Darzalex Faspro Adverse Reactions

Adverse reactions are adverse events that were considered to be reasonably associated with the use of daratumumab based on the comprehensive assessment of the available adverse event information. A causal relationship with daratumumab cannot be reliably established in individual cases. Further, 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 clinical practice.
Experience with DARZALEX FASPRO (subcutaneous daratumumab): The safety data of DARZALEX FASPRO subcutaneous (SC) formulation (1800 mg) was established in 638 patients with multiple myeloma (MM) including 260 patients from a Phase 3 active-controlled trial (Study MMY3012) who received DARZALEX FASPRO SC formulation as monotherapy, 149 patients from a Phase 3 active-controlled trial (Study MMY3013) who received DARZALEX FASPRO SC formulation in combination with pomalidomide and dexamethasone (D-Pd), and three open-label, clinical trials in which patients received DARZALEX FASPRO SC formulation either as monotherapy (N=31; MMY1004 and MMY1008) and MMY2040 in which patients received DARZALEX FASPRO SC formulation in combination with either bortezomib, melphalan and prednisone (D-VMP, n=67), lenalidomide and dexamethasone (D-Rd, n=65) or carfilzomib and dexamethasone (D-Kd, n=66).
The safety data of DARZALEX FASPRO SC formulation (1800 mg) was established in patients with newly diagnosed AL amyloidosis from a Phase 3 active-controlled trial (Study AMY3001) in which patients received DARZALEX FASPRO SC formulation in combination with bortezomib, cyclophosphamide and dexamethasone (D-VCd, n=193).
Monotherapy-relapsed/refractory multiple myeloma: MMY3012, a Phase 3 randomized, study compared treatment with DARZALEX FASPRO SC formulation (1800 mg) vs. intravenous (16 mg/kg) daratumumab in patients with relapsed or refractory multiple myeloma. The median DARZALEX FASPRO SC formulation treatment duration was 5.5 months (range: 0.03 to 19.35 months) and 6.0 months (range: 0.03 to 16.69 months) for intravenous daratumumab. The most common adverse reactions of any grade (≥20% patients) with DARZALEX FASPRO SC formulation were upper respiratory tract infections. Pneumonia was the only serious adverse reaction occurring in ≥5% of patients (6% IV vs. 6% SC).
Table 17 as follows lists the adverse reactions that occurred in patients who received DARZALEX FASPRO SC formulation or intravenous daratumumab in Study MMY3012. (See Table 17.)

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Laboratory abnormalities worsening during treatment from baseline are listed in Table 18. (See Table 18.)

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Combination therapies in multiple myeloma: Combination treatments: D-VMP, D-Rd, D-Kd: MMY2040 was an open-label trial of DARZALEX FASPRO SC formulation in combination with bortezomib, melphalan, prednisone (D-VMP) in patients with newly diagnosed MM who are ineligible for transplant, in combination with lenalidomide and dexamethasone (D-Rd) in patients with relapsed or refractory MM, and in combination with carfilzomib and dexamethasone (D-Kd) in patients with relapsed or refractory MM. The median treatment duration was as follows: 10.6 months (0.36 to 13.17 months) for D-VMP; 11.1 months (0.49 to 13.57 months) for D-Rd; 8.3 months (0 to 17 months) for D-Kd.
The most common adverse reactions of any grade (≥20% patients) with DARZALEX FASPRO SC formulation were constipation, diarrhea, nausea, vomiting, pyrexia, fatigue, asthenia, upper respiratory tract infection, pneumonia, back pain, muscle spasms, peripheral sensory neuropathy, insomnia, cough, hypertension, headache, edema peripheral and dyspnea. Serious adverse reactions reported in ≥5% of patients included pneumonia (D-VMP 9%; D-Rd 12%; D-Kd 3%); pyrexia (D-VMP 6%; D-Rd 5%; D-Kd 3%), influenza (D-VMP 1%; D-Rd 6%; D-Kd 2%), and diarrhea (D-VMP 1%; D-Rd 6%; D-Kd 0%).
Table 19 as follows lists the adverse reactions that occurred in patients who received DARZALEX FASPRO subcutaneous formulation in Study MMY2040. (See Table 19.)

