` CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`
`
`
`APPLICATION NUMBER:
`
`
`761145Orig1s000
`
`
`
`LABELING
`
`
`
`
`x
`
`x
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`
`DARZALEX FASPRO safely and effectively. See full prescribing
`
`information for DARZALEX FASPRO.
`DARZALEX FASPROTM (daratumumab and hyaluronidase-fihj)
`injection, for subcutaneous use
`
`Initial U.S. Approval: 2020
`-----------------------------INDICATIONS AND USAGE---------------------------
`
`DARZALEX FASPRO is a combination of daratumumab, a CD38-directed
`
`
`
`
`cytolytic antibody, and hyaluronidase, an endoglycosidase, for the treatment
`of adult patients with multiple myeloma:
`in combination with bortezomib, melphalan and prednisone in newly
`x
`
`
`diagnosed patients who are ineligible for autologous stem cell transplant
`in combination with lenalidomide and dexamethasone in newly diagnosed
`
`
`patients who are ineligible for autologous stem cell transplant and in
`
`
`patients with relapsed or refractory multiple myeloma who have received
`at least one prior therapy
`in combination with bortezomib and dexamethasone in patients who have
`received at least one prior therapy
`
`
`x as monotherapy, in patients who have received at least three prior lines of
`
`
`therapy including a proteasome inhibitor (PI) and an immunomodulatory
`
`agent or who are double-refractory to a PI and an immunomodulatory
`agent. (1)
`------------------------DOSAGE AND ADMINISTRATION-----------------------
`For subcutaneous use only.
`x Pre-medicate with a corticosteroid, acetaminophen and a histamine-1
`receptor antagonist. (2.3)
`
`x The recommended dosage of DARZALEX FASPRO is (1,800 mg
`daratumumab and 30,000 units hyaluronidase) administered
`subcutaneously into the abdomen over approximately 3 to 5 minutes
`according to recommended schedule. (2.2)
`x Administer post-medications as recommended. (2.3)
`----------------------DOSAGE FORMS AND STRENGTHS---------------------
`x Injection: 1,800 mg daratumumab and 30,000 units hyaluronidase per
`15 mL (120 mg and 2,000 units/mL) solution in a single-dose vial (3)
`
`-----------------------------CONTRAINDICATIONS---------------------------------
`Patients with a history of severe hypersensitivity to daratumumab or any of
`
`the components of the formulation. (4)
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`1
`INDICATIONS AND USAGE
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`Important Dosing Information
`2.1
`
`
`2.2
`Recommended Dosage
`
`
`2.3
`Recommended Concomitant Medications
`
`
`2.4
`Dosage Modifications for Adverse Reactions
`
`
`2.5
`Preparation and Administration
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`
`4 CONTRAINDICATIONS
`
`
`5 WARNINGS AND PRECAUTIONS
`
`Hypersensitivity and Other Administration
`5.1
`
`
`Reactions
`
`
`Neutropenia
`
`
`Thrombocytopenia
`
`
`Embryo-Fetal Toxicity
`
`
`Interference with Serological Testing
`
`Interference with Determination of Complete
`
`Response
`
`
`6 ADVERSE REACTIONS
`
`
`Clinical Trials Experience
`6.1
`
`
`Immunogenicity
`6.2
`
`
`Postmarketing Experience
`6.3
`
`7 DRUG INTERACTIONS
`
`5.2
`5.3
`5.4
`5.5
`5.6
`
`
`
`Reference ID: 4601659Reference ID: 4753174
`
`-------------------------WARNINGS AND PRECAUTIONS----------------------
`x Hypersensitivity and Other Administration Reactions: Permanently
`
`discontinue DARZALEX FASPRO for life-threatening reactions. (5.1)
`
`x Neutropenia: Monitor complete blood cell counts periodically during
`treatment. Monitor patients with neutropenia for signs of infection.
`Consider withholding DARZALEX FASPRO to allow recovery of
`
`neutrophils. (5 2)
`x Thrombocytopenia: Monitor complete blood cell counts periodically
`during treatment. Consider withholding DARZALEX FASPRO to allow
`
`recovery of platelets. (5.3)
`
`x Embryo-Fetal Toxicity: Can cause fetal harm. Advise pregnant women of
`
`the potential risk to a fetus and advise females of reproductive potential to
`use effective contraception (5.4, 8.1, 8.3).
