HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
BLENREP safely and effectively. See full prescribing information for
BLENREP.
--------------------- DOSAGE FORMS AND STRENGTHS --------------------
For injection: 100 mg as a lyophilized powder in a single-dose vial for
reconstitution and further dilution. (3)
------------------------------ CONTRAINDICATIONS -----------------------------
BLENREP (belantamab mafodotin-blmf) for injection, for intravenous
None. (4)
use
Initial U.S. Approval: 2020
----------------------- WARNINGS AND PRECAUTIONS ----------------------
• Thrombocytopenia: Perform complete blood counts at baseline and during
treatment as clinically indicated. Consider withholding and/or reducing the
dose based on severity. (2.3, 5.3)
WARNING: OCULAR TOXICITY
See full prescribing information for complete boxed warning.
●
●
BLENREP caused changes in the corneal epithelium resulting in
changes in vision, including severe vision loss and corneal ulcer, and
symptoms, such as blurred vision and dry eyes. (5.1)
Conduct ophthalmic exams at baseline, prior to each dose, and
promptly for worsening symptoms. Withhold BLENREP until
improvement and resume, or permanently discontinue, based on
severity. (2.3, 5.1)
• Infusion-Related Reactions: Monitor patients for infusion-related reactions.
Interrupt and then reduce the rate or permanently discontinue based on the
severity. (2.3, 5.4)
• Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of
reproductive potential of the potential risk to a fetus and to use effective
contraception. (5.5, 8.1, 8.3)
------------------------------ ADVERSE REACTIONS -----------------------------
• The most common adverse reactions (≥20%) are keratopathy (corneal
epithelium change on eye exam), decreased visual acuity, nausea, blurred
vision, pyrexia, infusion-related reactions, and fatigue. (6.1)
• The most common grade 3 or 4 laboratory abnormalities (≥5%) are platelets
decreased, lymphocytes decreased, hemoglobin decreased, neutrophils
decreased, creatinine increased, and gamma-glutamyl transferase increased.
(6.1)
●
BLENREP is available only through a restricted program, called the
BLENREP REMS. (5.2)
--------------------------- INDICATIONS AND USAGE---------------------------
BLENREP is a B-cell maturation antigen (BCMA)-directed antibody and
microtubule inhibitor conjugate indicated for the treatment of adult patients
with relapsed or refractory multiple myeloma who have received at least 4
prior therapies including an anti-CD38 monoclonal antibody, a proteasome
inhibitor, and an immunomodulatory agent.
To report SUSPECTED ADVERSE REACTIONS, contact
GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
This indication is approved under accelerated approval based on response rate.
Continued approval for this indication may be contingent upon verification
and description of clinical benefit in confirmatory trial(s). (1)
----------------------- USE IN SPECIFIC POPULATIONS ----------------------
-----------------------DOSAGE AND ADMINISTRATION ----------------------
• The recommended dosage is 2.5 mg/kg as an intravenous infusion over
approximately 30 minutes once every 3 weeks. (2.2)
Lactation: Advise not to breastfeed. (8.2)
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
• See Full Prescribing Information for instructions on preparation and
administration. (2.4)
Revised: 8/2020
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: OCULAR TOXICITY
8.2
8.3
8.4
8.5
Lactation
Females and Males of Reproductive Potential
Pediatric Use
1
2
INDICATIONS AND USAGE
DOSAGE AND ADMINISTRATION
2.1
2.2
2.3
2.4
Important Safety Information
Recommended Dosage
Dosage Modifications for Adverse Reactions
Preparation and Administration
Geriatric Use
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
3
4
5
DOSAGE FORMS AND STRENGTHS
CONTRAINDICATIONS
WARNINGS AND PRECAUTIONS
13
NONCLINICAL TOXICOLOGY
5.1
5.2
5.3
5.4
5.5
Ocular Toxicity
BLENREP REMS
Thrombocytopenia
Infusion-Related Reactions
Embryo-Fetal Toxicity
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2 Animal Toxicology and/or Pharmacology
CLINICAL STUDIES
14.1 Relapsed or Refractory Multiple Myeloma
15 REFERENCES
14
6
8
ADVERSE REACTIONS
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not
listed.
6.1
6.2
Clinical Trials Experience
Immunogenicity
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
1
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FULL PRESCRIBING INFORMATION
WARNING: OCULAR TOXICITY
BLENREP caused changes in the corneal epithelium resulting in changes in vision,
including severe vision loss and corneal ulcer, and symptoms, such as blurred vision and
dry eyes [see Warnings and Precautions (5.1)].
Conduct ophthalmic exams at baseline, prior to each dose, and promptly for worsening
symptoms. Withhold BLENREP until improvement and resume, or permanently
discontinue, based on severity [see Dosage and Administration (2.3), Warnings and
Precautions (5.1)].
Because of the risk of ocular toxicity, BLENREP is available only through a restricted
program under a Risk Evaluation and Mitigation Strategy (REMS) called the BLENREP
REMS [see Warnings and Precautions (5.2)].
1
INDICATIONS AND USAGE
BLENREP is indicated for the treatment of adults with relapsed or refractory multiple myeloma
who have received at least 4 prior therapies, including an anti-CD38 monoclonal antibody, a
proteasome inhibitor, and an immunomodulatory agent.
This indication is approved under accelerated approval based on response rate[see Clinical
Studies (14)]. Continued approval for this indication may be contingent upon verification and
description of clinical benefit in a confirmatory trial(s).
2
DOSAGE AND ADMINISTRATION
Important Safety Information
2.1
Perform an ophthalmic exam prior to initiation of BLENREP and during treatment [see
Warnings and Precautions (5.1)].
Advise patients to use preservative-free lubricant eye drops and avoid contact lenses unless
directed by an ophthalmologist[see Warnings and Precautions (5.1)].
2.2
Recommended Dosage
The recommended dosage of BLENREP is 2.5 mg/kg of actual body weight given as an
intravenous infusion over approximately 30 minutes once every 3 weeks until disease
progression or unacceptable toxicity.
