part of a combination therapy
for patients with light chain (AL) amyloidosis did not
include sufficient numbers of patients aged 65 and older to determine whether
effectiveness differs from that of younger patients. Adverse reactions that
occurred at a higher frequency in patients greater than or equal to 65 years of
age were peripheral edema, asthenia, pneumonia and hypotension.
No clinically
meaningful differences in the pharmacokinetics of daratumumab were observed in
geriatric patients compared to younger adult 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:
…
Infections
Inform
patients about the risk of developing infections during DARZALEX FASPRO
treatment, and to report immediately any fever or symptoms of infection to
their healthcare provider [see Warnings
and Precautions (5.3)].
…
PATIENT INFORMATION
Additions and/or
revisions underlined:
…
What is DARZALEX FASPRO?
DARZALEX FASPRO is a prescription medicine used:
…
- alone
to treat adults
with high-risk smoldering multiple myeloma (an early form of multiple
myeloma that has a higher chance of progressing to active
multiple myeloma).
…
The most common side effects of DARZALEX FASPRO
when used alone include:
cold-like symptoms (upper respiratory tract infection)
muscle, bone, and joint
pain
tiredness
diarrhea
rash
trouble sleeping, including sleep apnea and restless legs
nerve problems, including increased or
decreased sensitivity to touch,
temperature, or pain;
loss of smell;
and numbness, tingling, or burning sensations
…
The most common severe
abnormal blood test results with DARZALEX FASPRO
include decreased white
blood cells, platelets, and red blood cells.
…
Approved Drug Label (PDF)
5
Warnings and Precautions
5.1 Hypersensitivity and Other Administration Reactions
Additions and/or
revisions underlined:
![]()
…
Systemic Reactions
In a pooled safety population of 1249 patients
with multiple myeloma (N=1056) or light chain (AL) amyloidosis (N=193)
who received DARZALEX FASPRO as monotherapy or as part of a combination
therapy, 7% of patients experienced a systemic administration-related reaction
(Grade 2: 3.2%, Grade 3: 0.7%, Grade 4: 0.1%). Systemic administration-related
reactions occurred in 7% of patients with the first injection, 0.2%
with the second injection, and cumulatively 1% with subsequent injections. The
median time to onset was 2.9 hours (range: 5 minutes to 3.5
days). Of the 165 systemic administration-related reactions that
occurred in 93 patients, 144 (87%) occurred on the day of
DARZALEX FASPRO administration. Delayed systemic administration-related
reactions have occurred in 1% of the patients.
![]()
…
Local Reactions
In this pooled safety population, injection-site
reactions occurred in 7% of patients, including Grade 2 reactions in 0.8%.
The most frequent (>1%) injection-site reaction was injection site erythema.
These local reactions occurred a median of 5 minutes (range: 0 minutes to 6.5
days) after starting administration of DARZALEX FASPRO. Monitor for local
reactions and consider symptomatic management.
6
Adverse Reactions
6.1 Clinical Trials Experience
Additions and/or revisions underlined:
…
Newly Diagnosed Multiple Myeloma Eligible for
Autologous Stem Cell Transplant
In Combination with Bortezomib, Lenalidomide and Dexamethasone
The safety of DARZALEX FASPRO in combination with
bortezomib, lenalidomide and dexamethasone (n=351) from the start of induction
to the end of consolidation compared to bortezomib, lenalidomide and
dexamethasone (VRd) (n=347) was evaluated in PERSEUS [see Clinical Studies (14.1)]. Patients received DARZALEX FASPRO
1,800 mg/30,000 units administered subcutaneously once weekly from weeks 1 to 8
and once every 2 weeks from weeks 9 to 16 during induction in combination with
VRd or VRd alone. After week 16, patients underwent stem cell mobilization,
high dose chemotherapy, and ASCT. Within 12 weeks of ASCT, and when engraftment
was complete, patients received DARZALEX FASPRO once every 2 weeks from weeks 1
to 8 during consolidation in combination with VRd or VRd alone.
The median duration of treatment for induction and
consolidation was 9.9 months (0.5 to 18.5 months) for DARZALEX FASPRO-VRd.
Serious adverse reactions occurred in 37% of
patients who received DARZALEX FASPRO-VRd. The most frequent serious adverse
reaction in >5% of patients who received DARZALEX
FASPRO-VRd was pneumonia (6%). Fatal adverse
reactions occurred in 1.7% of patients who received DARZALEX FASPRO-VRd.