`x Interference with cross-matching and red blood cell antibody screening:
`Type and screen patients prior to starting treatment. Inform blood banks
`that a patient has received DARZALEX FASPRO. (5.5, 7.1)
`------------------------------ADVERSE REACTIONS-------------------------------
`x The most common adverse reaction (
`monotherapy is: upper respiratory tracts infection. (6.1)
`x The most common adYHUVH UHDFWLRQV
`
`respiratory tract infection, constipation, nausea, fatigue, pyrexia, peripheral
`
`sensory neuropathy, diarrhea, cough, insomnia, vomiting, and back pain.
`
`(6.1)
`x The most comPRQ DGYHUVH UHDFWLRQV
`diarrhea, upper respiratory tract infection, muscle spasms, constipation,
`
`
`
`pyrexia, pneumonia and dyspnea. (6.1)
`
`x The most common hematology laboratory abnormalities (40%) with
`
`
`DARZALEX FASPRO are decreased leukocytes, decreased lymphocytes,
`
`decreased neutrophils, decreased platelets, and decreased hemoglobin.
`
`(6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Janssen
`Biotech, Inc. at 1-800-526-7736 (1-800-JANSSEN) or FDA at 1-800-FDA-
`1088 or www.fda.gov/medwatch.
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved patient labeling.
`
`Revised: 05/2020
`
`
`
`
`Effects of Daratumumab on Laboratory Tests
`7.1
`
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1
`Pregnancy
`
`
`8.2
`Lactation
`
`
`8.3
`Females and Males of Reproductive Potential
`
`
`8.4
`Pediatric Use
`
`
`8.5 Geriatric Use
`
`
`11 DESCRIPTION
`
`
`12 CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`
`12.2 Pharmacodynamics
`
`
`12.3 Pharmacokinetics
`
`
`13 NONCLINICAL TOXICOLOGY
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of
`
`
`Fertility
`
`
`
`14 CLINICAL STUDIES
`
`
`14.1 Newly Diagnosed Multiple Myeloma
`
`
`14.2 Relapsed/Refractory Multiple Myeloma
`
`
`15 REFERENCES
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`17 PATIENT COUNSELING INFORMATION
`*Sections or subsections omitted from the full prescribing information are not
`
`
`listed.
`
`1
`
`
`
`FULL PRESCRIBING INFORMATION
`1
`INDICATIONS AND USAGE
`DARZALEX FASPRO is indicated for the treatment of adult patients with multiple myeloma:
`
`x
`
`x
`
`in combination with bortezomib, melphalan and prednisone in newly diagnosed patients
`who are ineligible for autologous stem cell transplant.
`in combination with lenalidomide and dexamethasone in newly diagnosed patients who
`
`
`
` are ineligible for autologous stem cell transplant and in patients with relapsed or
`refractory multiple myeloma who have received at least one prior therapy.
`in combination with bortezomib and dexamethasone in patients who have received at
`
`least one prior therapy.
`as monotherapy, in patients who have received at least three prior lines of therapy
`
`
`including a proteasome inhibitor (PI) and an immunomodulatory agent or who are
`
`double-refractory to a PI and an immunomodulatory agent.
`2 DOSAGE AND ADMINISTRATION
`Important Dosing Information
`2.1
`DARZALEX FASPRO is for subcutaneous use only.
`Administer medications before and after administration of DARZALEX FASPRO to
`
`
`minimize administration-related reactions [see Dosage and Administration (2.3)].
`Type and screen patients prior to starting DARZALEX FASPRO.
`x
`Recommended Dosage
`2.2
`The recommended dose of DARZALEX FASPRO is 1,800 mg/30,000 units (1,800 mg
`daratumumab and 30,000 units hyaluronidase) administered subcutaneously over approximately
`3-5 minutes. Tables 1, 2, and 3 provide the recommended dosing schedule when DARZALEX
`FASPRO is administered as monotherapy or as part of a combination therapy.
`
`x
`
`x
`
`x
`x
`
`Monotherapy and In Combination with Lenalidomide and Dexamethasone (D-Rd)
`Use the dosing schedule provided in Table 1 when DARZALEX FASPRO is administered:
`
`x
`x
`Table 1:
`
`in combination with lenalidomide and dexamethasone (4-week cycle) OR
`as monotherapy.