2.3
Dosage Modifications for Adverse Reactions
The recommended dose reduction for adverse reactions is:
• BLENREP 1.9 mg/kg intravenously once every 3 weeks.
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Discontinue BLENREP in patients who are unable to tolerate a dose of 1.9 mg/kg (see Tables 1
and 2).
Corneal Adverse Reactions
The recommended dosage modifications for corneal adverse reactions, based on both corneal
examination findings and changes in best-corrected visual acuity (BCVA), are provided in Table
1[see Warnings and Precautions (5.1)]. Determine the recommended dosage modification of
BLENREP based on the worst finding in the worst affected eye. Worst finding should be based
on either a corneal examination finding or a change in visual acuity per the Keratopathy and
Visual Acuity (KVA) scale.
Table 1. Dosage Modifications for Corneal Adverse Reactions per the KVA Scale
Recommended
Corneal Adverse Reaction
Dosage Modifications
Continue treatment at current
dose.
Grade 1 Corneal examination finding(s):
Mild superficial keratopathy
a
Change in BCVA
b
:
Decline from baseline of 1 line on Snellen
Visual Acuity
Grade 2 Corneal examination finding(s):
Moderate superficial keratopathy
Withhold BLENREP until
improvement in both corneal
examination findings and change
in BCVA to Grade 1 or better
and resume at same dose.
c
Change in BCVA :
b
Decline from baseline of 2 or 3 lines on
Snellen Visual Acuity and not worse than
20/200
Grade 3 Corneal examination finding(s):
Severe superficial keratopathy
Withhold BLENREP until
d
improvement in both corneal
examination findings and change
in BCVA to Grade 1 or better
and resume at reduced dose.
Change in BCVA :
b
Decline from baseline by more than 3 lines
on Snellen Visual Acuity and not worse
than 20/200
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Grade 4 Corneal examination finding(s):
Corneal epithelial defect
Consider permanent
e
discontinuation of BLENREP. If
continuing treatment, withhold
BLENREP until improvement in
both corneal examination
findings and change in BCVA to
Grade 1 or better and resume at
reduced dose.
Change in BCVA :
b
Snellen Visual Acuity worse than 20/200
a
Mild superficial keratopathy (documented worsening from baseline), with or without
symptoms.
b
c
Changes in visual acuity due to treatment-related corneal findings.
Moderate superficial keratopathy with or without patchy microcyst-like deposits, sub-epithelial
haze (peripheral), or a new peripheral stromal opacity.
d
Severe superficial keratopathy with or without diffuse microcyst-like deposits, sub-epithelial
haze (central), or a new central stromal opacity.
e
Corneal epithelial defect such as corneal ulcers.
Other Adverse Reactions
The recommended dosage modifications for other adverse reactions are provided in Table 2.
Table 2. Dosage Modifications for Other Adverse Reactions
Adverse Reaction
Thrombocytopenia
[see Warnings and
Precautions (5.3)]
Severity
Recommended Dosage Modifications
Platelet count 25,000 to Consider withholding BLENREP and/or
less than 50,000/mcL reducing the dose of BLENREP.
Platelet count less than Withhold BLENREP until platelet count
25,000/mcL
improves to Grade 3 or better. Consider
resuming at a reduced dose.
Infusion-related
reactions
[see Warnings and
Precautions (5.4)]
Grade 2 (moderate) or
Grade 3 (severe)
Interrupt infusion and provide supportive
care. Once symptoms resolve, resume at
lower infusion rate; reduce the infusion rate
by at least 50%.
Grade 4 (life
threatening)
Permanently discontinue BLENREP and
provide emergency care.
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Other Adverse
Reactions [see
Adverse Reactions
(6.1)]
Grade 3
Grade 4
Withhold BLENREP until improvement to
Grade 1 or better. Consider resuming at a
reduced dose.
Consider permanent discontinuation of
BLENREP. If continuing treatment,
withhold BLENREP until improvement to
Grade 1 or better and resume at reduced
dose.
2.4
Preparation and Administration
BLENREP is a hazardous drug. Follow applicable special handling and disposal procedures.
Calculate the dose (mg), total volume (mL) of solution required, and the number of vials of
1
BLENREP needed based on the patient’s actual body weight. More than 1 vial may be needed
for a full dose. Do not round down for partial vials.
Reconstitution
• Remove the vial(s) of BLENREP from the refrigerator and allow to stand for approximately
10 minutes to reach room temperature (68°F to 77°F [20°C to 25°C]).
• Reconstitute each 100-mg vial of BLENREP with 2 mL of Sterile Water for Injection, USP,
to obtain a final concentration of 50 mg/mL. Gently swirl the vial to aid dissolution. Do not
shake.
• If the reconstituted solution is not used immediately, store refrigerated at 36ºF to 46ºF (2ºC to
8ºC) or at room temperature (68°F to 77°F [20°C to 25°C]) for up to 4 hours in the original
container. Discard if not diluted within 4 hours. Do not freeze.
• Parenteral drug products should be inspected visually for particulate matter and discoloration
prior to administration, whenever solution and container permit. The reconstituted solution
should be clear to opalescent, colorless to yellow to brown liquid. Discard if extraneous
particulate matter is observed.
Dilution
• Withdraw the calculated volume of BLENREP from the appropriate number of vials and
dilute in a 250-mL infusion bag of 0.9% Sodium Chloride Injection, USP, to a final
concentration of 0.2 mg/mL to 2 mg/mL. The infusion bags must be made of
polyvinylchloride (PVC) or polyolefin (PO).
• Mix the diluted solution by gentle inversion. Do not shake.
• Discard any unused reconstituted solution of BLENREP left in the vial(s).
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• If the diluted infusion solution is not used immediately, store refrigerated at 36ºF to 46ºF
(2ºC to 8ºC) for up to 24 hours. Do not freeze. Once removed from refrigeration, administer
the diluted infusion solution of BLENREP within 6 hours (including infusion time).
