Darzalex Adverse Reactions

The following clinically significant adverse reactions are also described elsewhere in the monograph: Infusion-related reactions [see Infusion-Related Reactions under Precautions]; Neutropenia [see Neutropenia under Precautions]; Thrombocytopenia [see Thrombocytopenia under Precautions].
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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The safety data described as follows reflects exposure to DARZALEX (16 mg/kg) in 2,459 patients with multiple myeloma including 2,303 patients who received DARZALEX in combination with background regimens and 156 patients who received DARZALEX as monotherapy. In this pooled safety population, the most common adverse reactions (≥20%) were upper respiratory infection, neutropenia, infusion-related reactions, thrombocytopenia, diarrhea, constipation, anemia, peripheral sensory neuropathy, fatigue, peripheral edema, nausea, cough, pyrexia, dyspnea, and asthenia.
Newly Diagnosed Multiple Myeloma Ineligible for Autologous Stem Cell Transplant: Combination Treatment with Lenalidomide and Dexamethasone (DRd): The safety of DARZALEX in combination with lenalidomide and dexamethasone was evaluated in MAIA [see Pharmacology: Pharmacodynamics: Clinical Studies: Newly Diagnosed Multiple Myeloma under Actions]. Adverse reactions described in Table 16 reflect exposure to DARZALEX for a median treatment duration of 25.3 months (range: 0.1 to 40.44 months) for daratumumab-lenalidomide-dexamethasone (DRd) and of 21.3 months (range: 0.03 to 40.64 months) for lenalidomide-dexamethasone (Rd).
Serious adverse reactions with a 2% greater incidence in the DRd arm compared to the Rd arm were pneumonia (DRd 15% vs Rd 8%), bronchitis (DRd 4% vs Rd 2%) and dehydration (DRd 2% vs Rd <1%). (See Table 16.)

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Laboratory abnormalities worsening during treatment from baseline listed in Table 17. (See Table 17.)

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Combination Treatment with Bortezomib, Melphalan and Prednisone: The safety of DARZALEX in combination with bortezomib, melphalan and prednisone was evaluated in ALCYONE [see Pharmacology: Pharmacodynamics: Clinical Studies: Newly Diagnosed Multiple Myeloma under Actions]. Adverse reactions described in Table 18 reflect exposure to DARZALEX for a median treatment duration of 14.7 months (range: 0 to 25.8 months) for daratumumab, bortezomib, melphalan and prednisone (D-VMP) and of 12 months (range: 0.1 to 14.9 months) for VMP.
Serious adverse reactions with at least a 2% greater incidence in the D-VMP arm compared to the VMP arm were pneumonia (D-VMP 11% vs VMP 4%), upper respiratory tract infection (D-VMP 5% vs VMP 1%), and pulmonary edema (D-VMP 2% vs VMP 0%). (See Table 18.)

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Laboratory abnormalities worsening during treatment from baseline listed in Table 19. (See Table 19.)

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Newly Diagnosed Multiple Myeloma Eligible for Autologous Stem Cell Transplant: Combination Treatment with Bortezomib, Thalidomide and Dexamethasone (DVTd): The safety of DARZALEX in combination with bortezomib, thalidomide and dexamethasone was evaluated in CASSIOPEIA [see Pharmacology: Pharmacodynamics: Clinical Studies: Newly Diagnosed Multiple Myeloma under Actions]. Adverse reactions described in Table 20 reflect exposure to DARZALEX up to day 100 post-transplant. The median duration of induction/ASCT/consolidation treatment was 8.9 months (range: 7.0 to 12.0 months) for DVTd and 8.7 months (range: 6.4 to 11.5 months) for VTd.
Serious adverse reactions with a 2% greater incidence in the DVTd arm compared to the VTd arm were bronchitis (DVTd 2% vs VTd <1%) and pneumonia (DVTd 6% vs VTd 4%). (See Tables 20 and 21.)