Permanent treatment discontinuation due to an
adverse reaction occurred in 2% of patients who received DARZALEX FASPRO-VRd.
An adverse reaction which resulted in permanent discontinuation of DARZALEX FASPRO-VRd
in more than 1 patient included sepsis.
The most common adverse reactions (greater than or
equal to 20%) were peripheral neuropathy, fatigue, edema, pyrexia, upper
respiratory infection, constipation, diarrhea, musculoskeletal pain, insomnia,
and rash.
Table 7 summarizes the adverse reactions in patients
who received DARZALEX FASPRO in PERSEUS.
Please refer to label to view table 7.
Clinically relevant adverse reactions in <10% of
patients who received DARZALEX FASPRO with bortezomib, lenalidomide and
dexamethasone include:
Gastrointestinal disorders: vomiting, hemorrhoids
Musculoskeletal and connective tissue disorders: arthralgia
Infections: bronchitis, sepsis, urinary tract infection, herpes zoster, Covid-19,
cytomegalovirus infection
Respiratory, thoracic, and mediastinal disorders: dyspnea, pulmonary edema
Metabolism and nutrition disorders: hypocalcemia, decreased appetite, hyperglycemia, dehydration
Vascular disorders: hypotension, hypertension, orthostatic hypotension
General disorders and administration site conditions: infusion reactions, injection site reaction, chills
Nervous system disorders: dizziness, headache, syncope
Cardiac disorders: thrombosis, atrial fibrillation, tachycardia
Skin and subcutaneous tissue disorders: pruritus
8
Use in Specific Populations
8.5 Geriatric Use
Additions
and/or revisions underlined:
…
Of
the 355 patients who were newly diagnosed with multiple myeloma and eligible
for ASCT who received DARZALEX FASPRO as combination therapy with bortezomib,
lenalidomide and dexamethasone during induction and consolidation in the
clinical trial, 74% were <65 years of age, and 26% were 65 to 70 years of
age. The clinical trial did not enroll patients older than 70 years of age [see Clinical Studies (14.1)]. No
overall differences in effectiveness of DARZALEX.
FASPRO
in combination with bortezomib, lenalidomide and dexamethasone were observed
between patients <65 years of age compared to patients 65 to 70 years of
age. Adverse reactions that occurred at a higher frequency (greater than or
equal to 5% difference) in patients 65 to 70 years of age included
constipation, hemorrhoids, nausea, injection site erythema, bronchitis,
nasopharyngitis, back pain, myalgia, pain in extremity, dysgeusia, peripheral
motor neuropathy, and insomnia. Serious adverse reactions that occurred at a
higher frequency (greater than or equal to 2% difference) in patients 65 to 70
years of age included febrile bone marrow aplasia, atrial fibrillation,
pyrexia, and orthostatic hypotension.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT INFORMATION
Additions
and/or revisions underlined:
…
What is DARZALEX
FASPRO?
DARZALEX
FASPRO is a prescription medicine used to treat adult patients with multiple
myeloma:
in combination with the medicines bortezomib,
lenalidomide, and dexamethasone in newly diagnosed people who are eligible to
receive a type of stem cell transplant that uses their own stem cells
(autologous stem cell transplant).
…
The most common
side effects of DARZALEX FASPRO when used in combination therapy include:
…
…
Approved Drug Label (PDF)
5
Warnings and Precautions
5.1 Hypersensitivity and Other Administration Reactions
Additions underlined
…
Severe reactions include hypoxia, dyspnea,
hypertension, and tachycardia, and ocular adverse reactions, including
choroidal effusion, acute myopia, and acute angle closure glaucoma. Other
signs and symptoms of systemic administration-related reactions may include
respiratory symptoms, such as bronchospasm, nasal congestion, cough, throat
irritation, allergic rhinitis, and wheezing, as well as anaphylactic reaction,
pyrexia, chest pain, pruritus, chills, vomiting, nausea, hypotension, and
blurred vision.
![]()
…
Ocular adverse reactions, including acute myopia and
narrowing of the anterior chamber angle due to ciliochoroidal effusions with
potential for increased intraocular pressure or glaucoma, have occurred with
daratumumab-containing products. If ocular symptoms occur, interrupt DARZALEX
FASPRO and seek immediate ophthalmologic evaluation prior to restarting
DARZALEX FASPRO.