• Parenteral drug products should be inspected visually for particulate matter and discoloration
prior to administration, whenever solution and container permit. The diluted infusion solution
should be clear and colorless. Discard if particulate matter is observed.
Administration
• If refrigerated, allow the diluted infusion solution to equilibrate to room temperature (68ºF to
77ºF [20ºC to 25ºC]) prior to administration. Diluted infusion solution may be kept at room
temperature for no more than 6 hours (including infusion time).
• Administer by intravenous infusion over approximately 30 minutes using an infusion set
made of polyvinyl chloride (PVC) or polyolefin (PO).
• Filtration of the diluted solution is not required; however, if the diluted solution is filtered,
use a polyethersulfone (PES)-based filter (0.2 micron).
Do not mix or administer BLENREP as an infusion with other products. The product does not
contain a preservative.
3
DOSAGE FORMS AND STRENGTHS
For injection: 100 mg of belantamab mafodotin-blmf as a white to yellow lyophilized powder in
a single-dose vial for reconstitution and further dilution.
4
CONTRAINDICATIONS
None.
5
WARNINGS AND PRECAUTIONS
Ocular Toxicity
5.1
Ocular adverse reactions occurred in 77% of the 218 patients in the pooled safety
population. Ocular adverse reactions included keratopathy (76%), changes in visual acuity
(55%), blurred vision (27%), and dry eye (19%)[see Adverse Reactions (6.1)]. Among patients
with keratopathy (n = 165), 49% had ocular symptoms, 65% had clinically relevant visual acuity
changes (decline of 2 or more lines on Snellen Visual Acuity in any eye), and 34% had both
ocular symptoms and visual acuity changes.
Keratopathy
Keratopathy was reported as Grade 1 in 7% of patients, Grade 2 in 22%, Grade 3 in 45%, and
Grade 4 in 0.5% per the KVA scale. Cases of corneal ulcer (ulcerative and infective keratitis)
have been reported. Most keratopathy events developed within the first 2 treatment cycles
(cumulative incidence of 65% by Cycle 2). Of the patients with Grade 2 to 4 keratopathy
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(n = 149), 39% of patients recovered to Grade 1 or lower after median follow-up of 6.2 months.
Of the 61% who had ongoing keratopathy, 28% were still on treatment, 9% were in follow-up,
and in 24% the follow-up ended due to death, study withdrawal, or lost to follow up. For patients
in whom events resolved, the median time to resolution was 2 months (range: 11 days to 8.3
months).
Visual Acuity Changes
A clinically significant decrease in visual acuity of worse than 20/40 in the better-seeing eye was
observed in 19% of the 218 patients and of 20/200 or worse in the better-seeing eye in 1.4%. Of
the patients with decreased visual acuity of worse than 20/40, 88% resolved and the median time
to resolution was 22 days (range: 7 days to 4.2 months). Of the patients with decreased visual
acuity of 20/200 or worse, all resolved and the median duration was 22 days (range: 15 to 22
days).
Monitoring and Patient Instruction
Conduct ophthalmic examinations (visual acuity and slit lamp) at baseline, prior to each dose,
and promptly for worsening symptoms. Perform baseline examinations within 3 weeks prior to
the first dose. Perform each follow-up examination at least 1 week after the previous dose and
within 2 weeks prior to the next dose. Withhold BLENREP until improvement and resume at
same or reduced dose, or consider permanently discontinuing based on severity[see Dosage and
Administration (2.3)].
Advise patients to use preservative-free lubricant eye drops at least 4 times a day starting with
the first infusion and continuing until end of treatment. Avoid use of contact lenses unless
directed by an ophthalmologist[see Dosage and Administration (2.1)].
Changes in visual acuity may be associated with difficulty for driving and reading. Advise
patients to use caution when driving or operating machinery.
BLENREP is only available through a restricted program under a REMS[see Warnings and
Precautions (5.2)].
5.2
BLENREP REMS
BLENREP is available only through a restricted program under a REMS called the BLENREP
REMS because of the risks of ocular toxicity[see Warnings and Precautions (5.1)].
Notable requirements of the BLENREP REMS include the following:
• Prescribers must be certified with the program by enrolling and completing training in the
BLENREP REMS.
• Prescribers must counsel patients receiving BLENREP about the risk of ocular toxicity and
the need for ophthalmic examinations prior to each dose.
• Patients must be enrolled in the BLENREP REMS and comply with monitoring.
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• Healthcare facilities must be certified with the program and verify that patients are
authorized to receive BLENREP.
• Wholesalers and distributers must only distribute BLENREP to certified healthcare facilities.
Further information is available, at www.BLENREPREMS.com and 1-855-209-9188.
5.3
Thrombocytopenia
Thrombocytopenia occurred in 69% of 218 patients in the pooled safety population, including
Grade 2 in 13%, Grade 3 in 10%, and Grade 4 in 17%[see Adverse Reactions (6.1)]. The median
time to onset of the first thrombocytopenic event was 26.5 days. Thrombocytopenia resulted in
dose reduction, dose interruption, or discontinuation in 9%, 2.8%, and 0.5% of patients,
respectively.
Grade 3 to 4 bleeding events occurred in 6% of patients, including Grade 4 in 1 patient. Fatal
adverse reactions included cerebral hemorrhage in 2 patients.
Perform complete blood cell counts at baseline and during treatment as clinically indicated.
Consider withholding and/or reducing the dose based on severity[see Dosage and
Administration (2.3)].
5.4
Infusion-Related Reactions
Infusion-related reactions occurred in 18% of 218 patients in the pooled safety population,
including Grade 3 in 1.8%[see Adverse Reactions (6.1)].
Monitor patients for infusion-related reactions. For Grade 2 or 3 reactions, interrupt the infusion
and provide supportive treatment. Once symptoms resolve, resume at a lower infusion rate [see
Dosage and Administration (2.3)]. Administer premedication for all subsequent infusions.
