8.1 Adverse Reaction Overview
In phase II and III clinical trials, 3922 patients were treated with MONOFERRIC. 1638 (42 %) patients reported a total of 3622 adverse events (AEs). The most common treatment-emergent adverse events (TEAEs) (all causality) reported in more than 5 % of patients by preferred term were constipation (63 (2 %)), diarrhoea (71 (2 %)), dizziness (59 (2 %)) headache (92 (2 %)), nasopharyngitis (80 (2 %)) and nausea (97 (2%)).
Of the 3622 AEs, 346 serious adverse events (SAEs) were reported in 273 patients (7 %). No treatment-emergent SAEs were reported in > 1 % in patients treated with MONOFERRIC. The most common SAE was pneumonia (11 patients) and congestive heart failure (10 patients).
In the 3922 patients treated with MONOFERRIC, a total of 17 SARs reported in 16 patients (< 1 %) were considered as probably or possibly related to MONOFERRIC (all whom recovered). These were anaphylactic reaction, staphylococcal sepsis, angina unstable, generalized tonic-clonic seizure, dyspnea, rash pruritic, syncope, and eight cases of hypersensitivity, acute myocardial infarction, and infusion related reaction.
Of the 3922 patients treated with MONOFERRIC in clinical trials, 65 (2 %) patients experienced TEAEs leading to withdrawal from study.
Overall in clinical trials, a total of 28/3922 (0.7 %) patients reported a serious or severe hypersensitivity reaction, in which 8 of these cases occurred within one day of dosing with MONOFERRIC.
8.2 Clinical Trial Adverse Reactions
Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials, therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.
Across five randomized clinical trials a total of 2799 patients received MONOFERRIC.
Iron Deficiency Anemia (IDA) Studies:
In Study IDA-01, a total of 333 patients with IDA of various causes other than CKD were exposed to MONOFERRIC, of which, 32 (9.6 %) received a cumulative dose of 1000 mg, 164 (49.2 %) received a cumulative dose of 1500 mg, and 130 (39.0 %) received a cumulative dose of 2000 mg. Seven (2.1 %) patients were listed as receiving ‘other’ cumulative dose. MONOFERRIC was administered either as an IV infusion of 1000 mg over approximately 15 minutes or as an IV injection of 500 mg over 2 minutes per week, for an individual dose up to a maximum cumulative dose of 2000 mg. A total of 168 patients received 200 mg of IV iron sucrose by infusion up to twice weekly up to a cumulative dose of 2000 mg.
In Study IDA-03, a total of 989 patients with IDA of various causes were exposed to MONOFERRIC, which was administered as an IV infusion of a single fixed 1000 mg dose over 20 minutes. A total of 494 patients received iron sucrose administered as 200 mg IV injections repeated up to five times for a cumulative dose of 1000 mg. A total of three serious or severe hypersensitivity reactions occurred in 3/989 (0.3%; 95% CI 0.06; 0.88) patients in the MONOFERRIC group. The number of patients with adjudicated cardiovascular adverse events was 0.8% in the MONOFERRIC group.
Non-Dialysis-Dependent Chronic Kidney (NDD-CKD) Disease
A total of 228 non dialysis dependent patients with CKD (NDD-CKD) were exposed to MONOFERRIC in Study CKD-02. MONOFERRIC was administered either as IV infusions or IV bolus injections. The infusion was given in weekly doses for up to 2 weeks, to a maximum of 1000 mg iron each week until full replacement dose was achieved. The dose was diluted in 100 mL 0.9 % sodium chloride and given over approximately 15-20 minutes. Bolus injections of 500 mg were administered undiluted over approximately 2 minutes, once per week until full replacement dose was achieved. Oral iron was administered as 200 mg iron sulphate daily for 8 weeks. The mean cumulative dose of MONOFERRIC administered to the patients in the infusion and bolus subgroups were 907 ± 170 mg (range: 750:1500 mg) and 926 ± 241 mg (range: 500:2000 mg), respectively. The mean cumulative dose of MONOFERRIC was 916 ± 208 mg (range: 500:2000 mg).
In Study CKD-04, a total of 1019 non-dialysis dependent CKD (NDD-CKD) patients were exposed to MONOFERRIC, which was administered as an IV infusion of a single fixed 1000 mg dose over 20 minutes. A total of 506 patients received iron sucrose administered as 200 mg IV injections repeated up to five times for a cumulative dose of 1000 mg. A total of three serious or severe hypersensitivity reactions occurred in 3/1019 (0.3%; 95% CI 0.06; 0.86) patients in the MONOFERRIC group. The incidence of adjudicated and confirmed composite cardiovascular AEs in the MONOFERRIC group was 4.1%.