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Laboratory abnormalities worsening during treatment from baseline are listed in Table 20. (See Table 20.)

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Combination Treatment: D-Pd: MMY3013 was a Phase 3 randomized, open-label, active-controlled study that compared treatment with DARZALEX FASPRO SC formulation in combination with pomalidomide and low-dose dexamethasone (D-Pd) with pomalidomide and low-dose dexamethasone (Pd) in patients with relapsed or refractory multiple myeloma who received at least 1 prior treatment with lenalidomide and a protease inhibitor (PI). The median treatment duration was 11.5 months (0.13 to 36.17 months) for D-Pd and 6.6 months (0.03 to 27.33 months) for Pd.
The most common adverse reactions of any grade (≥20% patients) were fatigue, upper respiratory infection, asthenia, diarrhea and pneumonia. Serious adverse reactions with a 2% greater incidence in the D-Pd arm compared to the Pd arm were pneumonia (D-Pd 26% vs Pd 17%), neutropenia (D-Pd 5% vs. Pd 3%), thrombocytopenia (D-Pd: 3% vs Pd: 1%), and syncope (D-Pd: 2% vs Pd: 0%).
Table 21 as follows summarizes the adverse reactions in Study MMY3013. (See Table 21.)

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Laboratory abnormalities worsening during treatment from baseline are listed in Table 22. (See Table 22.)

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Combination treatment for AL Amyloidosis: The safety of DARZALEX FASPRO SC formulation (1800 mg) with bortezomib, cyclophosphamide and dexamethasone (D-VCd) compared to bortezomib, cyclophosphamide and dexamethasone (VCd) in patients with newly diagnosed AL amyloidosis was evaluated in an open-label, randomized, Phase 3 study, AMY3001. The median treatment duration was 9.6 months (range: 0.03 to 21.16 months) for D-VCd and 5.3 months (range: 0.03 to 7.33 months) for VCd.
Serious adverse reactions occurred in 43% of patients who received DARZALEX FASPRO in combination with VCd. Serious adverse reactions that occurred in at least 5% of patients in the DARZALEX FASPRO-VCd arm were pneumonia (9%), cardiac failure (8%), and sepsis (5%). Fatal adverse reactions occurred in 11% of patients. Fatal adverse reactions that occurred in more than one patient included cardiac arrest (4%), sudden death (3%), cardiac failure (3%), and sepsis (1%).
Permanent discontinuation of DARZALEX FASPRO due to an adverse reaction occurred in 5% of patients. Adverse reactions resulting in permanent discontinuation of DARZALEX FASPRO in more than one patient were pneumonia, sepsis, and cardiac failure.
Dosing interruptions (defined as dose delays or skipped doses) due to an adverse reaction occurred in 36% of patients who received DARZALEX FASPRO. Adverse reactions which required a dosage interruption in ≥3% of patients included upper respiratory tract infection (9%), pneumonia (6%), cardiac failure (4%), fatigue (3%), herpes zoster (3%), dyspnea (3%), and neutropenia (3%).
The most common adverse reactions of any grade (≥20%) were upper respiratory tract infection, diarrhea, constipation, peripheral sensory neuropathy, dyspnea and cough. Serious adverse reactions with a 2% greater incidence in the D-VCd arm compared to the VCd arm were pneumonia (D-VCd 9% vs VCd 6%) and sepsis (D-VCd 5% vs VCd 1%).
Table 23 as follows summarizes the adverse reactions in AMY3001. (See Table 23.)

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Laboratory abnormalities worsening during treatment from baseline are listed in Table 24. (See Table 24.)