Discontinue BLENREP for life-threatening infusion-related reactions and provide appropriate
emergency care.
5.5
Embryo-Fetal Toxicity
Based on its mechanism of action, BLENREP can cause fetal harm when administered to a
pregnant woman because it contains a genotoxic compound (the microtubule inhibitor,
monomethyl auristatin F [MMAF]) and it targets actively dividing cells.
Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential
to use effective contraception during treatment with BLENREP and for 4 months after the last
dose. Advise males with female partners of reproductive potential to use effective contraception
during treatment with BLENREP and for 6 months after the last dose[see Use in Specific
Populations (8.1, 8.3)].
6
ADVERSE REACTIONS
The following clinically significant adverse reactions are described elsewhere in the labeling:
8
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• Ocular toxicity[see Warnings and Precautions (5.1)].
• Thrombocytopenia[see Warnings and Precautions (5.3)].
• Infusion-related reactions[see Warnings and Precautions (5.4)].
6.1
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared with rates in the clinical
trials of another drug and may not reflect the rates observed in practice.
The pooled safety population described inWarnings and Precautionsreflects exposure to
BLENREP at a dosage of 2.5 mg/kg or 3.4 mg/kg (1.4 times the recommended dose)
administered intravenously once every 3 weeks in 218 patients in DREAMM-2. Of these
patients, 194 received a liquid formulation (not the approved dosage form) rather than the
lyophilized powder. Among the 218 patients, 24% were exposed for 6 months or longer.
Relapsed or Refractory Multiple Myeloma
The safety of BLENREP as a single agent was evaluated in DREAMM-2[see Clinical Studies
(14.1)]. Patients received BLENREP at the recommended dosage of 2.5 mg/kg administered
intravenously once every 3 weeks (n = 95). Among these patients, 22% were exposed for 6
months or longer.
Serious adverse reactions occurred in 40% of patients who received BLENREP. Serious adverse
reactions in >3% of patients included pneumonia (7%), pyrexia (6%), renal impairment (4.2%),
sepsis (4.2%), hypercalcemia (4.2%), and infusion-related reactions (3.2%). Fatal adverse
reactions occurred in 3.2% of patients, including sepsis (1%), cardiac arrest (1%), and lung
infection (1%).
Permanent discontinuation due to an adverse reaction occurred in 8% of patients who received
BLENREP; keratopathy (2.1%) was the most frequent adverse reaction resulting in permanent
discontinuation.
Dosage interruptions due to an adverse reaction occurred in 54% of patients who received
BLENREP. Adverse reactions which required a dosage interruption in >3% of patients included
keratopathy (47%), blurred vision (5%), dry eye (3.2%), and pneumonia (3.2%).
Dose reductions due to an adverse reaction occurred in 29% of patients. Adverse reactions which
required a dose reduction in >3% of patients included keratopathy (23%) and thrombocytopenia
(5%).
The most common adverse reactions (≥20%) were keratopathy, decreased visual acuity, nausea,
blurred vision, pyrexia, infusion-related reactions, and fatigue. The most common Grade 3 or 4
(≥5%) laboratory abnormalities were lymphocytes decreased, platelets decreased, hemoglobin
decreased, neutrophils decreased, creatinine increased, and gamma-glutamyl transferase
increased.
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Table 3 summarizes the adverse reactions in DREAMM-2 for patients who received the
recommended dosage of 2.5 mg/kg once every 3 weeks.
Table 3. Adverse Reactions (≥10%) in Patients Who Received BLENREP in DREAMM-2
BLENREP
N = 95
All Grades
(%)
Grade 3-4
(%)
Adverse Reactions
Eye disorders
Keratopathy
a
71
53
22
14
44
28
4
Decreased visual acuity
Blurred vision
Dry eyes
b
c
d
1
Gastrointestinal disorders
Nausea
24
13
13
0
0
1
Constipation
Diarrhea
General disorders and administration site
conditions
Pyrexia
22
20
3
2
Fatigue
e
Procedural complications
Infusion-related reactions
f
21
3
Musculoskeletal and connective tissue
disorders
Arthralgia
12
11
0
2
Back pain
Metabolic and nutritional disorders
Decreased appetite
Infections
12
11
0
0
Upper respiratory tract infection
g
a
Keratopathy was based on slit lamp eye examination, characterized as corneal epithelium
changes with or without symptoms.
b
c
d
e
f
Visual acuity changes were determined upon eye examination.
Blurred vision included diplopia, vision blurred, visual acuity reduced, and visual impairment.
Dry eyes included dry eye, ocular discomfort, and eye pruritus.
Fatigue included fatigue and asthenia.
Infusion-related reactions included infusion-related reaction, pyrexia, chills, diarrhea, nausea,
asthenia, hypertension, lethargy, tachycardia.
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g
Upper respiratory tract infection included upper respiratory tract infection, nasopharyngitis,
rhinovirus infections, and sinusitis.
Clinically relevant adverse reactions in <10% of patients included:
Eye Disorders:Photophobia, eye irritation, infective keratitis, ulcerative keratitis.
Gastrointestinal Disorders: Vomiting.
Infections: Pneumonia.
Investigations: Albuminuria.
Table 4 summarizes the laboratory abnormalities in DREAMM-2.
Table 4. Laboratory Abnormalities (≥20%) Worsening from Baseline in Patients Who
Received BLENREP in DREAMM-2
BLENREP
N = 95
All Grades
(%)
Grades 3-4
(%)
Laboratory Abnormality
Hematology
Platelets decreased
62
49
32
28
21
22
18
9
Lymphocytes decreased
Hemoglobin decreased
Neutrophils decreased
Chemistry
Aspartate aminotransferase increased
Albumin decreased
57
43
38
28
26
25
22
21
20
2
4
3
5
1
5
1
2
2
Glucose increased
Creatinine increased
Alkaline phosphatase increased
Gamma-glutamyl transferase increased
Creatinine phosphokinase increased
Sodium decreased
Potassium decreased
6.2
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
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the incidence of antibodies in the studies described below with the incidence of antibodies in
other studies or to other products may be misleading.
