Daratumumab Intravenous Injection

Name: Daratumumab Intravenous Injection

Indications

DARZALEX is indicated:

  • in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy.
  • in combination with pomalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor.
  • as monotherapy, for the treatment of patients with multiple myeloma 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.

Overdose

The dose of DARZALEX at which severe toxicity occurs is not known.

In the event of an overdose, monitor patients for any signs or symptoms of adverse effects and provide appropriate supportive treatment.

Side effects

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

  • Infusion reactions [see WARNINGS AND PRECAUTIONS].
  • Neutropenia [see WARNINGS AND PRECAUTIONS].
  • Thrombocytopenia [see WARNINGS AND PRECAUTIONS].

Adverse Reactions In Clinical Trials

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 820 patients with multiple myeloma including 526 patients from two Phase 3 active-controlled trials who received DARZALEX in combination with either lenalidomide (DRd, n=283; Study 3) or bortezomib (DVd, n=243; Study 4) and five open-label, clinical trials in which patients received DARZALEX either in combination with pomalidomide (DPd, n=103; Study 5), in combination with lenalidomide (n=35), or as monotherapy (n=156).

Combination Treatment With Lenalidomide

Adverse reactions described in Table 4 reflect exposure to DARZALEX (DRd arm) for a median treatment duration of 13.1 months (range: 0 to 20.7 months) and median treatment duration of 12.3 months (range: 0.2 to 20.1 months) for the lenalidomide group (Rd) in Study 3. 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 (12% vs Rd 10%), upper respiratory tract infection (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 4: Adverse reactions reported in ≥ 10% of patients and with at least a 5% frequency greater in the DRd arm in Study 3

Adverse Reaction DRd
(N=283) %
Rd
(N=281) %
Any Grade Grade 3 Grade 4 Any Grade Grade 3 Grade 4
Infusion reactionsa 48 5 0 0 0 0
Gastrointestinal disorders
  Diarrhea 43 5 0 25 3 0
  Nausea 24 1 0 14 0 0
  Vomiting 17 1 0 5 1 0
General disorders and administration site conditions
  Fatigue 35 6 < 1 28 2 0
  Pyrexia 20 2 0 11 1 0
Infections and infestations
  Upper respiratory tract infectionb 65 6 < 1 51 4 0
Musculoskeletal and connective tissue disorders
  Muscle spasms 26 1 0 19 2 0
Nervous system disorders
  Headache 13 0 0 7 0 0
Respiratory, thoracic and mediastinal disorders
  Coughc 30 0 0 15 0 0
  Dyspnead 21 3 < 1 12 1 0
Key: D=daratumumab, Rd=lenalidomide-dexamethasone.
a Infusion reaction includes terms determined by investigators to be related to infusion, see description of Infusion Reactions below.
b upper respiratory tract infection, bronchitis, sinusitis, respiratory tract infection viral, rhinitis, pharyngitis, respiratory tract infection, metapneumovirus infection, tracheobronchitis, viral upper respiratory tract infection, laryngitis, respiratory syncytial virus infection, staphylococcal pharyngitis, tonsillitis, viral pharyngitis, acute sinusitis, nasopharyngitis, bronchiolitis, bronchitis viral, pharyngitis streptococcal, tracheitis, upper respiratory tract infection bacterial, bronchitis bacterial, epiglottitis, laryngitis viral, oropharyngeal candidiasis, respiratory moniliasis, viral rhinitis, acute tonsillitis, rhinovirus infection
c cough, productive cough, allergic cough
d dyspnea, dyspnea exertional

Laboratory abnormalities worsening during treatment from baseline listed in Table 5.

Table 5: Treatment-emergent hematology laboratory abnormalities in Study 3

  DRd
(N=283) %
Rd
(N=281) %
Any Grade Grade 3 Grade 4 All Grades Grade 3 Grade 4
Anemia 52 13 0 57 19 0
Thrombocytopenia 73 7 6 67 10 5
Neutropenia 92 36 17 87 32 8
Lymphopenia 95 42 10 87 32 6
Key: D=Daratumumab, Rd=lenalidomide-dexamethasone.