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Experience with intravenous daratumumab combination therapies: The safety of intravenous (IV) daratumumab (16 mg/kg) has been established in 1910 patients with multiple myeloma including 1772 patients from five Phase 3 active-controlled trials who received IV daratumumab in combination with either lenalidomide and dexamethasone (D-Rd, n=283; MMY3003), bortezomib and dexamethasone (D-Vd, n=243; MMY3004), bortezomib, melphalan and prednisone (D-VMP, n=346; MMY3007), or lenalidomide and dexamethasone (D-Rd, n=364; MMY3008), or bortezomib and thalidomide and dexamethasone (D-VTd, n=536; MMY3006) and two open-label, clinical trials in which patients received IV daratumumab either in combination with pomalidomide and dexamethasone (D-Pd, n=103; MMY1001) or in combination with lenalidomide and dexamethasone (n=35).
Adverse reactions in Table 25 reflect exposure to IV daratumumab for a median treatment duration as follows: MMY3008: 25.3 months (range: 0.1 to 40.44 months) for the daratumumab-lenalidomide-dexamethasone (D-Rd) group; 21.3 months (range: 0.03 to 40.64 months) for the lenalidomide-dexamethasone (Rd) group.
MMY3007: 14.7 months (range: 0 to 25.8 months) for the daratumumab-bortezomib, melphalan-prednisone (D-VMP) group; 12 months (range: 0.1 to 14.9 months) for the VMP group.
MMY3003: 13.1 months (range: 0 to 20.7 months) for the daratumumab-lenalidomide-dexamethasone (D-Rd) group; 12.3 months (range: 0.2 to 20.1 months) for the lenalidomide-dexamethasone (Rd) group.
MMY3004: 6.5 months (range: 0 to 14.8 months) for the daratumumab-bortezomib-dexamethasone (D-Vd) group; 5.2 months (range: 0.2 to 8.0 months) for the bortezomib-dexamethasone (Vd) group.
Additionally, adverse reactions described in Table 25 reflect exposure to IV daratumumab up to day 100 post-transplant in a Phase 3 active-controlled study MMY3006 (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions). The median duration of induction/ASCT/consolidation treatment was 8.9 months (range: 7.0 to 12.0 months) for the D-VTd group and 8.7 months (range: 6.4 to 11.5 months) for the VTd group.
The most frequent adverse reactions (≥20%) were infusion-related reactions, fatigue, asthenia, nausea, diarrhea, constipation, decreased appetite, vomiting, muscle spasms, arthralgia, back pain, chills, pyrexia, dizziness, insomnia, cough, dyspnea, peripheral edema, peripheral sensory neuropathy, bronchitis, pneumonia, and upper respiratory tract infection. Serious adverse reactions with a 2% higher incidence in the IV daratumumab arms were pneumonia, bronchitis, upper respiratory tract infection, sepsis, pulmonary edema, influenza, pyrexia, dehydration, diarrhea, and atrial fibrillation. (See Table 25.)

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Combination treatment with pomalidomide and dexamethasone: Adverse reactions described reflect exposure to IV daratumumab, pomalidomide and dexamethasone (D-Pd) for a median treatment duration of 6 months (range: 0.03 to 16.9 months) in Study MMY1001. The most frequent adverse reactions (>10%) were infusion-related reactions, diarrhea, nausea, vomiting, fatigue, pyrexia, peripheral edema, pneumonia, upper respiratory tract infection, muscle spasms, headache, cough, and dyspnea. Adverse reactions resulted in discontinuations for 13% of patients.
Laboratory abnormalities worsening during IV daratumumab combination treatment trials are listed in Table 26. (See Table 26.)

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Combination treatment with twice-weekly (20/56 mg/m²) carfilzomib and dexamethasone: Adverse reactions described in the table as follows 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) in Phase 3 active-controlled study (Study 20160275). The most frequent (>20%) adverse reactions were infusion reactions, diarrhea, fatigue, upper respiratory tract infection, and pneumonia. Serious adverse reactions with a 2% greater incidence in the DKd arm compared to the Kd arm were pneumonia (DKd 14% vs Kd 11%), sepsis (DKd 6% vs Kd 3%), influenza (DKd 4% vs Kd 1%), pyrexia (DKd 4% vs Kd 2%), bronchitis (DKd 2% vs Kd 0%), and diarrhea (DKd 2% vs Kd 0%). Fatal events within 30 days of treatment cessation, regardless of causality, were reported in 10% of all patients treated with DKd versus 5% of patients treated with Kd and the most common cause was infection. Within the DKd group, fatal events occurred in 15% of the patients >65 years and 6% of the patients <65 years (see Infections, Other special population as follows).
Pre-specified infusion reaction-related terms that occurred on the same date or next date of any daratumumab dosing was 18% in the DKd arm and on the same date or next date of first daratumumab dosing was 12& in the DKd arm. Infusion reaction-related terms that occurred on the same date of any carfilzomib dosing was 41% in the DKd arm compared to 28% in the KD arm and on the same date of first carfilzomib dosing was 13% in the DKd arm compared to 1% in the Kd arm. (See Table 27.)