The immunogenicity of BLENREP was evaluated using an electrochemiluminescence (ECL)
based immunoassay to test for anti-belantamab mafodotin antibodies. In clinical studies of
BLENREP, 2/274 patients (<1%) tested positive for anti-belantamab mafodotin antibodies after
treatment. One of the 2 patients tested positive for neutralizing anti-belantamab mafodotin
antibodies following 4 weeks on therapy. Due to the limited number of patients with antibodies
against belantamab mafodotin-blmf, no conclusions can be drawn concerning a potential effect
of immunogenicity on pharmacokinetics, efficacy, or safety.
8
USE IN SPECIFIC POPULATIONS
Pregnancy
8.1
Risk Summary
Based on its mechanism of action, BLENREP can cause fetal harm when administered to a
pregnant woman, because it contains a genotoxic compound (the microtubule inhibitor, MMAF)
and it targets actively dividing cells[see Clinical Pharmacology (12.1), Nonclinical Toxicology
(13.1)]. Human immunoglobulin G (IgG) is known to cross the placenta; therefore, belantamab
mafodotin-blmf has the potential to be transmitted from the mother to the developing fetus.
There are no available data on the use of BLENREP in pregnant women to evaluate for drug-
associated risk. No animal reproduction studies were conducted with BLENREP. Advise
pregnant women of the potential risk to a fetus.
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 outcome. 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.
Data
Animal Data:Animal reproductive or developmental toxicity studies were not conducted with
belantamab mafodotin-blmf. The cytotoxic component of BLENREP, MMAF, disrupts
microtubule function, is genotoxic, and can be toxic to rapidly dividing cells, suggesting it has
the potential to cause embryotoxicity and teratogenicity.
8.2
Lactation
Risk Summary
There is no data on the presence of belantamab mafodotin-blmf in human milk or the effects on
the breastfed child or milk production. Because of the potential for serious adverse reactions in
the breastfed child, advise women not to breastfeed during treatment with BLENREP and for 3
months after the last dose.
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8.3
Females and Males of Reproductive Potential
BLENREP can cause fetal harm when administered to pregnant women[see Use in Specific
Populations (8.1)].
Pregnancy Testing
Pregnancy testing is recommended for females of reproductive potential prior to initiating
BLENREP.
Contraception
Females:Advise women of reproductive potential to use effective contraception during
treatment and for 4 months after the last dose.
Males:Because of the potential for genotoxicity, advise males with female partners of
reproductive potential to use effective contraception during treatment with BLENREP and for 6
months after the last dose[see Nonclinical Toxicology (13.1)].
Infertility
Based on findings in animal studies, BLENREP may impair fertility in females and males. The
effects were not reversible in male rats, but were reversible in female rats[see Nonclinical
Toxicology (13.1)].
8.4
Pediatric Use
The safety and effectiveness of BLENREP in pediatric patients have not been established.
Geriatric Use
8.5
Of the 218 patients who received BLENREP in DREAMM-2, 43% were aged 65 to less than 75
years and 17% were aged 75 years and older. Clinical studies of BLENREP did not include
sufficient numbers of patients aged 65 and older to determine whether the effectiveness differs
compared with that of younger patients. Keratopathy occurred in 80% of patients aged less than
65 years and 73% of patients aged 65 years and older. Among the patients who received
BLENREP at the 2.5-mg/kg dose in DREAMM-2 (n = 95), keratopathy occurred in 67% of
patients aged less than 65 years and 73% of patients aged 65 years and older. Clinical studies did
not include sufficient numbers of patients 75 years and older to determine whether they respond
differently compared with younger patients.
8.6
Renal Impairment
No dose adjustment is recommended for patients with mild or moderate renal impairment
(estimated glomerular filtration rate [eGFR] 30 to 89 mL/min/1.73m as estimated by the
2
Modification of Diet in Renal Disease [MDRD] equation)[see Clinical Pharmacology (12.3)].
13
Reference ID: 4652412
The recommended dosage has not been established in patients with severe renal impairment
(eGFR 15 to 29 mL/min/1.73 m ) or end-stage renal disease (ESRD) with eGFR <15
mL/min/1.73 m not on dialysis or requiring dialysis[see Clinical Pharmacology (12.3)].
2
2
8.7
Hepatic Impairment
No dose adjustment is recommended for patients with mild hepatic impairment (total bilirubin
≤upper limit of normal [ULN] and aspartate aminotransferase (AST) >ULN or total bilirubin 1 to
≤1.5 × ULN and any AST).
The recommended dosage of BLENREP has not been established in patients with moderate or
severe hepatic impairment (total bilirubin >1.5 × ULN and any AST)[see Clinical
Pharmacology (12.3)].
11
DESCRIPTION
Belantamab mafodotin-blmf is a B-cell maturation antigen (BCMA)-directed antibody and
microtubule inhibitor conjugate. Belantamab mafodotin-blmf is an antibody conjugate composed
of 3 components: 1) afucosylated, humanized immunoglobulin G1 monoclonal antibody
covalently linked to 2) the microtubule inhibitor MMAF via 3) a protease-resistant
maleimidocaproyl linker.
The antibody is produced in a mammalian cell line (Chinese Hamster Ovary) using recombinant
DNA technology and the microtubule inhibitor and linker are produced by chemical synthesis.
Approximately 4 molecules of mafodotin are attached to each antibody molecule. The molecular
weight of belantamab mafodotin-blmf is approximately 152 kDa. Belantamab mafodotin-blmf
has the following structure:
BLENREP (belantamab mafodotin-blmf) for injection is a sterile, preservative-free, white to
yellow, lyophilized powder in a single-dose vial for reconstitution and further dilution prior to
intravenous use. BLENREP is supplied as 100 mg per vial and requires reconstitution with 2 mL
of Sterile Water for Injection, USP, to obtain a concentration of 50 mg/mL.Each mL of
reconstituted solution contains belantamab mafodotin-blmf (50 mg) and the inactive ingredients,
citric acid (0.42 mg), disodium edetate dihydrate (0.019 mg), polysorbate 80 (0.2 mg), trehalose
dihydrate (75.6 mg), and trisodium citrate dihydrate (6.7 mg). The pH of the reconstituted
solution is 6.2.