`
` DARZALEX FASPRO dosing schedule in combination with lenalidomide and dexamethasone
`(4-week cycle) and for monotherapy
`
`Schedule
`Weeks
`weekly (total of 8 doses)
`Weeks 1 to 8
`every two weeks (total of 8 doses)
`Weeks 9 to 24a
`every four weeks
`
`
` Week 25 onwards until disease progressionb
`a
` First dose of the every-2-week dosing schedule is given at Week 9
`
`b
`First dose of the every-4-week dosing schedule is given at Week 25
`
`2
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`Reference ID: 4601659Reference ID: 4753174
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`
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`When DARZALEX FASPRO is administered as part of a combination therapy, see Clinical
`Studies (14.2) and the prescribing information for dosage recommendations for the other drugs.
`
`In Combination with Bortezomib, Melphalan and Prednisone (D-VMP)
`Use the dosing schedule provided in Table 2 when DARZALEX FASPRO is administered in
`combination with bortezomib, melphalan and prednisone (6-week cycle).
`
`Table 2:
`
` DARZALEX FASPRO dosing schedule in combination with bortezomib, melphalan and
`
`prednisone (6-week cycle)
`
`
`
`
`
`Weeks
` weekly (total of 6 doses)
`
`
`
`Weeks 1 to 6
`every three weeks (total of 16 doses)
`Weeks 7 to 54a
`every four weeks
`Week 55 onwards until disease progressionb
`a
`
` First dose of the every-3-week dosing schedule is given at Week 7
`b
`
`First dose of the every-4-week dosing schedule is given at Week 55
`
`Schedule
`
` When DARZALEX FASPRO is administered as part of a combination therapy, see Clinical
`
`Studies (14.1) and the prescribing information for dosage recommendations for the other drugs.
`
`In Combination with Bortezomib and Dexamethasone (D-Vd)
`Use the dosing schedule in Table 3 when DARZALEX FASPRO is administered in combination
`with bortezomib and dexamethasone (3-week cycle).
`
`Table 3:
`
` DARZALEX FASPRO dosing schedule in combination with bortezomib and dexamethasone (3-
`
`week cycle)
`
`
`
`Weeks
`Weeks 1 to 9
`Weeks 10 to 24a
`Week 25 onwards until disease progressionb
`a
`
` First dose of the every-3-week dosing schedule is given at Week 10
`b
`First dose of the every-4-week dosing schedule is given at Week 25
`
`
`Schedule
`weekly (total of 9 doses)
`
` every three weeks (total of 5 doses)
`
`every four weeks
`
` When DARZALEX FASPRO is administered as part of a combination therapy, see the
`
`
`prescribing information for dosage recommendations for the other drugs.
`Missed DARZALEX FASPRO Doses
`If a dose of DARZALEX FASPRO is missed, administer the dose as soon as possible and adjust
`the dosing schedule to maintain the dosing interval.
`2.3 Recommended Concomitant Medications
`Pre-medication
`Administer the following pre-medications 1-3 hours before each dose of DARZALEX FASPRO:
`
`x
`x
`
`Acetaminophen 650 to 1,000 mg orally
`Diphenhydramine 25 to 50 mg (or equivalent) orally or intravenously
`
`3
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`Reference ID: 4601659Reference ID: 4753174
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`
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`
`
`x
`
`Corticosteroid (long- or intermediate-acting)
`Monotherapy
`Administer methylprednisolone 100 mg (or equivalent) orally or intravenously. Consider
`reducing the dose of methylprednisolone to 60 mg (or equivalent) following the second
`dose of DARZALEX FASPRO.
`In Combination
` Administer dexamethasone 20 mg (or equivalent) orally or intravenously prior to every
`
`
`DARZALEX FASPRO administration.
` the
` regimen-specific corticosteroid,
`When dexamethasone
`is
`the background
`
`
`dexamethasone dose that is part of the background regimen will serve as pre-medication
`on DARZALEX FASPRO administration days [see Clinical Studies (14)].
`Do not administer background regimen-specific corticosteroids (e.g. prednisone) on
`DARZALEX FASPRO administration days when patients have received dexamethasone
`
`
`(or equivalent) as a pre-medication.