…
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
Additions
underlined
…
Hypersensitivity
and Other Administration Reactions
Advise
patients to seek immediate medical attention for any of the following signs and
symptoms of systemic administration-related reactions: itchy, runny or blocked
nose; chills, nausea, throat irritation, cough, headache, shortness of breath
or difficulty breathing, and blurred vision [see Warnings and Precautions (5.1)].
…
PATIENT INFORMATION
Additions
underlined
…
What are the
possible side effects of DARZALEX FASPRO?
DARZALEX FASPRO
may cause serious reactions, including:
…
…
Approved Drug Label (PDF)
5
Warnings and Precautions
5.1 Hypersensitivity and Other Administration Reactions
Additions and/or
revisions underlined:
Both systemic administration-related reactions,
including severe or life-threatening reactions, and local injection-site
reactions can occur with DARZALEX FASPRO. Fatal reactions have been reported
with daratumumab-containing products, including DARZALEX FASPRO [see Adverse Reactions (6.3)].
Systemic Reactions
In a pooled safety population of 898 patients
with multiple myeloma (N=705) or light chain (AL) amyloidosis (N=193)
who received DARZALEX FASPRO as monotherapy or as part of a combination
therapy, 9% of patients experienced a systemic administration-related reaction
(Grade 2: 3.2%, Grade 3: 1%). Systemic administration-related
reactions occurred in 8% of patients with the first injection, 0.3% with
the second injection, and cumulatively 1% with subsequent injections. The
median time to onset was 3.2 hours (range: 4 minutes to 3.5 days). Of
the 140 systemic administration-related reactions that occurred in 77
patients, 121 (86%) occurred on the day of DARZALEX FASPRO
administration. Delayed systemic administration- related reactions have
occurred in 1% of the patients.
Severe reactions included hypoxia, dyspnea,
hypertension and tachycardia. Other signs and symptoms of systemic
administration-related reactions may include respiratory symptoms, such as
bronchospasm, nasal congestion, cough, throat irritation, allergic rhinitis,
and wheezing, as well as anaphylactic reaction, pyrexia, chest pain, pruritus,
chills, vomiting, nausea, and hypotension.
Pre-medicate patients with histamine-1 receptor
antagonist, acetaminophen and corticosteroids [see Dosage and Administration (2.5)]. Monitor patients for
systemic administration-related reactions, especially following the first and
second injections. For anaphylactic reaction or life- threatening (Grade 4)
administration-related reactions, immediately and permanently discontinue DARZALEX
FASPRO. Consider administering corticosteroids and other medications after the administration
of DARZALEX FASPRO depending on dosing regimen and medical history to minimize
the risk of delayed (defined as occurring the day after administration) systemic
administration-related reactions [see
Dosage and Administration (2.5)].
Local Reactions
In this pooled safety population, injection-site
reactions occurred in 8% of patients, including Grade 2 reactions in 0.7%.
The most frequent (>1%) injection-site reaction was injection site erythema.
These local reactions occurred a median of 5 minutes (range: 0 minutes to 6.5
days) after starting administration of DARZALEX FASPRO. Monitor for local
reactions and consider symptomatic management.
6
Adverse Reactions
6.1 Clinical Trials Experience
Extensive changes; please refer
to label
6.2 Immunogenicity
Additions and/or
revisions underlined:
As
with all therapeutic proteins, there is the 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 studies described below with the
incidence of antibodies in other studies or to other daratumumab products or
other hyaluronidase products may be misleading.
In
patients with multiple myeloma and light chain (AL) amyloidosis who received
DARZALEX FASPRO as monotherapy or as part of a combination therapy, less than
1% of 819 patients developed treatment-emergent anti-daratumumab antibodies.