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12
CLINICAL PHARMACOLOGY
Mechanism of Action
12.1
Belantamab mafodotin-blmf is an antibody-drug conjugate (ADC). The antibody component is
an afucosylated IgG1 directed against BCMA, a protein expressed on normal B lymphocytes and
multiple myeloma cells. The small molecule component is MMAF, a microtubule inhibitor.
Upon binding to BCMA, belantamab mafodotin-blmf is internalized followed by release of
MMAF via proteolytic cleavage. The released MMAF intracellularly disrupts the microtubule
network, leading to cell cycle arrest and apoptosis.
Belantamab mafodotin-blmf had antitumor activity in multiple myeloma cells and mediated
killing of tumor cells through MMAF-induced apoptosis, as well as by tumor cell lysis through
antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis
(ADCP).
12.2
Pharmacodynamics
Exposure-Response Relationships
Higher belantamab mafodotin-blmf exposure was associated with higher incidence of some
adverse reactions (e.g., Grade ≥2 corneal toxicity). No exposure-response relationship for
efficacy was observed at doses of 2.5 mg/kg or 3.4 mg/kg (1.4 times the recommended dose)
after accounting for the effect of baseline disease-related characteristics, such as soluble BCMA,
IgG, and ß2-microglobulin.
Cardiac Electrophysiology
Belantamab mafodotin-blmf had no large QTc prolongation (>10 ms) at the recommended
dosage of 2.5 mg/kg once every 3 weeks.
12.3
Pharmacokinetics
Belantamab mafodotin-blmf exhibited dose-proportional pharmacokinetics, with a gradual
decrease in clearance over time; the time to reach steady state was ~70 days. After a planned
infusion duration of 0.5 hours, maximum belantamab mafodotin-blmf plasma concentrations
occurred at or shortly after the end of the infusion. Accumulation of belantamab mafodotin-blmf
was ~70% with a dosing regimen of every 3 weeks.
The pharmacokinetics of belantamab mafodotin-blmf after a dose of 2.5 mg/kg in Cycle 1 are
shown in Table 5.
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Table 5. Belantamab Mafodotin-blmf Pharmacokinetics at Cycle 1 in Patients Who
Received a Dose of 2.5 mg/kg
Belantamab Mafodotin-blmf
Parameter
n
Value
4,666 (46)
42 (26)
AUC (mcg.h/mL)
30
32
32
69
Cmax
tmax
Ctrough
(mcg/mL)
(h)
0.78 (0.4, 2.5)
2.4 (52)
(mcg/mL)
AUC = Area under curve over the dosing interval; Cmax = Maximum observed plasma
concentration; tmax = Time of Cmax; Ctrough = Observed plasma concentration prior to next dose.
Data presented as geometric mean (%CV), except tmax, which is presented as median (minimum,
maximum).
Distribution
The mean steady-state volume of distribution of belantamab mafodotin-blmf was 11 L (15%).
Elimination
Total plasma clearance (mean [CV%]) of belantamab mafodotin-blmf was approximately 22%
lower at steady state (0.7 L/day [50%]) than after the first dose (0.9 L/day [42%]). The terminal
phase half-life of belantamab mafodotin-blmf was 12 days after the first dose and 14 days at
steady state.
Metabolism:The monoclonal antibody portion of belantamab mafodotin-blmf is expected to be
metabolized into small peptides and individual amino acids by catabolic pathways. In vitro, cys
mcMMAF is mainly hydrolyzed and dehydrated to a cyclized isomeric form of cys-mcMMAF.
Specific Populations
No clinically significant differences in the pharmacokinetics of belantamab mafodotin-blmf were
observed based on age (34 to 89 years), sex, race (White vs. Black), body weight (42 to 130 kg),
2
mild or moderate renal impairment (eGFR 30 to 89 mL/min/1.73m ), or mild hepatic impairment
(total bilirubin ≤ULN and AST >ULN or total bilirubin 1 to ≤1.5 x ULN and any AST).
The effects of severe renal impairment (eGFR 15 to 29 mL/min/1.73 m ) or ESRD with eGFR
2
2
<15 mL/min/1.73 m not on dialysis or requiring dialysis, or moderate to severe hepatic
impairment (total bilirubin >1.5 x ULN and any AST) on the pharmacokinetics of belantamab
mafodotin-blmf are unknown.
Drug Interaction Studies
In Vitro Studies: Transporter Systems:Cys-mcMMAF is a substrate of organic anion
transporting polypeptide (OATP)1B1 and OATP1B3, multidrug resistance-associated protein
(MRP)1, MRP2, MRP3, bile salt export pump (BSEP), and a possible substrate of P
glycoprotein (P-gp).
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13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies have not been conducted with belantamab mafodotin-blmf.
Belantamab mafodotin-blmf was genotoxic in an in vitro micronucleus assay in human
lymphocytes through an aneugenic mechanism. These results are consistent with the
pharmacological effect of MMAF binding to tubulin causing microtubule depolymerization
resulting in spindle disorganization during cell division. Cys-mcMMAF was not mutagenic in
the bacterial reverse mutation assay (Ames test), the L5178Y mouse lymphoma forward
mutation assay, or the in vivo rat bone marrow micronucleus assay.