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Relapsed/Refractory Multiple Myeloma: Combination Treatment with Lenalidomide and Dexamethasone: The safety of DARZALEX in combination with lenalidomide and dexamethasone was evaluated in POLLUX [see Pharmacology: Pharmacodynamics: Clinical Studies: Relapsed/Refractory Multiple Myeloma under Actions]. Adverse reactions described in Table 22 reflect exposure to DARZALEX for a median treatment duration of 13.1 months (range: 0 to 20.7 months) for daratumumab-lenalidomide-dexamethasone (DRd) and of 12.3 months (range: 0.2 to 20.1 months) for lenalidomide-dexamethasone (Rd).
Serious adverse reactions occurred in 49% of patients in the DRd arm compared with 42% in the Rd arm. Serious adverse reactions with at least a 2% greater incidence in the DRd arm compared to the Rd arm were pneumonia (DRd 12% vs Rd 10%), upper respiratory tract infection (DRd 7% vs Rd 4%), influenza and pyrexia (DRd 3% vs Rd 1% for each). Adverse reactions resulted in discontinuations for 7% (n=19) of patients in the DRd arm versus 8% (n=22) in the Rd arm. (See Table 22.)

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Laboratory abnormalities worsening during treatment from baseline listed in Table 23. (See Table 23.)

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Combination Treatment with Bortezomib and Dexamethasone: The safety of DARZALEX in combination with bortezomib and dexamethasone was evaluated in CASTOR [see Pharmacology: Pharmacodynamics: Clinical Studies: Relapsed/Refractory Multiple Myeloma under Actions]. Adverse reactions described in Table 24 reflect exposure to DARZALEX for a median treatment duration of 6.5 months (range: 0 to 14.8 months) for daratumumab-bortezomib-dexamethasone (DVd) and of 5.2 months (range: 0.2 to 8.0 months) for bortezomib-dexamethasone (Vd) arm.
Serious adverse reactions occurred in 42% of patients in the DVd arm compared with 34% in the Vd arm. Serious adverse reactions with at least a 2% greater incidence in the DVd arm compared to the Vd arm were upper respiratory tract infection (DVd 5% vs Vd 2%), diarrhea and atrial fibrillation (DVd 2% vs Vd 0% for each).
Adverse reactions resulted in discontinuations for 7% (n=18) of patients in the DVd arm versus 9% (n=22) in the Vd arm. (See Table 24.)

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Laboratory abnormalities worsening during treatment are listed in Table 25. (See Table 25.)

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Combination Treatment with Twice-Weekly (20/56 mg/m²) Carfilzomib and Dexamethasone: The safety of DARZALEX in combination with twice weekly carfilzomib and dexamethasone was evaluated in CANDOR [see Pharmacology: Pharmacodynamics: Clinical Studies under Actions]. Adverse reactions described in Table 26 reflect exposure to DARZALEX for a median treatment duration of 16.1 months (range: 0.1 to 23.7 months) for the daratumumab-carfilzomib-dexamethasone (DKd) group and median treatment duration of 9.3 months (range: 0.1 to 22.4 months) for the carfilzomib-dexamethasone group (Kd).
Serious adverse reactions occurred in 56% of patients who received DARZALEX in combination with Kd and 46% of patients who received Kd. The most frequent serious adverse reactions reported in the DKd arm as compared with the Kd arm were pneumonia (DKd 14% vs Kd 9%), pyrexia (DKd 4.2% vs Kd 2.0%), influenza (DKd 3.9% vs Kd 1.3%), sepsis (DKd 3.9% vs Kd 1.3%), anemia (DKd 2.3% vs Kd 0.7%), bronchitis (DKd 1.9% vs Kd 0%), and diarrhea (DKd 1.6% vs Kd 0%). Fatal adverse reactions within 30 days of the last dose of any study treatment occurred in 10% of 308 patients who received DARZALEX in combination with Kd versus 5% of 153 patients who received Kd. The most frequent fatal adverse reaction was infection (4.5% vs 2.6%).
Permanent discontinuation of DARZALEX due to an adverse reaction occurred in 9% of patients. Adverse reactions (>1%) which resulted in permanent discontinuation of DARZALEX included pneumonia.
Infusion-related reactions that occurred on the day of administration of any DARZALEX dose or on the next day occurred in 18% of patients and that occurred on the day of administration of the first DARZALEX dose or the next day occurred in 12%. (See Table 26.)