In
patients with multiple myeloma and light chain (AL) amyloidosis who received
DARZALEX FASPRO as monotherapy or as part of a combination therapy, 7% of 812
patients developed treatment-emergent anti-rHuPH20 antibodies. The anti-rHuPH20
antibodies did not appear to affect daratumumab exposure. None of the patients
who tested positive for anti-rHuPH20 antibodies tested positive for
neutralizing antibodies.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT INFORMATION
Extensive changes; please refer
to label
Approved Drug Label (PDF)
5
Warnings and Precautions
5.1 Hypersensitivity and Other Administration Reactions
(Additions and/or revisions underlined)
Both systemic administration-related reactions, including
severe or life-threatening reactions, and local injection-site reactions can
occur with DARZALEX FASPRO. Fatal reactions have been reported with
daratumumab-containing products, including DARAZLEX FASPRO [see Adverse
Reactions (6.3)].
Systemic Reactions
In a pooled safety population of 832 patients with multiple myeloma (N=639) or light chain (AL) amyloidosis (N=193) who received
DARZALEX FASPRO as monotherapy or as part of a combination therapy, 9% of patients
experienced a systemic
administration-related reaction (Grade 2: 3.5%, Grade 3: 0.8%). Systemic
administration-related reactions occurred in 8% of patients
with the first injection, 0.4% with the second
injection, and cumulatively 1% with subsequent injections. The median time to onset was 3.2 hours
(range: 9 minutes to 3.5 days).
Of the 129
systemic administration-related reactions
that occurred
in
74
patients, 110 (85%) occurred
on the day of DARZALEX FASPRO administration. Delayed systemic administration- related
reactions have occurred
in 1% of the patients.
Severe reactions
included hypoxia, dyspnea, hypertension and tachycardia.
Other signs and symptoms
of systemic administration-related reactions may include respiratory symptoms, such as bronchospasm, nasal congestion, cough, throat irritation, allergic rhinitis, and wheezing,
as well as anaphylactic reaction, pyrexia, chest pain,
pruritus, chills, vomiting, nausea, and hypotension.
Pre-medicate patients with histamine-1 receptor antagonist, acetaminophen and corticosteroids [see Dosage and Administration (2.5)]. Monitor patients
for systemic administration-related reactions, especially following the first and second injections. For anaphylactic reaction or life-threatening (Grade 4) administration-related reactions, immediately and permanently discontinue DARZALEX FASPRO. Consider administering corticosteroids and other medications after the administration of DARZALEX
FASPRO depending on dosing regimen and medical
history to minimize
the risk of delayed (defined
as occurring the day after administration) systemic administration-related reactions
[see
Dosage and Administration (2.5)].
Local Reactions
In this pooled safety population, injection-site reactions occurred in 8% of patients, including Grade
2 reactions in 0.6%. The most frequent
(>1%) injection-site reaction was injection site erythema.
These local reactions
occurred a median of 5.5 minutes (range:
0 minutes to 6.5 days) after starting
administration of DARZALEX
FASPRO. Monitor
for local reactions and consider symptomatic management.
5.5 Embryo-Fetal Toxicity
(Additions and/or revisions underlined)
The combination of DARZALEX
FASPRO with lenalidomide, thalidomide or pomalidomide is contraindicated in pregnant
women, because lenalidomide, thalidomide or pomalidomide may cause birth defects and death of the unborn child.
Refer to the lenalidomide, thalidomide or pomalidomide prescribing information on use during pregnancy.
6
Adverse Reactions
6.1 Clinical Trials Experience
(Extensive
changes; please refer to label)
6.2 Immunogenicity
(Additions and/or revisions underlined)
In patients with multiple myeloma and light chain (AL) amyloidosis who received DARZALEX FASPRO as monotherapy or as part of a combination therapy, less than 1% of 756 patients developed treatment-emergent anti-daratumumab
antibodies.
In patients with multiple myeloma and light chain (AL) amyloidosis who received DARZALEX FASPRO as monotherapy or as part of a combination therapy, 7% of 750 patients developed treatment-emergent anti- rHuPH20 antibodies. The anti-rHuPH20 antibodies did not appear to affect daratumumab exposure. None of the patients who tested
positive for anti-rHuPH20 antibodies
tested positive for neutralizing
antibodies.
6.3 Postmarketing Experience
(Additions and/or revisions underlined)
The following
adverse reactions
have been identified with post-approval use of daratumumab. 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.
Immune
System: Anaphylactic reaction; systemic administration reactions (including death)
8
Use in Specific Populations
8.1 Pregnancy
(Additions and/or revisions underlined)
Risk Summary
The combination of DARZALEX
FASPRO and lenalidomide, thalidomide or pomalidomide is contraindicated in pregnant
women, because lenalidomide, thalidomide and pomalidomide may cause birth defects and death of the unborn child. Lenalidomide, thalidomide and pomalidomide are only available
through a REMS program. Refer
to the lenalidomide, thalidomide
or pomalidomide prescribing information on use
during pregnancy.