`Post-medication
`Administer the following post-medications:
`Monotherapy
`Administer methylprednisolone 20 mg (or an equivalent dose of an intermediate- or long-
`acting corticosteroid) orally for 2 days starting the day after the administration of
`
`DARZALEX FASPRO.
`In Combination
`Consider administering oral methylprednisolone at a dose of less than or equal to 20 mg
`
`(or an equivalent dose of an intermediate- or long-acting corticosteroid) beginning the
`day after administration of DARZALEX FASPRO.
`If a background regimen-specific corticosteroid (e.g. dexamethasone, prednisone) is
`
`administered the day after the administration of DARZALEX FASPRO, additional
`corticosteroids may not be needed [see Clinical Studies (14)].
`If the patient does not experience a major systemic administration-related reaction after the first
`
`3 doses of DARZALEX FASPRO, consider discontinuing the administration of corticosteroids
`(excluding any background regimen-specific corticosteroid).
`For patients with a history of chronic obstructive pulmonary disease, consider prescribing short
`
`and long-acting bronchodilators and inhaled corticosteroids. Following the first 4 doses of
`DARZALEX FASPRO, consider discontinuing these additional post-medications, if the patient
`does not experience a major systemic administration-related reaction.
`
`
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`Reference ID: 4601659Reference ID: 4753174
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`4
`
`
`
`Prophylaxis for Herpes Zoster Reactivation
` Initiate antiviral prophylaxis to prevent herpes zoster reactivation within 1 week after starting
`
`DARZALEX FASPRO and continue for 3 months following the end of treatment [see Adverse
`Reactions (6.1)].
`Dosage Modifications for Adverse Reactions
`2.4
`No dose reductions of DARZALEX FASPRO are recommended. Consider withholding
`DARZALEX FASPRO to allow recovery of blood cell counts in the event of myelosuppression
`
`[see Warnings and Precautions (5.2, 5.3)].
`Preparation and Administration
`2.5
`DARZALEX FASPRO should be administered by a healthcare provider.
`To prevent medication errors, check the vial labels to ensure that the drug being prepared and
`administered is DARZALEX FASPRO for subcutaneous use. Do not administer DARZALEX
`FASPRO intravenously.
`DARZALEX FASPRO is ready to use.
`Preparation
`Remove the DARZALEX FASPRO vial from refrigerated storage [2°C to 8°C (36°F to
`
`x
`46°F)] and equilibrate to ambient temperature [15°C to 30°C (59°F to 86°F)]. Store the
`unpunctured vial at ambient temperature and ambient light for a maximum of 24 hours.
`Keep out of direct sunlight. Do not shake.
`Withdraw 15 mL from the vial into a syringe.
`DARZALEX FASPRO is compatible with polypropylene or polyethylene syringe
`material; polypropylene, polyethylene, or polyvinyl chloride (PVC) subcutaneous
`
`
`infusion sets; and stainless steel transfer and injection needles. Use the product
`immediately.
`After the solution of DARZALEX FASPRO is withdrawn into the syringe, replace the
`
`transfer needle with a syringe closing cap. Label the syringe appropriately to include the
`
`route of administration per institutional standards. Label the syringe with the peel-off
`
`
`label.
`To avoid needle clogging, attach the hypodermic injection needle or subcutaneous
`infusion set to the syringe immediately prior to injection.
`Parenteral drug products should be inspected visually for particulate matter and
`
`discoloration prior to administration, whenever solution and container permit. Do not use
`if opaque particles, discoloration or other foreign particles are present.
`
`x
`x
`
`x
`
`x
`
`x
`
`
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`Reference ID: 4601659Reference ID: 4753174
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`5
`
`
`
`Storage
`
`x
`
`x
`
`x
`x
`
`x
`
`x
`
` If the syringe containing DARZALEX FASPRO is not used immediately, store the
`
`DARZALEX FASPRO solution for up to 4 hours at ambient temperature and ambient
`light. Discard after 4 hours, if not used.
`Administration
`Inject 15 mL DARZALEX FASPRO into the subcutaneous tissue of the abdomen
`approximately 3 inches [7.5 cm] to the right or left of the navel over approximately
`3-5 minutes. No data are available on performing the injection at other sites of the body.