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Laboratory abnormalities worsening during treatment from baseline are listed in the table as follows. (See Table 28.)

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Combination treatment with once-weekly carfilzomib (20/70 mg/m²) and dexamethasone: Adverse reactions described in the table as follows reflect exposure to DARZALEX, carfilzomib and dexamethasone (DKd) for a median treatment duration of 19.8 months (range: 0.3 to 34.5 months) in Study MMY1001. Fatal events within 30 days of treatment cessation, regardless of causality, were reported in 4% of all patients treated with DKd. (See Table 29.)

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Laboratory abnormalities worsening during treatment from baseline listed in the table as follows. (See Table 30.)

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Monotherapy: The data described as follows reflect exposure to DARZALEX in three pooled open-label clinical studies that included 156 patients with relapsed and refractory multiple myeloma treated with DARZALEX at 16 mg/kg. The median duration of DARZALEX treatment was 3.3 months, with the longest duration of treatment being 14.2 months.
Adverse reactions occurring at a rate of ≥10% are presented in the table as follows. The most frequently reported adverse reactions (≥20%) were IRRs, fatigue, nausea, back pain, anemia, neutropenia and thrombocytopenia. Four percent of patients discontinued DARZALEX treatment due to adverse reactions, none of which were considered drug-related.
Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10000 to <1/1000) and very rare (<1/10000). (See Table 31.)

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Infusion-related reactions: In clinical trials (monotherapy and combination treatments; N=898) with DARZALEX FASPRO SC formulation, the incidence of any grade infusion-related reactions was 8.2% with the first injection of DARZALEX FASPRO SC formulation (1800 mg, Week 1), 0.4% with the Week 2 injection, and 1.1% with subsequent injections. Grade 3 IRRs were seen in 1.0% of patients. No patients had Grade 4 IRRs.
Signs and symptoms of IRRs may include respiratory symptoms, such as nasal congestion, cough, throat irritation, allergic rhinitis, wheezing as well as pyrexia, chest pain, pruritis, chills, vomiting, nausea, and hypotension. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension and tachycardia (see Precautions).
Injection site reactions (ISRs): In clinical trials (N=898) with DARZALEX FASPRO SC formulation, the incidence of any grade injection site reaction was 7.7%. There were no Grade 3 or 4 ISRs. The most common (≥1%) ISRs was erythema.
Infections: In patients with multiple myeloma receiving daratumumab monotherapy, the overall incidence of infections was similar between DARZALEX FASPRO SC formulation (52.9%) and IV daratumumab groups (50.0%). Grade 3 or 4 infections also occurred at similar frequencies between DARZALEX FASPRO SC formulation (11.7%) and IV daratumumab (14.3%). Most infections were manageable and rarely led to treatment discontinuation. Pneumonia was the most commonly reported 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 were primarily due to pneumonia and sepsis.
In patients with multiple myeloma receiving intravenous daratumumab combination therapy, the following infections were reported: Grade 3 or 4 infections: Relapsed/refractory patient studies: D-Vd: 21%, Vd: 19%; D-Rd: 28%, Rd: 23%; D-Pd: 28%; D-Kd^a: 36%, Kd^a: 27%; D-Kd^b: 21%.
^awhere carfilzomib 20/56 mg/m² was administered twice-weekly.
^bwhere carfilzomib 20/70 mg/m² was administered once-weekly.
Newly diagnosed patient studies: D-VMP: 23%, VMP: 15%; D-Rd: 32%, Rd: 23%; D-VTd: 22%, VTd: 20%.
Grade 5 (fatal) infections: Relapsed/refractory patient studies: D-Vd: 1%, Vd: 2%; D-Rd: 2%, Rd: 1%; D-Pd: 2%; D-Kd^a: 5%, Kd^a: 3%; D-Kd^b: 0%.
^awhere carfilzomib 20/56 mg/m² was administered twice-weekly.
^bwhere carfilzomib 20/70 mg/m² was administered once-weekly.
Newly diagnosed patient studies: D-VMP: 1%, VMP: 1%; D-Rd: 2%, Rd: 2%; D-VTd: 0%, VTd: 0%.
In patients with multiple myeloma receiving DARZALEX FASPRO SC formulation combination therapy, the following were reported: Grade 3 or 4 infections: D-Pd: 28%, Pd: 23%; Grade 5 (fatal) infections: D-Pd: 5%, Pd: 3%.
In patients with AL amyloidosis receiving DARZALEX FASPRO SC formulation combination therapy, the following were reported: Grade 3 or 4 infections: D-VCd: 17%, VCd: 10%; Grade 5 (fatal) infections: D-VCd: 1%, VCd: 1%.
Haemolysis: There is a theoretical risk of haemolysis. Continuous monitoring for this safety signal will be performed in clinical studies and post-marketing safety data.
Cardiac disorders and AL amyloidosis-related cardiomyopathy: The majority of patients in AMY3001 had AL amyloidosis-related cardiomyopathy at baseline (D-VCd 72% vs. VCd 71%). Grade 3 or 4 cardiac disorders occurred in 11% of D-VCd patients compared to 10% of VCd patients, while serious cardiac disorders occurred in 16% vs. 13% of D-VCd and VCd patients, respectively. Serious cardiac disorders occurring in ≥2% of patients included cardiac failure (D-VCd 6.2% vs. VCd 4.3%), cardiac arrest (D-VCd 3.6% vs. VCd 1.6%) and atrial fibrillation (D-VCd 2.1% vs. VCd 1.1%). All D-VCd patients who experienced serious or fatal cardiac disorders had AL amyloidosis-related cardiomyopathy at baseline. The longer median duration of treatment in the D-VCd arm compared to the VCd arm (9.6 months vs. 5.3 months, respectively) should be taken into consideration when comparing the frequency of cardiac disorders between the two treatment groups. Exposure-adjusted incidence rates (number of patients with the event per 100 patient-months at risk) of overall Grade 3 or 4 cardiac disorders (1.2 vs. 2.3), cardiac failure (0.5 vs. 0.6), cardiac arrest (0.1 vs. 0.0) and atrial fibrillation (0.2 vs. 0.1) were comparable in the D-VCd arm vs. the VCd arm, respectively.
With a median follow-up of 11.4 months, overall deaths (D-VCd 14% vs. VCd 15%) in Study AMY3001 were primarily due to AL amyloidosis-related cardiomyopathy in both treatment arms.
Other Adverse Reactions: Other adverse reactions reported in patients treated with daratumumab in clinical trials are listed in Table 32. (See Table 32.)

