Side Effects of Darzalex (daratumumab)

Darzalex (daratumumab) is monoclonal antibody used to treat multiple myeloma: 

• in combination with the medicines bortezomib, melphalan and prednisone, in people with newly diagnosed with multiple myeloma who cannot receive a type of stem cell transplant that uses their own stem cells (autologous stem cell transplant);
• in combination with the medicines lenalidomide and dexamethasone, or bortezomib and dexamethasone, in people who have received at least one prior medicine to treat multiple myeloma;
• in combination with the medicines pomalidomide and dexamethasone in people who have received at least two prior medicines to treat multiple myeloma, including lenalidomide and a proteasome inhibitor; and
• alone in people who have received at least three prior medicines to treat multiple myeloma, including a proteasome inhibitor and an immunomodulatory agent, or did not respond to a proteasome inhibitor and an immunomodulatory agent.

Common side effects of Darzalex include

• tiredness,
• nausea,
• diarrhea,
• shortness of breath,
• fever,
• cough,
• muscle spasms,
• back pain,
• cold-like symptoms (upper respiratory infection),
• nerve damage causing tingling,
• numbness or pain,
• swollen hands ankles or feet,
• constipation,
• trouble sleeping,
• joint pain,
• vomiting,
• chills, and
• dizziness.

Serious side effects of Darzalex include

• infusion reactions (shortness of breath or trouble breathing, dizziness or lightheadedness, cough, wheezing, throat tightness, runny or stuffy nose, headache, itching, nausea, vomiting, chills, and fever),
• changes in blood tests,
• decreased white blood cell counts which help fight infections, and
• decreased platelets which help to clot blood. 

Drug interactions of Darzalex include interference with compatibility testing, including antibody screening and cross-matching.

• Darzalex may be detected on serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for monitoring disease monoclonal immunoglobulins (M protein). This can lead to false positive SPE and IFE assay results for patients with IgG kappa myeloma protein impacting initial assessment of complete responses by International Myeloma Working Group (IMWG) criteria. 

Darzalex may harm a fetus. Females who are able to become pregnant should use an effective method of birth control during treatment and for at least 3 months after your final dose of Darzalex. 

It is unknown if Darzalex passes into breast milk. Consult your doctor before breastfeeding. 

It is not known if Darzalex is safe and effective in children.

Before you receive Darzalex, tell your healthcare provider about all of your medical conditions, including if you:

• have a history of breathing problems
• have had shingles (herpes zoster)

Darzalex may cause serious reactions, including:

• Infusion reactions. Infusion reactions are common with Darzalex and can be severe. Your healthcare provider may temporarily stop your infusion or completely stop treatment with Darzalex if you have infusion reactions. Get medical help right away if you get any of the following symptoms:
  • shortness of breath or trouble breathing
  • dizziness or lightheadedness (hypotension)
  • cough
  • wheezing
  • throat tightness
  • runny or stuffy nose
  • headache
  • itching
  • nausea
  • vomiting
  • chills
  • fever
• Changes in blood tests. Darzalex can affect the results of blood tests to match your blood type. These changes can last for up to 6 months after your final dose of Darzalex. Your healthcare provider will do blood tests to match your blood type before you start treatment with Darzalex. Tell all of your healthcare providers that you are being treated with Darzalex before receiving blood transfusions.
• Decreases in blood cell counts. Darzalex can decrease white blood cell counts which help fight infections and blood cells called platelets which help to clot blood. Your healthcare provider will check your blood cell counts during treatment with Darzalex. Tell your healthcare provider if you develop fever or have signs of bruising or bleeding.

• tiredness
• nausea
• diarrhea
• shortness of breath
• fever
• cough
• muscle spasms
• back pain
• cold-like symptoms (upper respiratory infection)
• nerve damage causing tingling, numbness or pain
• swollen hands ankles or feet
• constipation
• trouble sleeping
• joint pain
• vomiting
• chills
• dizziness

Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of Darzalex. Call your doctor for medical advice about side effects.

