Source: Health Products Regulatory Authority (IE) Revision Year: 2020 Publisher: Pharmacosmos A/S, Roervangsvej 30, DK-4300 Holbaek, Denmark
Pharmacotherapeutic group: Iron parenteral preparation
ATC code: B03AC
Monover solution for injection is a colloid with strongly bound iron in spheroidal iron-carbohydrate particles. The Monover formulation contains iron in a complex that enables a controlled and slow release of bioavailable iron to iron-binding proteins with little risk of free iron.
Each particle consists of a matrix of iron(III) atoms and derisomaltose with an average molecular weight of 1000 Da and a narrow molecular weight distribution that is almost devoid of mono- and disaccharides. INN name: Ferric derisomaltose (also known as iron(III) isomaltoside 1000).
The chelation of iron(III) with carbohydrate confers to the particles a structure resembling ferritin that is suggested to protect against the toxicity of unbound inorganic iron(III).
The iron is available in a non-ionic water-soluble form in an aqueous solution with pH between 5.0 and 7.0.
Evidence of a therapeutic response can be seen within a few days of administration of Monover as an increase in the reticulocyte count. Due to the slow release of bioavailable iron serum ferritin peaks within days after an intravenous dose of Monover and slowly returns to baseline after weeks.
The efficacy of Monover has been studied in the different therapeutic areas necessitating IV iron to correct iron deficiency. The main trials are described in more detail below.
The P-Monofer-IDA-01 trial was an open-label, comparative, randomised, multi-centre, non-inferiority trial conducted in 511 patients with IDA randomised 2:1 to either Monover or iron sucrose. 90% of recruited patients were females. The dosing of Monover was performed according to the Simplified Table as described in section 4.2 above and dosing of iron sucrose was calculated according to Ganzoni and administered as 200 mg infusions. The primary endpoint was the proportion of patients with an Hb increase ≥2 g/dl from baseline at any time between weeks 1 to 5. A higher proportion of patients treated with Monover compared to iron sucrose reached the primary endpoint, 68.5% vs 51.6%, respectively. (FAS, p<0.0001).
The P-Monofer-IDA-03 trial was an open-label, comparative, randomised, multi-centre trial conducted in 1512 patients with IDA randomised 2:1 to either Monofer 1000 mg infused over 20 min (1009 subjects)or iron sucrose administered as 200 mg IV injections repeated up to a cumulative dose of 1000 mg (503 subjects). For the co-primary efficacy endpoint the change from baseline to week 8 in Hb was 2.49 g/dL in the Monofer group and 2.49 g/dL in the iron sucrose group. The estimated treatment difference [95% CI] of iron isomaltoside – iron sucrose was 0.00 g/dL [-0.13; 0.13]. Since the lower bound of the 95% CI for the treatment difference was above -0.5 g/dL, non-inferiority was concluded. For the co-primary safety endpoint, a total of 3 treatment emergent serious or severe hypersensitivity reactions in 989 subjects (0.3%) were adjudicated and confirmed by the adjudication committee in the iron isomaltoside group. The 95% CI was [0.06%; 0.88%] and as the upper bound was <3%, the primary safety objective was considered met. In the iron sucrose group 2 treatment emergent serious or severe hypersensitivity reactions in 494 subjects (0.4%) were adjudicated and confirmed by the adjudication committee. The risk difference between iron isomaltoside and iron sucrose was estimated to -0.10% [95% CI: -0.91; 0.71].
The P-Monofer-CKD-02 trial was an open-label, comparative, randomised, multi-centre, non-inferiority trial conducted in 351 iron deficient non-dialysis dependent (NDD) chronic kidney disease (CKD) patients, randomised 2:1 to either Monover or oral iron sulphate administered as 100 mg elemental oral iron twice daily (200 mg daily) for 8 weeks. The patients in the Monover group were randomised to infusion of 1000 mg single dose or bolus injections of 500 mg. Monover was non-inferior to oral iron at week 4 (p<0.001) and also sustained a superior increase in Hb compared to oral iron from week 3 until the end of trial at week 8 (p=0.009 at week 3). The P-Monofer-CKD-04 trial was an open-label, comparative, randomised, multi-centre trial conducted in 1538 NDD-CKD patients with IDA randomised 2:1 to either Monofer 1000 mg infused over 20 min (1027 subjects)or iron sucrose administered as 200 mg IV injections repeated up to a cumulative dose of 1000 mg (511 subjects). For the co-primary efficacy endpoint, the change from baseline to week 8 in Hb was 1.22 g/dL in the Monofer group and 1.14 g/dL in the iron sucrose group. The estimated treatment difference was 0.08 g/dL [95% CI: -0.06; 0.23]. Since the lower bound of the 95% CI was above -0.5 g/dL, non-inferiority was concluded. For the co-primary safety endpoint, a total of 3 treatment emergent serious or severe hypersensitivity reactions in 1019 subjects (0.3%) were adjudicated and confirmed by the adjudication committee in the iron isomaltoside group. The 95% CI was [0.06%; 0.86%] and as the upper bound was <3%, the primary safety objective was considered met. No treatment emergent serious or severe hypersensitivity reactions were adjudicated and confirmed by the adjudication committee in the iron sucrose group. The risk difference between iron isomaltoside and iron sucrose was estimated to 0.29% [95% CI: -0.19; 0.77]. Haemodialysis-dependent chronic kidney disease The P-Monofer-CKD-03 trial was an open-label, comparative, randomised, multi-centre, non-inferiority trial conducted in 351 haemodialysis patients randomised 2:1 to either Monover or iron sucrose. Patients were randomised to either a single injection of 500 mg or 500 mg in split doses of Monover or 500 mg iron sucrose in split doses. Both treatments showed similar efficacy with more than 82% of patients with Hb in the target range (non-inferiority, p=0.01).