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Other special population: In the phase III study MMY3007, which compared treatment with D-VMP to treatment with VMP in patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant, safety analysis of the subgroup of patients with an ECOG performance score of 2 (D-VMP: n=89, VMP: n=84), was consistent with the overall population.
Elderly: Of the 3615 patients who received daratumumab (n-898 SC; n=2717 IV) at the recommended dose, 38% were 65 to less than 75 years of age, and 16% were 75 years of age or older. No overall differences in effectiveness were observed based on age. The incidence of serious adverse reactions was higher in older than in younger patients (see as follows, Pharmacology: Pharmacodynamics: Clinical Studies under Actions). Among patients with relapsed and refractory multiple myeloma (n=2042), the most common serious adverse reactions that occurred more frequently in elderly (≥65 years of age) were pneumonia and sepsis. Among patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant (n=777), the most common serious adverse reaction that occurred more frequently in elderly (≥75 years of age) was pneumonia. Among patients with newly diagnosed AL amyloidosis (n=193), the most common serious adverse reaction that occurred more frequently in elderly (≥65 years of age) was pneumonia.
Postmarketing data: In addition to the previously mentioned, adverse reactions identified during postmarketing experience with daratumumab are included in Table 33. The frequencies are provided according to the following convention: Very common ≥1/10; Common ≥1/100 to <1/10; Uncommon ≥1/1000 to <1/100; Rare ≥1/10000 to <1/1000; Very rare <1/10000, including isolated reports; Not known frequency cannot be estimated from the available data.
In Table 33, adverse reactions are presented by frequency category based on spontaneous reporting rates, as well as frequency category based on precise incidence in a clinical trial, when known. (See Table 33.)

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