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Adverse Reactions Occurring at a Frequency of <15%: Blood and lymphatic system disorders: neutropenia, lymphopenia, leukopenia, febrile neutropenia.
Cardiac disorders: atrial fibrillation.
Gastrointestinal disorders: vomiting, constipation.
General disorders and administration site conditions: peripheral edema, asthenia, chills.
Infections: influenza, urinary tract infection, sepsis, septic shock.
Metabolism and nutrition disorders: decreased appetite, hyperglycemia, hypocalcemia, dehydration.
Musculoskeletal and connective tissue disorders: muscle spasms, arthralgia, musculoskeletal chest pain.
Nervous system disorders: headache, dizziness, peripheral sensory neuropathy, paresthesia, posterior reversible encephalopathy syndrome.
Respiratory, thoracic and mediastinal disorders: pulmonary edema.
Skin and subcutaneous tissue disorders: rash, pruritus.
Combination Treatment with Once-Weekly (20/70 mg/m²) Carfilzomib and Dexamethasone: The safety of DARZALEX in combination with once-weekly carfilzomib and dexamethasone was evaluated in EQUULEUS [see Pharmacology: Pharmacodynamics: Clinical Studies under Actions]. Adverse reactions described in Table 27 reflect exposure to DARZALEX for a median treatment duration of 19.8 months (range: 0.3 to 34.5 months).
Serious adverse reactions were reported in 48% of patients. The most frequent serious adverse reactions reported were pneumonia (4.7%), upper respiratory tract infection (4.7%), basal cell carcinoma (4.7%), influenza (3.5%), general physical health deterioration (3.5%), and hypercalcemia (3.5%). Fatal adverse reactions within 30 days of the last dose of any study treatment occurred in 3.5% of patients who died of general physical health deterioration, multi-organ failure secondary to pulmonary aspergillosis, and disease progression.
Permanent discontinuation of DARZALEX due to an adverse reaction occurred in 8% of patients. No adverse reactions which resulted in permanent discontinuation of DARZALEX occurred in more than one patient.
Infusion-related reactions that occurred on the day of administration of any DARZALEX dose or on the next day occurred in 44% of patients. For patients who received the split first dose of DARZALEX, infusion-related reactions that occurred in 36% and 4% on the first and second day of administration of DARZALEX, respectively. (See Table 27.)

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Adverse Reactions Occurring at a Frequency of <15%: Blood and lymphatic system disorders: leukopenia, febrile neutropenia.
Cardiac disorders: atrial fibrillation.
Gastrointestinal disorders: pancreatitis.
General disorders and administration site conditions: peripheral edema, chills.
Infections: pneumonia, urinary tract infection, sepsis, septic shock.
Metabolism and nutrition disorders: decreased appetite, hyperglycemia, dehydration, hypocalcemia.
Musculoskeletal and connective tissue disorders: muscle spasms, musculoskeletal chest pain, arthralgia.
Nervous system disorders: dizziness, paraesthesia, peripheral sensory neuropathy.
Skin and subcutaneous tissue disorders: pruritus, rash.
Combination Treatment with Pomalidomide and Dexamethasone: The safety of DARZALEX in combination with pomalidomide and dexamethasone was evaluated in EQUULEUS [see Pharmacology: Pharmacodynamics: Clinical Studies: Relapsed/Refractory Multiple Myeloma under Actions]. Adverse reactions described in Table 28 reflect exposure to DARZALEX, pomalidomide and dexamethasone (DPd) for a median treatment duration of 6 months (range: 0.03 to 16.9 months).
The overall incidence of serious adverse reactions was 49%. Serious adverse reactions reported in ≥5% patients included pneumonia (7%). Adverse reactions resulted in discontinuations for 13% of patients. (See Table 28.)