The following clinically significant adverse reactions are also described elsewhere in the labeling:

• Infusion reactions
• Neutropenia
• Thrombocytopenia

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 below reflects exposure to Darzalex (16 mg/kg) in 2,066 patients with multiple myeloma including 1,910 patients who received Darzalex in combination with background regimens and 156 patients who received Darzalex as monotherapy.

Newly Diagnosed Multiple Myeloma Ineligible For Autologous Stem Cell Transplant

Combination Treatment with Lenalidomide and Dexamethasone (DRd)

Adverse reactions described in the table below reflect exposure to Darzalex for a median treatment duration of 25.3 months (range: 0.1 to 40.44 months) for the daratumumablenalidomide-dexamethasone (DRd) group and median treatment duration of 21.3 months (range: 0.03 to 40.64 months) for the lenalidomide-dexamethasone group (Rd) in a Phase 3 active-controlled study MAIA.

The most frequent (≥20%) adverse reactions were

• infusion reactions,
• diarrhea,
• constipation,
• nausea,
• peripheral edema,
• fatigue,
• back pain,
• asthenia,
• pyrexia,
• upper respiratory tract infection,
• bronchitis,
• pneumonia,
• decreased appetite,
• muscle spasms,
• peripheral sensory neuropathy,
• dyspnea and
• cough.

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%).

Table 6: Adverse Reactions Reported in ≥10% of Patients and With at Least a 5% Greater Frequency in the DRd Arm in MAIA

Laboratory abnormalities worsening during treatment from baseline listed in Table 7.

Table 7: Treatment-Emergent Hematology Laboratory Abnormalities in MAIA

Combination Treatment with Bortezomib, Melphalan and Prednisone

• Adverse reactions described in Table 8 reflect exposure to Darzalex for a median treatment duration of 14.7 months (range: 0 to 25.8 months) for the daratumumab, bortezomib, melphalan and prednisone (D-VMP) group, and median treatment duration of 12 months (range: 0.1 to 14.9 months) for the VMP group in a Phase 3 active-controlled study ALCYONE.
• The most frequent adverse reactions (≥20% with at least 5% greater frequency in the D-VMP arm) were infusion reactions, upper respiratory tract infection and edema peripheral.
• 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%).

Table 8: Adverse Reactions Reported in ≥10% of Patients and With at Least a 5% Greater Frequency in the D-VMP Arm in ALCYONE

Laboratory abnormalities worsening during treatment from baseline listed in Table 9.

Table 9: Treatment-Emergent Hematology Laboratory Abnormalities in ALCYONE

Newly Diagnosed Multiple Myeloma Eligible For Autologous Stem Cell Transplant

Combination Treatment with Bortezomib, Thalidomide and Dexamethasone (DVTd)

• Adverse reactions described in Table 10 reflect exposure to Darzalex up to day 100 post-transplant in a Phase 3 active-controlled study CASSIOPEIA.
• The median duration of induction/ASCT/consolidation treatment was 8.9 months (range: 7.0 to 12.0 months) for the DVTd group and 8.7 months (range: 6.4 to 11.5 months) for the VTd group.
• The most frequent adverse reactions (>20% with at least 5% greater frequency in the DVTd group) were
  • infusion reactions,
  • nausea,
  • pyrexia,
  • upper respiratory tract infection and
  • bronchitis.
• 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%).

Table 10: Adverse Reactions Reported in ≥ 10% of Patients and With at Least a 5% Greater Frequency in the DVTd Arm in CASSIOPEIA

Table 11: Treatment-Emergent Hematology Laboratory Abnormalities in CASSIOPEIA

Relapsed/Refractory Multiple Myeloma

Combination Treatment with Lenalidomide and Dexamethasone

• Adverse reactions described in Table 12 reflect exposure to Darzalex for a median treatment duration of 13.1 months (range: 0 to 20.7 months) for the daratumumab-lenalidomidedexamethasone (DRd) group and median treatment duration of 12.3 months (range: 0.2 to 20.1 months) for the lenalidomide-dexamethasone (Rd) group in a Phase 3 active-controlled study POLLUX.
• The most frequent adverse reactions (≥20%) were
  • infusion reactions,
  • diarrhea,
  • nausea,
  • fatigue,
  • pyrexia,
  • upper respiratory tract infection,
  • muscle spasms,
  • cough and
  • dyspnea.
• The overall incidence of serious adverse reactions was 49% for the DRd group compared with 42% for the Rd group.
• 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.