8.2 Lactation
(Additions and/or revisions underlined)
Risk Summary
There is no data on the presence of daratumumab and hyaluronidase in human milk, the effects on the breastfed child,
or the effects
on milk production. Maternal immunoglobulin G is known to be present
in human milk. Published data suggest that antibodies in breast
milk do not enter the neonatal and infant circulations in substantial amounts. Because of the potential for serious
adverse reactions in the breastfed child when DARZALEX
FASPRO is administered with lenalidomide, thalidomide or pomalidomide, advise women not to breastfeed during treatment with DARZALEX FASPRO. Refer to lenalidomide, thalidomide or pomalidomide prescribing information for
additional information.
8.3 Females and Males of Reproductive Potential
(Additions and/or revisions underlined)
Pregnancy Testing
With the combination of DARZALEX FASPRO with lenalidomide, thalidomide or pomalidomide, refer to the lenalidomide, thalidomide or pomalidomide labeling for pregnancy testing requirements prior to initiating treatment in females
of reproductive
potential.
Contraception
Advise females of reproductive potential to use effective
contraception during treatment
with DARZALEX FASPRO and for 3 months after the last dose. Additionally, refer to the lenalidomide, thalidomide or pomalidomide
labeling for additional
recommendations for contraception.
8.5 Geriatric Use
(Newly
added information)
Of the 214 patients
who received DARZALEX FASPRO as combination therapy with pomalidomide and dexamethasone or DARZALEX
FASPRO as combination therapy with lenalidomide and low-dose
dexamethasone for relapsed
and refractory multiple
myeloma, 43% were 65 to <75
years of age, and 18% were 75 years
of age or older.
No overall differences in effectiveness were observed between patient 65 years and older (n=131)
and <65 years (n=85). Adverse reactions
occurring at a higher frequency (> or equal to 5% difference) in patients 65 years of age or older included
fatigue, pyrexia,
peripheral edema, urinary tract infection, diarrhea, constipation, vomiting, dyspnea, cough, and hyperglycemia. Serious adverse reactions occurring at a higher frequency
(> or equal to 2% difference) in patients 65
years of age and older included
neutropenia, thrombocytopenia, diarrhea, anemia, COVID-19, ischemic colitis, deep vein thrombosis, general physical health deterioration, pulmonary embolism, and urinary
tract infection.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
(Additions and/or revisions underlined)
Advise
patients that lenalidomide, thalidomide and
pomalidomide have
the potential to cause fetal harm and have specific
requirements regarding contraception, pregnancy testing, blood and sperm donation,
and transmission in sperm.
Lenalidomide, thalidomide and
pomalidomide are only available through a REMS program
[see
Use in Specific Populations
(8.1, 8.3)].
Patient Information
(Additions and/or revisions underlined)
DARZALEX FASPRO may be used with other medicines called
lenalidomide, thalidomide or pomalidomide. You should also read the Medication
Guide that comes with lenalidomide, thalidomide or pomalidomide if you use
DARZALEX FASPRO with these medicines.
DARZALEX FASPRO is a prescription medicine used to treat
adult patients with multiple myeloma:
• in
combination with the medicines pomalidomide and dexamethasone in people who
have received at least one prior medicine including lenalidomide and a
proteasome inhibitor to treat multiple myeloma.
Do not receive DARZALEX FASPRO if you have a history of a
severe allergic reaction to daratumumab, hyaluronidase or any of the
ingredients in DARZALEX FASPRO. See the end of this leaflet for a complete list
of ingredients in DARZALEX FASPRO.
Before you receive DARZALEX FASPRO, tell your healthcare
provider about all of your medical conditions, including if you:
- Before starting DARZALEX FASPRO in combination with
lenalidomide, thalidomide or pomalidomide, females and males must agree
to the instructions in the lenalidomide, thalidomide or pomalidomide REMS
program.
- The lenalidomide, thalidomide and pomalidomide REMS
have more information about effective methods of birth control, pregnancy
testing, and blood donation for females who can become pregnant.