`Rotate injection sites for successive injections.
`Never inject DARZALEX FASPRO into areas where the skin is red, bruised, tender, hard
`or areas where there are scars.
`Pause or slow down delivery rate if the patient experiences pain. In the event pain is not
`
`alleviated by pausing or slowing down delivery rate, a second injection site may be
`
`chosen on the opposite side of the abdomen to deliver the remainder of the dose.
`During treatment with DARZALEX FASPRO, do not administer other medications for
`
`subcutaneous use at the same site as DARZALEX FASPRO.
`DOSAGE FORMS AND STRENGTHS
`3
`Injection: 1,800 mg daratumumab and 30,000 units hyaluronidase per 15 mL (120 mg and
`
`2,000 units/mL) colorless to yellow and clear to opalescent solution in a single-dose vial.
`4 CONTRAINDICATIONS
`DARZALEX FASPRO is contraindicated in patients with a history of severe hypersensitivity to
`
`
`daratumumab, hyaluronidase or any of the components of the formulation [see Warnings and
`Precautions (5.1) and Adverse Reactions (6.3)].
`5 WARNINGS AND PRECAUTIONS
`Hypersensitivity and Other Administration Reactions
`5.1
`Both systemic administration-related reactions, including severe or life-threatening reactions,
`
`
`and local injection-site reactions can occur with DARZALEX FASPRO.
`Systemic Reactions
`In a pooled safety population of 490 patients who received DARZALEX FASPRO as
`monotherapy or in combination, 11% of patients experienced a systemic administration-related
`reaction (Grade 2: 3.9%, Grade 3: 1.4%). Systemic administration-related reactions occurred in
`10% of patients with the first injection, 0.2% with the second injection, and cumulatively 0.8%
`with subsequent injections. The median time to onset was 3.7 hours (range: 9 minutes to
`
`3.5 days). Of the 84 systemic administration-related reactions that occurred in 52 patients,
`
`73 (87%) occurred on the day of DARZALEX FASPRO administration. Delayed systemic
`administration-related reactions have occurred in less than 1% of the patients.
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`
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`Reference ID: 4601659Reference ID: 4753174
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`6
`
`
`
`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, pruritis, chills, vomiting, nausea, and
`
`hypotension.
`Pre-medicate patients with histamine-1 receptor antagonist, acetaminophen and corticosteroids
`[see Dosage and Administration (2.3)]. 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 (2.3)].
`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 7 minutes (range: 0 minutes to 4.7 days)
`after starting administration of DARZALEX FASPRO. Monitor for local reactions and consider
`
`
`
`symptomatic management.
`5.2 Neutropenia
`Daratumumab may increase neutropenia induced by background therapy [see Adverse Reactions
`
`
`(6.1)].
`Monitor complete blood cell counts periodically during treatment according to manufacturer’s
`prescribing information for background therapies. Monitor patients with neutropenia for signs of
`infection. Consider withholding DARZALEX FASPRO until recovery of neutrophils. In lower
`body weight patients receiving DARZALEX FASPRO, higher rates of Grade 3-4 neutropenia
`were observed.
`5.3
`Thrombocytopenia
`Daratumumab may increase thrombocytopenia induced by background therapy [see Adverse
`Reactions (6.1)].
`Monitor complete blood cell counts periodically during treatment according to manufacturer’s
`
`
`prescribing information for background therapies. Consider withholding DARZALEX FASPRO
`until recovery of platelets.
`5.4 Embryo-Fetal Toxicity
`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
`
`
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`
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`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 is contraindicated in pregnant
`
`
` women, because lenalidomide may cause birth defects and death of the unborn child. Refer to the
`lenalidomide prescribing information on use during pregnancy.
`Interference with Serological Testing
`5.5
` Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive Indirect
`
`
` Antiglobulin Test (Indirect Coombs test). Daratumumab-mediated positive indirect antiglobulin
`
` test may persist for up to 6 months after the last daratumumab administration. Daratumumab
`
`
`bound to RBCs masks detection of antibodies to minor antigens in the patient’s serum [see
`References (15)]. The determination of a patient’s ABO and Rh blood type are not impacted [see
`
`
`Drug Interactions (7.1)].