The P-Monofer-CIA-01 trial was an open-label, comparative, randomised, multi-centre, non-inferiority trial conducted in 350 cancer patients with anaemia randomised 2:1 to either Monover or oral iron sulphate administered as 100 mg elemental oral iron twice daily (200 mg daily) for 12 weeks. The patients in the Monover group were randomised to either an infusion of max 1000 mg single doses over 15 min or bolus injections of 500 mg over 2 min. The primary endpoint was change in Hb concentrations from baseline to week 4. Monover was non-inferior to oral iron at week 4 (p<0.001) and a faster onset of the Hb response was observed with infusion of Monover.
The P-Monofer-IBD-01 trial was an open-label, comparative, randomised, multi-centre, non-inferiority trial conducted in 338 inflammatory bowel disease (IBD) patients randomised 2:1 to receive either Monover or oral iron sulphate administered as 100 mg elemental oral iron twice daily for 8 weeks (200 mg daily). The patients in the Monover group were randomised to either an infusion of max 1000 mg single doses over 15 min or bolus injections of 500 mg over 2 min. A modified Ganzoni formula was used to calculate the IV iron need with a target Hb of only 13 g/dl resulting in an average iron dose of 884 mg elemental iron compared to oral iron administered as 200 mg oral iron sulfate once daily for 8 weeks (11,200 mg elemental oral iron in total). The primary endpoint was change in Hb concentrations from baseline to week 8. The patients had mild to moderate disease activity. Non-inferiority in change of Hb to week 8 could not be demonstrated. The doseresponse relationship observed with Monover suggests that the true iron demand of IV iron was underestimated by the modified Ganzoni formula. The Hb response (Hb increase ≥2 g/dl) rate was 93% for patients receiving >1000 mg Monover.
The P-Monofer-PP-01 trial was an open-label, comparative, randomised, single-centre, trial conducted in 200 healthy women with postpartum haemorrhage exceeding 700 mL and ≤1000 ml or PPH >1000 ml and Hb >6.5 g/dl measured >12 hours after delivery. The women were randomised 1:1 to receive either a single dose of 1200 mg Monover or standard medical care. The primary endpoint was the aggregated change in physical fatigue within 12 weeks postpartum. The difference in aggregated change in physical fatigue score within 12 weeks postpartum was -0.97 (p=0.006), in favour of Monover.
The Monover formulation contains iron in a strongly bound complex that enables a controlled and slow release of bioavailable iron to iron-binding proteins with little risk of free iron toxicity. After administration of a single dose of Monover of 100 to 1000 mg of iron in pharmacokinetic studies, the iron injected or infused was cleared from the plasma with a half-life that ranged from 1 to 4 days. Renal elimination of iron was negligible.
Following intravenous administration, ferric derisomaltose is rapidly taken up by the cells in the reticuloendothelial system (RES), particularly in the liver and spleen from where iron is slowly released.
Circulating iron is removed from the plasma by cells of the reticuloendothelial system which split the complex into its components of iron and derisomaltose. The iron is immediately bound to the available protein moieties to form hemosiderin or ferritin, the physiological storage forms of iron, or to a lesser extent, to the transport molecule transferrin. This iron, which is subject to physiological control, replenishes haemoglobin and depleted iron stores.
Iron is not easily eliminated from the body and accumulation can be toxic. Due to the size of the complex, Monover is not eliminated via the kidneys. Small quantities of iron are eliminated in urine and faeces.
Derisomaltose is either metabolised or excreted.
Iron complexes have been reported to be teratogenic and embryocidal in non-anaemic pregnant animals at high single doses above 125 mg iron/kg body weight. The highest recommended dose in clinical use is 20 mg iron/kg body weight.
In a fertility study with Monover in rats no effects on female on male reproductive performance and spermatogenic parameters were found at the dose level tested.
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