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Laboratory abnormalities worsening during treatment are listed in Table 29. (See Table 29.)

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Monotherapy: The safety of DARZALEX was evaluated in 156 adult patients with relapsed and refractory multiple myeloma in three open-label, clinical trials. Patients received DARZALEX 16 mg/kg. The median duration of exposure was 3.3 months (range: 0.03 to 20.04 months).
Serious adverse reactions were reported in 51 (33%) patients. The most frequent serious adverse reactions were pneumonia (6%), general physical health deterioration (3%), and pyrexia (3%).
Adverse reactions resulted in treatment delay for 24 (15%) patients, most frequently for infections. Adverse reactions resulted in discontinuations for 6 (4%) patients.
Adverse reactions occurring in at least 10% of patients are presented in Table 30. Table 31 describes Grade 3-4 laboratory abnormalities reported at a rate of ≥10%. (See Tables 30 and 31.)

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Herpes Zoster Virus Reactivation: Prophylaxis for Herpes Zoster Virus reactivation was recommended for patients in some clinical trials of DARZALEX. In monotherapy studies, herpes zoster was reported in 3% of patients. In the combination therapy studies, herpes zoster was reported in 2-5% of patients receiving DARZALEX.
Infections: Grade 3 or 4 infections were reported as follows: Relapsed/refractory patient studies: DVd: 21% vs. Vd: 19%; DRd: 28% vs. Rd: 23%; DPd: 28%; DKd^a: 37%, Kd^a: 29%; DKd^b: 21%.
^a where carfilzomib 20/56 mg/m² was administered twice-weekly.
^b where carfilzomib 20/70 mg/m² was administered once-weekly.
Newly diagnosed patient studies: D-VMP: 23%, VMP: 15%; DRd: 32%, Rd: 23%; DVTd: 22%; VTd: 20%.
Pneumonia was the most commonly reported severe (Grade 3 or 4) infection across studies. In active controlled studies, discontinuations from treatment due to infections occurred in 1-4% of patients.
Fatal infections (Grade 5) were reported as follows: Relapsed/refractory patient studies: DVd: 1%, Vd: 2%; DRd: 2%, Rd: 1%; DPd: 2%; DKd^a: 5%, Kd^a: 3%; DKd^b: 0%.
^a where carfilzomib 20/56 mg/m² was administered twice-weekly.
^b where carfilzomib 20/70 mg/m² was administered once-weekly.
Newly diagnosed patient studies: D-VMP: 1%, VMP: 1%; DRd: 2%, Rd: 2%; DVTd: 0%, VTd: 0%.
Fatal infections were generally infrequent and balanced between the DARZALEX containing regimens and active control arms. Fatal infections were primarily due to pneumonia and sepsis.
Hepatitis B Virus (HBV) Reactivation: Hepatitis B virus reactivation has been reported in less than 1% of patients (including fatal cases) treated with DARZALEX in clinical trials.
Other Clinical Trials Experience: The following adverse reactions have been reported following administration of daratumumab and hyaluronidase for subcutaneous injection: Nervous System disorders: Syncope.
Immunogenicity: 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 as follows with the incidence of antibodies in other studies or to other daratumumab products may be misleading.
In clinical trials of patients with multiple myeloma treated with DARZALEX as monotherapy or as combination therapies, 0.35% (6/1,713) of patients developed treatment-emergent anti-daratumumab antibodies. Of those, 4 patients tested positive for neutralizing antibodies.
Postmarketing Experience: The following adverse reactions have been identified during 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 disorders: Anaphylactic reaction; IRR (including deaths).
Gastrointestinal disorders: Pancreatitis.
Infections: Cytomegalovirus, Listeriosis.