`Notify blood transfusion centers of this interference with serological testing and inform blood
`
`banks that a patient has received DARZALEX FASPRO. Type and screen patients prior to
`starting DARZALEX FASPRO [see Dosage and Administration (2.1)].
`Interference with Determination of Complete Response
`5.6
`
`Daratumumab is a human IgG kappa monoclonal antibody that can be detected on both the
`
`serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical
`
`monitoring of endogenous M-protein [see Drug Interactions (7.1)]. This interference can impact
`the determination of complete response and of disease progression in some DARZALEX
`
`
`FASPRO-treated patients with IgG kappa myeloma protein.
`6 ADVERSE REACTIONS
`The following clinically significant adverse reactions are described elsewhere in the labeling:
`
`x
`
`Hypersensitivity and Other Administration Reactions [see Warning and Precautions
`(5.1)].
`Neutropenia [see Warning and Precautions (5.2)].
`x
`Thrombocytopenia [see Warning and Precautions (5.3)].
`x
`Clinical Trials Experience
`6.1
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates
`observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials
`
`
`of another drug and may not reflect the rates observed in practice.
`Newly Diagnosed Multiple Myeloma
`In Combination with Bortezomib, Melphalan and Prednisone
`The safety of DARZALEX FASPRO with bortezomib, melphalan and prednisone (D-VMP) was
`evaluated in a single-arm cohort of PLEIADES [see Clinical Studies (14.1)]. Patients received
`
`
`
`8
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`Reference ID: 4601659Reference ID: 4753174
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`
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`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 54 and once every 4 weeks starting with
`
`
`
`
`
`week 55 until disease progression or unacceptable toxicity (N=67) in combination with
`bortezomib, melphalan and prednisone. Among these patients, 93% were exposed for 6 months
`or longer and 19% were exposed for greater than one year.
`Serious adverse reactions occurred in 39% of patients who received DARZALEX FASPRO.
`
`
`Serious adverse reactions in >5% of patients included pneumonia and pyrexia. Fatal adverse
`
`reactions occurred in 3.0% of patients.
`Permanent discontinuation of DARZALEX FASPRO due to an adverse reaction occurred in
`4.5% of patients. The adverse reaction resulting in permanent discontinuation of DARZALEX
`FASPRO in more than 1 patient was neutropenic sepsis.
`Dosage interruptions (defined as dose delays or skipped doses) due to an adverse reaction
`occurred in 51% of patients who received DARZALEX FASPRO. Adverse reactions requiring
`dosage interruptions in >5% of patients included thrombocytopenia, neutropenia, anemia, and
`pneumonia.
`The most common adverse reactions (
`nausea, fatigue, pyrexia, peripheral sensory neuropathy, diarrhea, cough, insomnia, vomiting,
`and back pain.
`Table 4 summarizes the adverse reactions in patients who received DARZALEX FASPRO with
`bortezomib, melphalan and prednisone (D-VMP) in PLEIADES.
`
`Table 4:
`
`
`
` AdversH 5HDFWLRQV
`
`
` Melphalan and Prednisone (D-VMP) in PLEIADES
`
`
`
`Adverse Reaction
`Infections
`Upper respiratory tract infectiona
`Bronchitis
`Pneumoniab
`Gastrointestinal disorders
`Constipation
`Nausea
`Diarrhea
`Vomiting
`Abdominal painc
`
`General disorders and administration site conditions
`Fatigued
`Pyrexia
`Edema peripherale
`
` Nervous system disorders
` Peripheral sensory neuropathy
`
`Dizziness
`
`
`
`Reference ID: 4601659Reference ID: 4753174
`
` DARZALEX FASPRO
`
`with Bortezomib, Melphalan and Prednisone
`(N=67)
`
`All Grades
`
`(%)
`
`Grades 3
`(%)
`
`39
`16
`15
`
`37
`36
`33
`21
`13
`
`36
`34
`13
`
`34
`10
`
`0
`0
`7#
`
`0
`0
`3#
`0
`0
`
`3
`0
`1#
`
`1#
`0
`
`9
`
`
`
`24
`
`22
`
`21
`12
`
`15
`
`13
`12
`
`0
`
`3#
`
`3#
`0
`
`1#
`
`0
`0
`
`Respiratory, thoracic and mediastinal disorders
`Coughf
`Psychiatric disorders
`Insomnia
`Musculoskeletal and connective tissue disorders
`Back pain
`Musculoskeletal chest pain
`
`
`Metabolism and nutrition disorders
`Decreased appetite
`Skin and subcutaneous tissue disorders
`Rash
`Pruritus
`Vascular disorders
`6#
`13
`Hypertension
`3#
`10
`Hypotension
`a Upper respiratory tract infection includes nasopharyngitis, respiratory syncytial virus infection, respiratory tract infection, rhinitis, tonsillitis,
`upper respiratory tract infection, and viral pharyngitis.