Fertility studies have not been conducted with belantamab mafodotin-blmf. Results of repeat-
dose toxicity studies with intravenous administration of belantamab mafodotin-blmf in rats
indicate the potential for impaired male and female reproductive function and fertility. In rats,
weekly dosing for 3 weeks at doses ≥10 mg/kg (approximately 4 times the exposure at the
maximum recommended human dose [MRHD] of 2.5 mg/kg based on the AUC of belantamab
mafodotin-blmf) resulted in degeneration and atrophy of seminiferous tubules in the testes and
luteinized nonovulatory follicles in the ovaries. Findings in females were reversible; findings in
the testes were not reversible at the end of the 12-week recovery period with weekly dosing or
when given every 3 weeks for 13 weeks at doses ≥10 mg/kg. In male monkeys, the highest dose
tested of 10 mg/kg (approximately 4 times the exposure at the MRHD based on AUC of
belantamab mafodotin-blmf) given weekly for 13 weeks resulted in seminiferous tubules
degeneration in the testes that was fully reversed following the 12-week recovery period.
13.2
Animal Toxicology and/or Pharmacology
Increased mitoses of corneal epithelial cells with bilateral single-cell necrosis were observed
following intravenous administration of belantamab mafodotin-blmf in rats and rabbits.
14
CLINICAL STUDIES
14.1
Relapsed or Refractory Multiple Myeloma
The efficacy of BLENREP was evaluated in DREAMM-2, an open-label, multicenter study
(NCT 03525678). Eligible patients had relapsed or refractory multiple myeloma, had previously
received 3 or more prior therapies, including an anti-CD38 monoclonal antibody, and were
refractory to an immunomodulatory agent and a proteasome inhibitor. Patients had measurable
disease by International Myeloma Working Group (IMWG) criteria. Patients with corneal
epithelial disease, except mild punctate keratopathy, at baseline were excluded from the study.
Patients with mild or moderate renal impairment (eGFR 30 to 89 mL/min/1.73m ) at baseline
2
were also eligible for the study. Patients received either BLENREP 2.5 mg/kg or 3.4 mg/kg
intravenously once every 3 weeks until disease progression or unacceptable toxicity. The major
efficacy outcome measure was overall response rate as evaluated by an Independent Review
17
Reference ID: 4652412
Committee (IRC) based on the IMWG Uniform Response Criteria for Multiple Myeloma. Only
the results of the recommended dosage of 2.5 mg/kg are described below.
A total of 97 patients received BLENREP at a dose of 2.5 mg/kg administered intravenously
once every 3 weeks. The median age was 65 years (range: 39 to 85 years), 53% were male, 74%
were White, and 16% were Black. Most patients (77%) were International Staging System (ISS)
Stage II or III, 87% had received prior autologous stem cell transplantation (ASCT), and 16%
had an Eastern Cooperative Oncology Group (ECOG) performance status of 2. High-risk
cytogenetic factors (presence of t[4;14], t[14;16] and 17p13del) were present in 27% of patients.
The median number of prior lines of therapy was 7 (range: 3 to 21).
Efficacy results are summarized in Table 6. The median time to first response was 1.4 months
(95% CI: 1.0, 1.6). Seventy-three percent of responders had a duration of response ≥6 months.
Table 6. Efficacy in DREAMM-2
BLENREP
N = 97
Overall response rate (ORR), n (%)
(97.5% CI)
30 (31%)
(21%, 43%)
2 (2%)
Stringent complete response (sCR), n (%)
Complete response (CR), n (%)
Very good partial response (VGPR), n (%)
Partial response (PR), n (%)
1 (1%)
15 (15%)
12 (12%)
Median duration of response in months
NR = Not reached.
a
(range)
NR [NR to NR]
a
15
REFERENCES
1. “OSHA Hazardous Drugs.”OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html.
16
HOW SUPPLIED/STORAGE AND HANDLING
BLENREP (belantamab mafodotin-blmf) for injection is a sterile, preservative-free, white to
yellow lyophilized powder for reconstitution and further dilution prior to intravenous use.
BLENREP is supplied in a carton containing one 100-mg single-dose vial with a rubber stopper
(not made with natural rubber latex) and aluminum overseal with removable cap (NDC 0173
0896-01).
Store vials refrigerated at 36ºF to 46ºF (2ºC to 8ºC).
BLENREP is a hazardous drug. Follow applicable special handling and disposal procedures.
1
17
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
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Ocular Toxicity
• Advise patients that ocular toxicity may occur during treatment with BLENREP [see
Warnings and Precautions (5.1)].
• Advise patients to administer preservative-free lubricant eye drops as recommended during
treatment and to avoid wearing contact lenses during treatment unless directed by a
healthcare professional[see Dosage and Administration (2.3), Warnings and Precautions
(5.1)].
• Advise patients to use caution when driving or operating machinery as BLENREP may
adversely affect their vision[see Warnings and Precautions (5.1)].
BLENREP REMS
BLENREP is available only through a restricted program called BLENREP REMS [see
Warnings and Precautions (5.2)]. Inform the patient of the following notable requirements:
• Patients must complete the enrollment form with their provider.
• Patients must comply with ongoing monitoring for eye exams[see Warnings and
Precautions (5.1)].
Thrombocytopenia
• Advise patients to inform their healthcare provider if they develop signs or symptoms of
bleeding[see Warnings and Precautions (5.3)].
Infusion-Related Reactions
• Advise patients to immediately report any signs and symptoms of infusion-related reactions
to their healthcare provider[see Warnings and Precautions (5.4)].
Embryo-Fetal Toxicity
• Advise pregnant women of the potential risk 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 women of reproductive potential to use highly effective contraception during
treatment and for 4 months after the last dose[see Warnings and Precautions (5.5), Use in
Specific Populations (8.3)].
• Advise males with female partners of reproductive potential to use effective contraception
during treatment with BLENREP and for 6 months after the last dose[see Use in Specific
Populations (8.3), Nonclinical Toxicology (13.1)].
Lactation
• Advise women not to breastfeed during treatment with BLENREP and for 3 months after the
last dose[see Use in Specific Populations (8.2)].
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Reference ID: 4652412
Infertility
• Advise males and females of reproductive potential that BLENREP may impair fertility [see
Use in Specific Populations (8.3)].