Table 12: Adverse Reactions Reported in ≥ 10% of Patients and With at Least a 5% Greater Frequency in the DRd Arm in POLLUX

Laboratory abnormalities worsening during treatment from baseline listed in Table 13.

Table 13: Treatment-Emergent Hematology Laboratory Abnormalities in POLLUX

Combination Treatment with Bortezomib and Dexamethasone

• Adverse reactions described in Table 14 reflect exposure to Darzalex for a median treatment duration of 6.5 months (range: 0 to 14.8 months) in the daratumumab-bortezomibdexamethasone (DVd) group and median treatment duration of 5.2 months (range: 0.2 to 8.0 months) for the bortezomib-dexamethasone (Vd) group in a Phase 3 active-controlled study CASTOR.
• The most frequent adverse reactions (>20%) were
  • infusion reactions,
  • diarrhea,
  • peripheral edema,
  • upper respiratory tract infection,
  • peripheral sensory neuropathy,
  • cough and
  • dyspnea.
• The overall incidence of serious adverse reactions was 42% for the DVd group compared with 34% for the Vd group.
• 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.

Table 14: Adverse Reactions Reported in ≥10% of Patients and With at Least a 5% Greater Frequency in the DVd Arm CASTOR

• Laboratory abnormalities worsening during treatment are listed in Table 15.

Table 15: Treatment-Emergent Hematology Laboratory Abnormalities in CASTOR

Combination Treatment with Pomalidomide and Dexamethasone

• Adverse reactions described in Table 16 reflect exposure to Darzalex, pomalidomide and dexamethasone (DPd) for a median treatment duration of 6 months (range: 0.03 to 16.9 months) in EQUULEUS.
• The most frequent adverse reactions (>20%) were
  • infusion reactions,
  • diarrhea,
  • constipation,
  • nausea,
  • vomiting,
  • fatigue,
  • pyrexia,
  • upper respiratory tract infection,
  • muscle spasms,
  • back pain,
  • arthralgia,
  • dizziness,
  • insomnia,
  • cough and
  • dyspnea.
• 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.

Table 16: Adverse Reactions With Incidence ≥10% Reported in EQUULEUS

• Laboratory abnormalities worsening during treatment are listed in Table 17.

Table 17: Treatment-Emergent Hematology Laboratory Abnormalities in EQUULEUS

Monotherapy

• The safety data reflect exposure to Darzalex in 156 adult patients with relapsed and refractory multiple myeloma treated with Darzalex at 16 mg/kg in three open-label, clinical trials.
• 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 18. Table 19 describes Grade 3–4 laboratory abnormalities reported at a rate of ≥10%.

Table 18: Adverse Reactions With Incidence ≥10% in Patients With Multiple Myeloma Treated With Darzalex 16 mg/kg

Table 19: Treatment-Emergent Grade 3-4 Laboratory Abnormalities (≥10%)