Combination Treatment With Bortezomib

Adverse reactions described in Table 6 reflect exposure to DARZALEX (DVd arm) for a median treatment duration of 6.5 months (range: 0 to 14.8 months) and median treatment duration of 5.2 months (range: 0.2 to 8.0 months) for the bortezomib group (Vd) in Study 4. 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 6: Adverse reactions reported in ≥ 10% of patients and with at least a 5% frequency greater in the DVd arm Study 4

Adverse Reaction DVd (N=243) % Vd (N=237) %
Any Grade Grade 3 Grade 4 Any Grade Grade 3 Grade 4
Infusion reactionsa 45 9 0 0 0 0
Gastrointestinal disorders
  Diarrhea 32 3 < 1 22 1 0
  Vomiting 11 0 0 4 0 0
General disorders and administration site conditions
  Edema peripheralb 22 1 0 13 0 0
  Pyrexia 16 1 0 11 1 0
Infections and infestations
  Upper respiratory tract infectionc 44 6 0 30 3 < 1
Nervous system disorders
  Peripheral sensory neuropathy 47 5 0 38 6 < 1
Respiratory, thoracic and mediastinal disorders
  Coughd 27 0 0 14 0 0
  Dyspneae 21 4 0 11 1 0
Key: D=daratumumab, Vd=bortezomib-dexamethasone.
a Infusion reaction includes terms determined by investigators to be related to infusion, see description of Infusion Reactions below.
b edema peripheral, edema, generalized edema, peripheral swelling
c upper respiratory tract infection, bronchitis, sinusitis, respiratory tract infection viral, rhinitis, pharyngitis, respiratory tract infection, metapneumovirus infection, tracheobronchitis, viral upper respiratory tract infection, laryngitis, respiratory syncytial virus infection, staphylococcal pharyngitis, tonsillitis, viral pharyngitis, acute sinusitis, nasopharyngitis, bronchiolitis, bronchitis viral, pharyngitis streptococcal, tracheitis, upper respiratory tract infection bacterial, bronchitis bacterial, epiglottitis, laryngitis viral, oropharyngeal candidiasis, respiratory moniliasis, viral rhinitis, acute tonsillitis, rhinovirus infection
d cough, productive cough, allergic cough
e dyspnea, dyspnea exertional

Laboratory abnormalities worsening during treatment are listed in Table 7.

Table 7: Treatment-emergent hematology laboratory abnormalities in Study 4

  DVd
(N=243) %
Vd
(N=237) %
Any Grade Grade 3 Grade 4 Any Grade Grade 3 Grade 4
Anemia 48 13 0 56 14 0
Thrombocytopenia 90 28 19 85 22 13
Neutropenia 58 12 3 40 5 < 1
Lymphopenia 89 41 7 81 24 3
Key: D=Daratumumab, Vd=bortezomib-dexamethasone.

Combination Treatment With Pomalidomide

Adverse reactions described in Table 8 reflect exposure to DARZALEX, pomalidomide and dexamethasone (DPd) for a median treatment duration of 6 months (range: 0.03 to 16.9 months) in Study 5. 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 8: Adverse reactions with incidence ≥ 10% reported in Study 5

Body System Adverse Reaction DPd
(N=103)
Any Grade (%) Grade 3 (%) Grade 4 (%)
Infusion reactionsa 50 4 0
Gastrointestinal disorders
  Diarrhea 38 3 0
  Constipation 33 0 0
  Nausea 30 0 0
  Vomiting 21 2 0
General disorders and administration site conditions
  Fatigue 50 10 0
  Pyrexia 25 1 0
  Chills 20 0 0
  Edema peripheralb 17 4 0
  Asthenia 15 0 0
  Non-cardiac chest pain 15 0 0
  Pain 11 0 0
Infections and infestations
  Upper respiratory tract infectionc 50 4 1
  Pneumoniad 15 8 2
Metabolism and nutrition disorders
  Hypokalemia 16 3 0
  Hyperglycemia 13 5 1
  Decreased appetite 11 0 0
Musculoskeletal and connective tissue disorders
  Muscle spasms 26 1 0
  Back pain 25 6 0
  Arthralgia 22 2 0
  Pain in extremity 15 0 0
  Bone pain 13 4 0
  Musculoskeletal chest pain 13 2 0
Nervous system disorders
  Dizziness 21 2 0
  Tremor 19 3 0
  Headache 17 0 0
Psychiatric disorders
  Insomnia 23 2 0
  Anxiety 13 0 0
Respiratory, thoracic and mediastinal disorders
  Coughe 43 1 0
  Dyspneaf 33 6 1
  Nasal congestion 16 0 0
Key: D=Daratumumab, Pd=pomalidomide-dexamethasone.
a Infusion reaction includes terms determined by investigators to be related to infusion, see description of Infusion Reactions below.
b edema, edema peripheral, peripheral swelling.
c acute tonsillitis, bronchitis, laryngitis, nasopharyngitis, pharyngitis, respiratory syncytial virus infection, rhinitis, sinusitis, tonsillitis, upper respiratory tract infection
d lung infection, pneumonia, pneumonia aspiration
e cough, productive cough, allergic cough
f dyspnea, dyspnea exertional

Laboratory abnormalities worsening during treatment are listed in Table 9.