Trademarks are owned by or licensed to the GSK group of companies.
Manufactured by:
GlaxoSmithKline Intellectual Property Development Ltd. England
Brentford, Middlesex, UK TW8 9GS
U.S. License No. XXXX
including by use of Potelligent technology licensed from BioWa, Inc.
For:
GlaxoSmithKline
Research Triangle Park, NC 27709
©2020 GSK group of companies or its licensor.
BRP:1PI
20
Reference ID: 4652412
MEDICATION GUIDE
BLENREP (BLEN-REP)
(belantamab mafodotin-blmf)
for injection, for intravenous use
What is the most important information I should know about BLENREP?
Before you receive BLENREP, you must read and agree to all of the instructions in the BLENREP
REMS. Before prescribing BLENREP, your healthcare provider will explain the BLENREP REMS to
you and have you sign the Patient Enrollment Form.
BLENREP can cause serious side effects, including:
Eye problems. Eye problems are common with BLENREP. BLENREP can cause changes to the
surface of your eye that can lead to dry eyes, blurred vision, worsening vision, severe vision loss, and
corneal ulcer. Tell your healthcare provider if you have any vision changes or eye problems during
treatment with BLENREP.
•
•
•
Your healthcare provider will send you to an eye specialist to check your eyes before you start
treatment with BLENREP, prior to each dose of BLENREP, and for worsening symptoms of eye
problems.
Even if your vision seems fine, it is important that you get your eyes checked during treatment with
BLENREP because some changes can happen without symptoms and may only be seen on an
eye exam.
You should use preservative-free lubricant eye drops at least 4 times per day during treatment with
BLENREP as instructed by your healthcare provider.
•
•
You should use caution when driving or operating machinery as BLENREP may affect your vision.
Avoid wearing contact lenses during treatment with BLENREP unless directed by your eye
specialist.
See “What are the possible side effects of BLENREP?” for more information about serious side
effects.
What is BLENREP?
BLENREP is a prescription medicine used to treat adults with multiple myeloma who:
•
•
have received at least 4 prior medicines to treat multiple myeloma, and
their cancer has come back or did not respond to prior treatment.
It is not known if BLENREP is safe and effective in children.
Before receiving BLENREP, tell your healthcare provider about all of your medical conditions,
including if you:
•
•
•
have a history of vision or eye problems.
have bleeding problems or a history of bleeding problems.
are pregnant or plan to become pregnant. BLENREP can harm your unborn baby.
Females who are able to become pregnant:
o
Your healthcare provider may do a pregnancy test before you start treatment with
BLENREP.
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o
o
You should use effective birth control during treatment with BLENREP and for 4 months
after the last dose. Talk to your healthcare provider about birth control methods you can
use during this time.
Tell your healthcare provider if you become pregnant or think you may be pregnant during
treatment with BLENREP.
Males with female partners who are able to become pregnant should use effective birth
control during treatment with BLENREP and for 6 months after the last dose.
are breastfeeding or plan to breastfeed. It is not known if BLENREP passes into your breast milk.
Do not breastfeed during treatment with BLENREP and for 3 months after the last dose.
BLENREP may affect fertility in males and females. Talk to your healthcare provider if this is a
concern for you.
•
•
Tell your healthcare provider about all the medicines you take, including prescription and over-the
counter medicines, vitamins, and herbal supplements.
How will I receive BLENREP?
•
BLENREP will be given to you by your healthcare provider by intravenous infusion into your vein
over approximately 30 minutes.
•
•
•
BLENREP is usually given every 3 weeks.
Your healthcare provider will decide how many treatments you need.
Your healthcare provider may decrease your dose, temporarily stop or completely stop treatment
with BLENREP if you have serious side effects.
•
If you miss any appointments, call your healthcare provider as soon as possible to reschedule your
appointment.
What are the possible side effects of BLENREP?
BLENREP can cause serious side effects, including:
•
See Eye Problems in “What is the most important information I should know about
BLENREP?”
•
Decrease in platelets (thrombocytopenia) is common with BLENREP, and can also be serious.
Platelets are a type of blood cell that help your blood to clot. Your healthcare provider will check
your blood cell counts before you start treatment with BLENREP and during treatment. Tell your
healthcare provider if you have bleeding or bruising during treatment with BLENREP.
Infusion reactions are common with BLENREP, and can also be serious. Tell your healthcare
provider or nurse right away if you get any of the following signs or symptoms of an infusion
reaction while receiving BLENREP:
•
ochills or shaking
odizziness
oredness of your face (flushing)
oitching or rash
ofeel like passing out
otiredness
oshortness of breath, cough, or wheezing
oswelling of your lips, tongue, throat, or face
ofever
ofeel like your heart is racing (palpitations)
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•
The most common side effects of BLENREP include vision or eye changes such as findings on
eye exam (keratopathy), decreased vision or blurred vision, nausea, low blood cell counts, fever,
infusion-related reactions, tiredness, and changes in kidney or liver function blood tests.
These are not all the possible side effects of BLENREP.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800
FDA-1088.
General information about the safe and effective use of BLENREP.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You
can ask your pharmacist or healthcare provider for information about BLENREP that is written for
health professionals.
What are the ingredients in BLENREP?
Active Ingredient: belantamab mafodotin-blmf
Inactive Ingredients: citric acid, disodium edetate dihydrate, polysorbate 80, trehalose dihydrate,
trisodium citrate dihydrate.
Manufactured by:
For:
GlaxoSmithKline Intellectual Property Development Ltd., England
Brentford, Middlesex, UK TW8 9GS
GlaxoSmithKline, Research Triangle Park, NC
27709
U.S. License No. XXXX
including by use of Potelligent technology licensed from BioWa, Inc.
©2020 GSK group of companies or its licensor.
BRP:1MG
For more information, call GlaxoSmithKline (GSK) at 1-888-825-5249.
Trademarks are owned by or licensed to the GSK group of companies.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Issued: 08/2020
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