Dialysis-Dependent Chronic Kidney Disease (DD-CKD) Studies
In Study CKD-03, a total of 230 hemodialysis-dependent CKD (DD-CKD) patients were exposed to MONOFERRIC, of which, 114 (50 %) received a dose of 500 mg by IV single bolus injection and 116 (50 %) received a total dose of 500 mg as fractionated (100 mg + 200 mg + 200 mg) IV bolus injections. A total of 117 patients received 500 mg of IV iron sucrose administered as 500 mg fractionated (100 mg + 200 mg + 200 mg) IV bolus injections.
| ||||||||
| Iron Deficiency Anemia IDA-01+IDA-03 | Chronic Kidney Disease CKD-02 | Chronic Kidney Disease CKD-03 | Chronic Kidney Disease CKD-04 | |||||
|---|---|---|---|---|---|---|---|---|
| ferric derisomaltose | iron sucrose | ferric derisomaltose | oral iron | ferric derisomaltose | iron sucrose | ferric derisomaltose | iron sucrose | |
| N [%] | N [%] | N [%] | N [%] | N [%] | N [%] | N [%] | N [%] | |
| Safety Analysis Set | 1322 | 662 | 228 | 117 | 230 | 114 | 1019 | 506 |
| Any AE(s) | 460 (35%) | 208 (31%) | 95 (42%) | 53 (45%) | 110 (48%) | 47 (41%) | 335 (33%) | 168 (33%) |
| Infections and infestations | 97 (7%) | 41 (6%) | 25 (11%) | 12 (10%) | 22 (10%) | 15 (13%) | 81 (8%) | 40 (8%) |
| - Nasopharyngitis | 19 (1%) | 5 (<1%) | 7 (3%) | 4 (3%) | 6 (3%) | 1 (<1%) | 10 (<1%) | 2 (<1%) |
| - Urinary tract infection | 19 (1%) | 8 (1%) | 4 (2%) | 1 (<1%) | 25 (2%) | 16 (3%) | ||
| - Lower respiratory tract infection | 1 (<1%) | 1 (<1%) | 4 (2%) | 3 (3%) | 2 (<1%) | |||
| Gastrointestinal disorders | 128 (10%) | 59 (9%) | 22 (10%) | 15 (13%) | 19 (8%) | 6 (5%) | 58 (6%) | 24 (5%) |
| - Faeces discoloured | 4 (<1%) | 5 (4%) | 1 (<1%) | |||||
| - Nausea | 48 (4%) | 23 (3%) | 2 (<1%) | 2 (2%) | 1 (<1%) | 16 (2%) | 7 (1%) | |
| - Diarrhoea | 17 (1%) | 9 (1%) | 7 (3%) | 4 (3%) | 5 (2%) | 2 (2%) | 15 (1%) | 7 (1%) |
| - Vomiting | 15 (1%) | 11 (2%) | 6 (3%) | 1 (<1%) | 3 (1%) | 2 (2%) | 10 (<1%) | 5 (<1%) |
| Injury, poisoning and procedural complications | 21 (2%) | 19 (3%) | 2 (<1%) | 25 (11%) | 9 (8%) | 16 (2%) | 19 (4%) | |
| - Fall | 2 (<1%) | 1 (<1%) | 1 (<1%) | 7 (3%) | 3 (<1%) | 9 (2%) | ||
| - Procedural hypotension | 5 (2%) | 1 (<1%) | ||||||
| General disorders and administration site conditions | 87 (7%) | 48 (7%) | 23 (10%) | 9 (8%) | 10 (4%) | 5 (4%) | 40 (4%) | 26 (5%) |
| - Pyrexia | 15 (1%) | 4 (<1%) | 7 (3%) | 4 (3%) | 1 (<1%) | 3 (<1%) | 2 (<1%) | |
| - Oedema peripheral | 8 (<1%) | 1 (<1%) | 5 (2%) | 2 (2%) | 13 (1%) | 5 (<1%) | ||
| Nervous system disorders | 83 (6%) | 62 (9%) | 14 (6%) | 6 (5%) | 13 (6%) | 6 (5%) | 35 (3%) | 22 (4%) |
| - Headache | 40 (3%) | 25 (4%) | 2 (<1%) | 2 (2%) | 7 (3%) | 4 (4%) | 9 (<1%) | 10 (2%) |
| - Dizziness | 32 (2%) | 18 (3%) | 5 (2%) | 1 (<1%) | 5 (<1%) | 8 (2%) | ||
| - Dysgeusia | 3 (<1%) | 15 (2%) | 1 (<1%) | 3 (<1%) | 1 (<1%) | |||
| Metabolism and nutrition disorders | 24 (2%) | 8 (1%) | 12 (5%) | 2 (2%) | 8 (3%) | 8 (7%) | 62 (6%) | 30 (6%) |
| - Hyperphosphataemia | 1 (<1%) | 1 (<1%) | 5 (2%) | 4 (4%) | 5 (<1%) | 1 (<1%) | ||
| - Hyperkalaemia | 4 (<1%) | 1 (<1%) | 6 (3%) | 1 (<1%) | 1 (<1%) | 25 (2%) | 9 (2%) | |
| Musculoskeletal and connective tissue disorders | 66 (5%) | 27 (4%) | 10 (4%) | 3 (3%) | 16 (7%) | 1 (<1%) | 32 (3%) | 15 (3%) |
| - Back pain | 17 (1%) | 4 (<1%) | 5 (2%) | 7 (<1%) | 3 (<1%) | |||
| - Pain in extremity | 7 (<1%) | 7 (1%) | 1 (<1%) | 1 (<1%) | 5 (2%) | 3 (<1%) | 4 (<1%) | |
| Skin and subcutaneous tissue disorders | 89 (7%) | 14 (2%) | 10 (4%) | 1 (<1%) | 26 (3%) | 11 (2%) | ||
| - Rash | 35 (3%) | 4 (<1%) | 2 (<1%) | 11 (1%) | 2 (<1%) | |||