`Pneumonia includes lower respiratory tract infection, lung infection, pneumocystis jirovecii pneumonia, pneumonia, and pneumonia
`bacterial.
`c Abdominal pain includes abdominal pain, and abdominal pain upper.
`d
`Fatigue includes asthenia, and fatigue.
`e
`Edema peripheral includes edema, edema peripheral, and peripheral swelling.
`f
`Cough includes cough, and productive cough.
`# Only grade 3 adverse reactions occurred.
`
`b
`
`x
`
`Clinically relevant adverse reactions in <10% of patients who received DARZALEX FASPRO
`with bortezomib, melphalan and prednisone (D-VMP) include:
`General disorders and administration site conditions: infusion reaction, injection site
`reaction, chills
`Infections: herpes zoster, urinary tract infection, influenza, sepsis
`x
`Musculoskeletal and connective tissue disorders: arthralgia, muscle spasms
`x
`Nervous system disorders: headache, paresthesia
`x
`Metabolism and nutrition disorders: hypocalcemia, hyperglycemia
`x
`Respiratory, thoracic and mediastinal disorders: dyspnea, pulmonary edema
`x
`Cardiac disorders: atrial fibrillation
`x
`Table 5 summarizes the laboratory abnormalities in patients who received DARZALEX
`FASPRO with bortezomib, melphalan and prednisone (D-VMP) in PLEIADES.
`Select Hematology Laboratory Abnormalities Worsening from Baseline in Patients Who
`Table 5:
`Received DARZALEX FASPRO with Bortezomib, Melphalan and Prednisone (D-VMP) in
`
`PLEIADES
`
`
`Laboratory Abnormality
`Decreased leukocytes
`Decreased lymphocytes
`Decreased platelets
`
`
`
`DARZALEX FASPRO
`with Bortezomib, Melphalan and Prednisone a
`All Grades
`Grades 3-4
`
`(%)
`(%)
`96
`52
`93
`84
`93
`42
`
`10
`
`
`
`Reference ID: 4601659Reference ID: 4753174
`
`
`
`88
`Decreased neutrophils
`48
`Decreased hemoglobin
`a Denominator is based on the safety population treated with D-VMP (N=67).
`
`49
`19
`
`Relapsed/Refractory Multiple Myeloma
`In Combination with Lenalidomide and Dexamethasone
`The safety of DARZALEX FASPRO with lenalidomide and dexamethasone (D-Rd) was
`
`evaluated in a single-arm cohort of PLEIADES [see Clinical Studies (14.2)]. Patients received
`DARZALEX FASPRO 1,800 mg/30,000 units administered subcutaneously once weekly from
`weeks 1 to 8, once every 2 weeks from weeks 9 to 24 and once every 4 weeks starting with
`
`
`week 25 until disease progression or unacceptable toxicity (N=65) in combination with
`
`lenalidomide and dexamethasone. Among these patients, 92% were exposed for 6 months or
`longer and 20% were exposed for greater than one year.
`Serious adverse reactions occurred in 48% of patients who received DARZALEX FASPRO.
`
`Serious adverse reactions in >5% of patients included pneumonia, influenza and diarrhea. Fatal
`adverse reactions occurred in 3.1% of patients.
`Permanent discontinuation of DARZALEX FASPRO due to an adverse reaction occurred in 11%
`of patients who received DARZALEX FASPRO. Adverse reactions resulting in permanent
`
`discontinuation of DARZALEX FASPRO in more than 1 patient were pneumonia and anemia.