Table 9: Treatment-emergent hematology laboratory abnormalities in Study 5

  DPd
(N=103) %
Any Grade Grade 3 Grade 4
Anemia 57 30 0
Thrombocytopenia 75 10 10
Neutropenia 95 36 46
Lymphopenia 94 45 26
Key: D=Daratumumab, Pd=pomalidomide-dexamethasone.

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 10. Table 11 describes Grade 3-4 laboratory abnormalities reported at a rate of ≥ 10%.

Table 10: Adverse reactions with incidence ≥ 10% in patients with multiple myeloma treated with DARZALEX 16 mg/kg

Adverse Reaction DARZALEX 16 mg/kg
N=156
Incidence (%)
Any Grade Grade 3 Grade 4
Infusion reactiona 48 3 0
General disorders and administration site conditions
  Fatigue 39 2 0
  Pyrexia 21 1 0
  Chills 10 0 0
Respiratory, thoracic and mediastinal disorders
  Cough 21 0 0
  Nasal congestion 17 0 0
  Dyspnea 15 1 0
Musculoskeletal and connective tissue disorders
  Back pain 23 2 0
  Arthralgia 17 0 0
  Pain in extremity 15 1 0
  Musculoskeletal chest pain 12 1 0
Infections and infestations
  Upper respiratory tract infection 20 1 0
  Nasopharyngitis 15 0 0
  Pneumoniab 11 6 0
Gastrointestinal disorders
  Nausea 27 0 0
  Diarrhea 16 1 0
  Constipation 15 0 0
  Vomiting 14 0 0
Metabolism and nutrition disorders
  Decreased appetite 15 1 0
Nervous system disorders
  Headache 12 1 0
Vascular disorders
  Hypertension 10 5 0
a Infusion reaction includes terms determined by investigators to be related to infusion, see below.
b Pneumonia also includes the terms streptococcal pneumonia and lobar pneumonia.

Table 11: Treatment emergent Grade 3-4 laboratory abnormalities ( ≥ 10%)

  Daratumumab 16 mg/kg
(N=156)
All Grade (%) Grade 3 (%) Grade 4 (%)
Anemia 45 19 0
Thrombocytopenia 48 10 8
Neutropenia 60 17 3
Lymphopenia 72 30 10

Infusion Reactions

In clinical trials (monotherapy and combination treatments; N=820) the incidence of any grade infusion reactions was 46% with the first infusion of DARZALEX, 2% with the second infusion, and 3% with subsequent infusions. Less than 1% of patients had a Grade 3 infusion reaction with second or subsequent infusions.

The median time to onset of a reaction was 1.4 hours (range: 0.02 to 72.8 hours). The incidence of infusion modification due to reactions was 42%. Median durations of infusion for the 1st, 2nd and subsequent infusions were 7.0, 4.3, and 3.5 hours respectively.

Severe (Grade 3) infusion reactions included bronchospasm, dyspnea, laryngeal edema, pulmonary edema, hypoxia, and hypertension. Other adverse infusion reactions (any Grade, ≥ 5%) were nasal congestion, cough, chills, throat irritation, vomiting and nausea.

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 randomized controlled combination therapy studies, herpes zoster was reported in 2% each in the DRd and Rd groups respectively (Study 3), in 5% versus 3% in the DVd and Vd groups respectively (Study 4) and in 2% of patients receiving DPd (Study 5).

Infections

In patients receiving DARZALEX combination therapy, Grade 3 or 4 infections were reported with DARZALEX combinations and background therapies (DVd: 21%, Vd: 19%; DRd: 28%, Rd: 23%; DPd: 28%). Pneumonia was the most commonly reported severe (Grade 3 or 4) infection across studies. Discontinuations from treatment were reported in 3% versus 2% of patients in the DRd and Rd groups respectively, 4% versus 3% of patients in the DVd and Vd groups respectively and in 5% of patients receiving DPd. Fatal infections were reported in 0.8% to 2% of patients across studies, primarily due to pneumonia and sepsis.

Immunogenicity

As with all therapeutic proteins, there is the potential for immunogenicity. 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 (0.7%) of the 298 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 anti-daratumumab antibodies in the presence of high concentrations of daratumumab; therefore, the incidence of antibody development might not have been reliably determined.

Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Additionally, the observed incidence of a positive result in a test method may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication and the underlying disease. Therefore, comparison of the incidence of antibodies to daratumumab with the incidence of antibodies to other products may be misleading.

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