- For males who have female partners who can become pregnant,
there is information in the lenalidomide, thalidomide and pomalidomide
REMS about sperm donation and how lenalidomide, thalidomide and pomalidomide
can pass into human semen.
- are breastfeeding or plan to breastfeed. It is not known
if DARZALEX FASPRO passes into your breast milk. You should not breastfeed
during treatment with DARZALEX FASPRO. Talk to your healthcare provider about
the best way to feed your baby during treatment with DARZALEX FASPRO.
Approved Drug Label (PDF)
5
Warnings and Precautions
5.5 Embryo-Fetal
Toxicity
(Additions and/or revisions underlined)
Based on the mechanism of action, DARZALEX FASPRO can cause
fetal harm when administered to a pregnant woman. DARZALEX FASPRO may cause
depletion of fetal immune cells and decreased bone density. Advise pregnant
women of the potential risk to a fetus. Advise females with reproductive
potential to use effective contraception during treatment with DARZALEX FASPRO
and for 3 months after the last dose [see
Use in Specific Populations (8.1, 8.3)].
The combination
of DARZALEX FASPRO with lenalidomide or thalidomide is contraindicated
in pregnant women, because lenalidomide and thalidomide may cause birth
defects and death of the unborn child. Refer to the lenalidomide or
thalidomide prescribing information on use during pregnancy.
8
Use in Specific Populations
8.1 Pregnancy
(Additions and/or revisions underlined)
Risk Summary
DARZALEX FASPRO
can cause fetal harm when administered to a pregnant woman. The assessment of
associated risks with daratumumab products is based on the mechanism of action
and data from target antigen CD38 knockout animal models (see Data). There are no available data on the use of DARZALEX
FASPRO in pregnant women to evaluate drug-associated risk of major birth
defects, miscarriage or adverse maternal or fetal outcomes. Animal reproduction
studies have not been conducted.
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% to 4% and 15% to 20%, respectively.
The combination
of DARZALEX FASPRO and lenalidomide or thalidomide is contraindicated in
pregnant women, because lenalidomide and thalidomide may cause birth
defects and death of the unborn child. Lenalidomide and thalidomide are
only available through a REMS program. Refer to the lenalidomide or
thalidomide prescribing information on use during pregnancy.
8.2 Lactation
(Additions and/or revisions underlined)
Risk Summary
There is no data
on the presence of daratumumab and hyaluronidase in human milk, the effects on
the breastfed child, or the effects on milk production. Maternal immunoglobulin
G is known to be present in human milk. Published data suggest that antibodies
in breast milk do not enter the neonatal and infant circulations in substantial
amounts. Because of the potential for serious adverse reactions in the
breastfed child when DARZALEX FASPRO is administered with lenalidomide or
thalidomide and dexamethasone, advise women not to breastfeed during
treatment with DARZALEX FASPRO. Refer to lenalidomide or thalidomide
prescribing information for additional information.
8.3 Females and Males of Reproductive Potential
(Additions and/or revisions
underlined)
DARZALEX FASPRO can cause fetal harm when
administered to a pregnant woman [see Use
in Specific Populations (8.1)].
Pregnancy
Testing
With the
combination of DARZALEX FASPRO with lenalidomide or thalidomide, refer
to the lenalidomide or thalidomide labeling for pregnancy testing
requirements prior to initiating treatment in females of reproductive
potential.
Contraception
Advise females of
reproductive potential to use effective contraception during treatment with
DARZALEX FASPRO and for 3 months after the last dose. Additionally, refer to
the lenalidomide or thalidomide labeling for additional
recommendations for contraception.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION
(Additions and/or revisions underlined)
Embryo-Fetal Toxicity
Advise pregnant women of the
potential hazard to a fetus. Advise females of reproductive potential to inform
their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.5), Use in
Specific Populations (8.1, 8.3)].
Advise females of
reproductive potential to avoid becoming pregnant during treatment with
DARZALEX FASPRO and for at least 3 months after the last dose [see Use in Specific Populations (8.1, 8.3)].
Advise patients
that lenalidomide and thalidomide have the potential to cause fetal harm
and have specific requirements regarding contraception, pregnancy
testing, blood and sperm donation, and transmission in sperm. Lenalidomide and
thalidomide are only available through a REMS program [see Use in Specific Populations (8.1,
8.3)].
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