`Dosage interruptions due to an adverse reaction occurred in 63% of patients who received
`
`DARZALEX FASPRO. Adverse reactions requiring dosage interruptions in >5% of patients
`included neutropenia, pneumonia, upper respiratory tract infection, influenza, dyspnea, and
`blood creatinine increased.
`The most common adverse reaFWLRQV 20%) were fatigue, diarrhea, upper respiratory tract
`
`infection, muscle spasms, constipation, pyrexia, pneumonia, and dyspnea.
`Table 6 summarizes the adverse reactions in patients who received DARZALEX FASPRO with
`
`lenalidomide and dexamethasone (D-Rd) in PLEIADES.
`Table 6:
`$GYHUVH 5HDFWLRQV 10%) in Patients Who Received DARZALEX FASPRO with Lenalidomide
`and Dexamethasone (D-Rd) in PLEIADES
`
`Adverse Reaction
`General disorders and administration site conditions
`
`Fatiguea
`Pyrexia
`Edema peripheral
`Gastrointestinal disorders
`Diarrhea
`Constipation
`Nausea
`Vomiting
`
`
`
`Reference ID: 4601659Reference ID: 4753174
`
`
`DARZALEX FASPRO
`with Lenalidomide and Dexamethasone
`(N=65)
`
`All Grades
`(%)
`
`Grades 3
`(%)
`
`52
`23
`18
`
`45
`26
`12
`11
`
`5#
`2#
`3#
`
`5#
`2#
`0
`0
`
`11
`
`
`
`Infections
`Upper respiratory tract infectionb
`Pneumoniac
`Bronchitisd
`Urinary tract infection
`
`Musculoskeletal and connective tissue disorders
`Muscle spasms
`Back pain
` Respiratory, thoracic and mediastinal disorders
`Dyspneae
`Coughf
`
` Nervous system disorders
` Peripheral sensory neuropathy
`
`Psychiatric disorders
`Insomnia
` Metabolism and nutrition disorders
`
`Hyperglycemia
`Hypocalcemia
`a
`Fatigue includes asthenia, and fatigue.
`b Upper respiratory tract infection includes nasopharyngitis, pharyngitis, respiratory tract infection viral, rhinitis, sinusitis, upper respiratory
`tract infection, and upper respiratory tract infection bacterial.
`c
` Pneumonia includes lower respiratory tract infection, lung infection, and pneumonia.
`d Bronchitis includes bronchitis, and bronchitis viral.
`e Dyspnea includes dyspnea, and dyspnea exertional.
`
`f
`
`
`Cough includes cough, and productive cough.
`# Only grade 3 adverse reactions occurred.
`
`43
`23
`14
`11
`
`31
`14
`
`22
`14
`
`17
`
`17
`
`12
`11
`
`3#
`17
`2#
`0
`
`2#
`0
`
`3
`0
`
`2#
`
`5#
`
`9#
`0
`
`
`
`
`
`
`
`x
`
`Clinically relevant adverse reactions in <10% of patients who received DARZALEX FASPRO
`with lenalidomide and dexamethasone (D-Rd) include:
`Musculoskeletal and connective tissue disorders: arthralgia, musculoskeletal chest
`pain
`Nervous system disorders: dizziness, headache, paresthesia
`Skin and subcutaneous tissue disorders: rash, pruritus
`Gastrointestinal disorders: abdominal pain
`Infections: influenza, sepsis, herpes zoster
`Metabolism and nutrition disorders: decreased appetite
`Cardiac disorders: atrial fibrillation
`General disorders and administration site conditions: chills, infusion reaction,
`
`
`injection site reaction
`Vascular disorders: hypotension, hypertension
`x
`Table 7 summarizes the laboratory abnormalities in patients who received DARZALEX
`FASPRO with lenalidomide and dexamethasone (D-Rd) in PLEIADES.
`
`x
`x
`x
`x
`x
`x
`x
`
`
`
`Reference ID: 4601659Reference ID: 4753174
`
`12
`
`
`
`Table 7:
`
` Select Hematology Laboratory Abnormalities Worsening from Baseline in Patients Who
`
`
`
` Received DARZALEX FASPRO with Lenalidomide and Dexamethasone (D-Rd) in PLEIADES
`DARZALEX FASPRO
`
`
`with Lenalidomide and Dexamethasone a
`
`
`Laboratory Abnormality
` All