Infusion Reactions

• In clinical trials (monotherapy and combination treatments; N=2,066) the incidence of any grade infusion reactions was 37% with the first (16 mg/kg, Week 1) infusion of Darzalex, 2% with the Week 2 infusion, and cumulatively 6% with subsequent infusions.
• Less than 1% of patients had a Grade 3/4 infusion reaction at Week 2 or subsequent infusions.
• The median time to onset of a reaction was 1.5 hours (range: 0 to 72.8 hours). The incidence of infusion modification due to reactions was 36%.
• Median durations of 16 mg/kg infusions for the 1st week, 2nd week and subsequent infusions were approximately 7, 4, and 3 hours respectively.
• Severe infusion reactions included
  • bronchospasm,
  • dyspnea,
  • laryngeal edema,
  • pulmonary edema,
  • hypoxia, and
  • hypertension.
• Other adverse infusion reactions included
  • nasal congestion,
  • cough,
  • chills,
  • throat irritation,
  • vomiting and
  • nausea.
• When Darzalex dosing was interrupted in the setting of ASCT (Study CASSIOPEIA) for a median of 3.75 months (range: 2.4; 6.9 months), upon re-initiation of Darzalex the incidence of IRRs was 11% for the first infusion following ASCT.
• Infusion rate/dilution volume used upon re-initiation was that used for the last Darzalex infusion prior to interruption for ASCT. IRRs occurring at re-initiation of Darzalex following ASCT were consistent in terms of symptoms and severity (Grade 3 or 4:<1%) with those reported in previous studies at Week 2 or subsequent infusions.
• In EQUULEUS, patients receiving daratumumab combination treatment (n=97) were administered the first 16 mg/kg daratumumab dose at Week 1 split over two days i.e. 8 mg/kg on Day 1 and Day 2 respectively.
• The incidence of any grade infusion-related reactions was 42%, with 36% of patients experiencing infusion reactions on Day 1 of Week 1, 4% on Day 2 of Week 1, and 8% with subsequent infusions.
• The median time to onset of a reaction was 1.8 hours (range: 0.1 to 5.4 hours).
• The incidence of infusion interruptions due to reactions was 30%. Median durations of infusions were 4.2 h for Week 1-Day 1, 4.2 h for Week 1-Day 2, and 3.4 hours for the subsequent infusions.

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

• In patients receiving Darzalex combination therapy, Grade 3 or 4 infections were reported as follows:
• Relapsed/refractory patient studies: DVd: 21%, Vd: 19%; DRd: 27%, Rd: 23%; DPd: 28% 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 the active controlled studies, discontinuations from treatment due to infections (1-4%) and 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.

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 to daratumumab in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.
• In clinical trials of patients with multiple myeloma treated with Darzalex as monotherapy or as combination therapies, none of the 111 evaluable monotherapy patients, and 2 of the 1,050 evaluable combination therapy patients, tested positive for anti-daratumumab antibodies.
• One patient administered Darzalex as combination therapy, developed transient neutralizing antibodies against daratumumab.
• However, this assay has limitations in detecting antidaratumumab antibodies in the presence of high concentrations of daratumumab; therefore, the incidence of antibody development might not have been reliably determined.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Darzalex. 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

Effects Of Daratumumab On Laboratory Tests

Interference With Indirect Antiglobulin Tests (Indirect Coombs Test)

• Daratumumab binds to CD38 on RBCs and interferes with compatibility testing, including antibody screening and cross matching.
• Daratumumab interference mitigation methods include treating reagent RBCs with dithiothreitol (DTT) to disrupt daratumumab binding or genotyping.
• Since the Kell blood group system is also sensitive to DTT treatment, K-negative units should be supplied after ruling out or identifying alloantibodies using DTT-treated RBCs.
• If an emergency transfusion is required, non-cross-matched ABO/RhD-compatible RBCs can be given per local blood bank practices.

Interference With Serum Protein Electrophoresis And Immunofixation Tests

• Daratumumab may be detected on serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for monitoring disease monoclonal immunoglobulins (M protein).
• False positive SPE and IFE assay results may occur for patients with IgG kappa myeloma protein impacting initial assessment of complete responses by International Myeloma Working Group (IMWG) criteria.
• In patients with persistent very good partial response, where daratumumab interference is suspected, consider using a FDA-approved daratumumab-specific IFE assay to distinguish daratumumab from any remaining endogenous M protein in the patient’s serum, to facilitate determination of a complete response.