MONOFERRIC (Iron Isomaltoside 1000 for Injection) 8 Adverse Reactions

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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.

Table 2: Clinical Trial TEAEs Reported in ≥ 2% of Patients by Study (IDA-01, IDA-03, in patients with IDA and CKD-02, CKD-03, and CKD-04 in patients with CKD)
 
N: Number of patients
 
(%): Percentage of patients
 
Preferred terms in all treatment groups presented if incidence in at least one group >= 2%. If no preferred term within a study has incidence >= 2%, the corresponding system organ class is not presented
 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 sucroseferric
derisomaltose
oral ironferric
derisomaltose
iron sucroseferric derisomaltoseiron sucrose
 N [%]N [%]N [%]N [%]N [%]N [%]N [%]N [%]
 
Safety Analysis Set13226622281172301141019506
 
Any AE(s)460 (35%)208 (31%)95 (42%)53 (45%)110 (48%)47 (41%)335 (33%)168 (33%)
 
Infections and infestations97 (7%)41 (6%)25 (11%)12 (10%)22 (10%)15 (13%)81 (8%)40 (8%)
- Nasopharyngitis19 (1%)5 (<1%)7 (3%)4 (3%)6 (3%)1 (<1%)10 (<1%)2 (<1%)
- Urinary tract infection19 (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 disorders128 (10%)59 (9%)22 (10%)15 (13%)19 (8%)6 (5%)58 (6%)24 (5%)
- Faeces discoloured4 (<1%)  5 (4%)   1 (<1%) 
- Nausea48 (4%)23 (3%)2 (<1%)2 (2%)1 (<1%) 16 (2%)7 (1%)
- Diarrhoea17 (1%)9 (1%)7 (3%)4 (3%)5 (2%)2 (2%)15 (1%)7 (1%)
- Vomiting15 (1%)11 (2%)6 (3%)1 (<1%)3 (1%)2 (2%)10 (<1%)5 (<1%)
 
Injury, poisoning and procedural complications21 (2%)19 (3%)2 (<1%) 25 (11%)9 (8%)16 (2%)19 (4%)
- Fall2 (<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%)
- Pyrexia15 (1%)4 (<1%)7 (3%)4 (3%)1 (<1%) 3 (<1%)2 (<1%)
- Oedema peripheral8 (<1%)1 (<1%)5 (2%)2 (2%)  13 (1%)5 (<1%)
 
Nervous system disorders83 (6%)62 (9%)14 (6%)6 (5%)13 (6%)6 (5%)35 (3%)22 (4%)
- Headache40 (3%)25 (4%)2 (<1%)2 (2%)7 (3%)4 (4%)9 (<1%)10 (2%)
- Dizziness32 (2%)18 (3%)5 (2%) 1 (<1%) 5 (<1%)8 (2%)
- Dysgeusia3 (<1%)15 (2%)1 (<1%)   3 (<1%)1 (<1%)
 
Metabolism and nutrition disorders24 (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%)
- Hyperkalaemia4 (<1%)1 (<1%)6 (3%) 1 (<1%)1 (<1%)25 (2%)9 (2%)
 
Musculoskeletal and connective tissue disorders66 (5%)27 (4%)10 (4%)3 (3%)16 (7%)1 (<1%)32 (3%)15 (3%)
- Back pain17 (1%)4 (<1%)5 (2%)   7 (<1%)3 (<1%)
- Pain in extremity7 (<1%) 7 (1%)1 (<1%)1 (<1%)5 (2%) 3 (<1%)4 (<1%)
 
Skin and subcutaneous tissue disorders89 (7%)14 (2%)10 (4%)1 (<1%)  26 (3%)11 (2%)
- Rash35 (3%)4 (<1%)2 (<1%)   11 (1%)2 (<1%)
 
Cardiac disorders12 (<1%)9 (1%)6 (3%)3 (3%)  31 (3%)29 (6%)
- Cardiac failure congestive1 (<1%)1 (<1%)1 (<1%)   8 (<1%)11 (2%)
 
Investigations48 (4%)25 (4%)  11 (5%)5 (4%)46 (5%)28 (6%)
- C-reactive protein increased5 (<1%)3 (<1%)  6 (3%)1 (<1%)1 (<1%) 
 
Vascular disorders34 (3%)19 (3%)8 (4%)4 (3%)8 (3%)1 (<1%)29 (3%)19 (4%)
- Hypertension13 (<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