| Cardiac disorders | 12 (<1%) | 9 (1%) | 6 (3%) | 3 (3%) | 31 (3%) | 29 (6%) | ||
| - Cardiac failure congestive | 1 (<1%) | 1 (<1%) | 1 (<1%) | 8 (<1%) | 11 (2%) | |||
| Investigations | 48 (4%) | 25 (4%) | 11 (5%) | 5 (4%) | 46 (5%) | 28 (6%) | ||
| - C-reactive protein increased | 5 (<1%) | 3 (<1%) | 6 (3%) | 1 (<1%) | 1 (<1%) | |||
| Vascular disorders | 34 (3%) | 19 (3%) | 8 (4%) | 4 (3%) | 8 (3%) | 1 (<1%) | 29 (3%) | 19 (4%) |
| - Hypertension | 13 (<1%) | 6 (<1%) | 7 (3%) | 2 (2%) | 3 (1%) | 1 (<1%) | 14 (1%) | 13 (3%) |
8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data
Clinical trial findings
Hypophosphataemia:
In Study IDA-01, 65 (19.5 %) patients in the MONOFERRIC group and 7 (4.2 %) patients in the iron sucrose group had serum phosphate (s-phosphate) level < 2 mg/dL. Hypophosphataemia defined as s-phosphate < 2 mg/dL was reported in 3 patients in CKD-02 and 4 patients in CKD‑03 (1.3 % and 1.7 %, respectively) in the MONOFERRIC group compared to 1 patient (< 1 %) in the oral iron sulfate group in Study CKD-02 and 2 patients (1.8 %) in the iron sucrose group in Study CKD-03.
One (1) patient treated with MONOFERRIC had s-phosphate level < 1 mg/dL (0.8 mg/dL) at week 4 which was normalised (2.6 mg/dL) at the following visit in Study IDA-01. Two patients in the MONOFERRIC group had s-phosphate level < 1 mg/dL in Study CKD-03 and none in Study CKD-02.
Most patients exposed to MONOFERRIC had low s-phosphate values for 1-4 weeks and 7 (2.2 %) patients had s-phosphate < 2 mg/dL at week 5 in Study IDA-01. In the iron sucrose group, most patients had low s-phosphate values for 1-2 weeks and 1 patient had s-phosphate < 2 mg/dL at week 5. Thus, the hypophosphataemia events were transient and, in most cases, normalised at the end of the trial.
No event of hypophosphataemia was considered as an AE in both Study CKD-02 and CKD-03 but was reported as an AE in Study IDA-01 in 6 (2 %) patients.
8.5 Post-Market Adverse Reactions
Because these adverse events are spontaneously reported in a voluntary manner from a population of uncertain size, it is not possible to reliably estimate their frequency. The following adverse reactions have been reported from the post-marketing spontaneous reports with MONOFERRIC:
Cardiac disorders:
Fetal bradycardia due to maternal hypersensitivity reactions, cardiac arrest, tachycardia
General disorders and administration site conditions:
Asthenia, chest discomfort, chest pain, chills, feeling abnormal, feeling hot, Fishbane reaction, influenza like illness, infusion site erythema, injection site discolouration, injection site extravasation, pain, pyrexia
Immune system disorders:
Hypersensitivity, anaphylactic and anaphylactoid reactions, including very rare cases of anaphylactic shock with a fatal outcome, have been reported
Investigations:
Blood pressure decreased, blood pressure increased, body temperature increased
Musculoskeletal and connective tissue disorders:
Joint swelling, pain in extremity
Nervous system disorders:
Burning sensation, cerebrovascular accident, generalized tonic-clonic seizure, head discomfort, loss of consciousness, paraesthesia, seizure, syncope, tremor
Respiratory, thoracic and mediastinal disorders:
Asphyxia, bronchospasm, pharyngeal edema, respiratory arrest, respiratory distress, wheezing
Skin and subcutaneous tissue disorders:
Angioedema, dermatitis allergic, erythema, generalized erythema, purpura, rash generalized, skin discolouration, swelling face, urticaria
Vascular disorders:
Circulatory collapse, flushing, hypotension, shock