Summary of medicine characteristics - IRON SUCROSE 20 MG IRON/ML SOLUTION FOR INJECTION /INFUSION
This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.
1 NAME OF THE MEDICINAL PRODUCT
Iron Sucrose 20 mg iron/ml, Solution for injection /infusion
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each ml of solution contains 20 mg iron as iron sucrose [iron (III)-hydroxide-sucrose-Complex]
Each 5 ml ampoule of Sucrofer 20 mg iron/ml, Solution for injection / infusion contains 100 mg iron as iron sucrose [iron (III)-hydroxide-sucrose- complex].
For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Solution for injection / infusion.
Sucrofer is a dark brown, slightly viscous liquid
pH : Between 10.50 and 11.00 at 20° C.
Osmolality : Between 1150 mOsmol/kg and 1350 mOsmol/kg.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Sucrofer is indicated for the intravenous treatment of iron deficiency in the following indications:
Where there is a clinical need for a rapid iron supply.
In patients who cannot tolerate oral iron therapy or who are non-compliant, In active inflammatory bowel disease where oral iron preparations are ineffective. In chronic kidney disease when oral iron preparations are less effective.
The diagnosis of iron deficiency must be based on appropriate laboratory tests (e.g. Hb, serum ferritin, TSAT, serum iron, etc). (Hb haemoglobin, TSAT transferrin saturation)
4.2 Posology and method of administration
Monitor carefully patients for signs and symptoms of hypersensitivity reactions during and following each administration of Sucrofer.
Sucrofer should only be administered when staff trained to evaluate and manage anaphylactic reactions is immediately available, in an environment where full resuscitation facilities can be assured. The patients should be observed for adverse effects for at least 30 minutes following each Sucrofer (section 4.4)
Posology
The cumulative dose of Sucrofer must be calculated for each patient individually and must not be exceeded.
Calculation of dosage
The total cumulative dose of Sucrofer, equivalent to the total iron deficit (mg), is determined by the haemoglobin level (Hb) and body weight (BW). The dose of Sucrofer must be individually calculated for each patient according to the total iron deficit calculated with the following Ganzoni formula, for example:
Total iron deficit = body weight [kg] x (target Hb – actual Hb) [g/dl] x 2.4* + [mg] storage iron [mg]
Below 35 kg body weight: target Hb = 13 g/dl and storage iron = 15 mg/kg body weight
35 kg body weight and above: Target Hb = 15 g/dl and storage iron = 500 mg
* Factor 2.4 = 0.0034 (Iron content of haemoglobin = 0.34%) x 0.07 (Blood volume 7% of body weight) x 1000 (conversion from g to [mg]) x 10.
Total Sucrofer to administered (in ml)
Total iron deficit [mg]
20mg iron/ml
For UK: The unit of Hb is g/L.
Total amount of Sucrofer (ml) to be administered according to body weight, actual Hb level and target Hb level*:
| Body Weight | Total amount of Sucrofer to be administered | |||
| Hb 6.0 | Hb 7.5 | Hb 9.0 | Hb 10.5 | |
| 30 kg | 47.5 ml | 42.5 ml | 37.5 ml | 32.5 ml |
| 35 kg | 62.5 ml | 57.5 ml | 50 ml | 45 ml |
| 40 kg | 67.5 ml | 60 ml | 55 ml | 47.5 ml |
| 45 kg | 75 ml | 65 ml | 57.5 ml | 50 ml |
| 50 kg | 80 ml | 70 ml | 60 ml | 52.5 ml |
| 55 kg | 85 ml | 75 ml | 65 ml | 55 ml |
| 60 kg | 90 ml | 80 ml | 67.5 ml | 57.5 ml |
| 65 kg | 95 ml | 82.5 ml | 72.5 ml | 60 ml |
| 70 kg | 100 ml | 87.5 ml | 75 ml | 62.5 ml |
| 75 kg | 105 ml | 92.5 ml | 80 ml | 65 ml |
| 80 kg | 112.5 | 97.5 ml | 82.5 ml | 67.5 ml |
| 85 kg | 117.5 | 102.5 | 85 ml | 70 ml |
| 90 kg | 122.5 | 107.5 | 90 ml | 72.5 ml |
| Below 35 kg BW | : | Target H | b = 13g/dl | |
35 kg BW and above : Target Hb = 15g/dl
To convert Hb (mM) to Hb (g/dl), multiply the former by 1.6
If the total necessary dose exceeds the maximum allowed single dose, then the administration must be divided.
Posology
Adults
5– 10 ml of Sucrofer (100– 200 mg Iron) 1 to 3 times a week. For administration time and dilution ratio see “Method of administration".
Paediatric population
The use of Sucrofer has not been adequately studied in children and, therefore. Sucrofer is not recommended for use in children and adolescents under 18 years of age.
Patients with renal impairment
No dose adjustment is necessary.
Patients with hepatic impairment See section 4.4 Special warnings.
Method of administration
Sucrofer must only be administered by the intravenous route. This may be by a slow intravenous injection, by an intravenous drip infusion or directly into the venous line of the dialysis machine.
Intravenous drip infusion
Sucrofer must only be diluted in sterile 0.9% m/V sodium chloride (NaCl) solution.
Dilution must take place immediately prior to infusion and the solution should be administered as follows:
| Sucrofer dose (mg of iron) | Sucrofer dose (ml of Sucrofer) | Maximum dilution volume of sterile 0.9% m/v NaCl solution | Minimum Infusion Time |
| 50 mg | 2.5 ml | 50 ml | 8 minutes |
| 100 mg | 5 ml | 100 ml | 15 minutes |
| 200 mg | 10 ml | 200 ml | 30 minutes |
For stability reasons, dilutions to lower Sucrofer concentrations are not permissible.
Intravenous injection:
Sucrofer may be administered by slow intravenous injection at a rate of 1 ml undiluted solution per minute and not exceeding 10ml Sucrofer (200 mg iron) per injection.
Injection into venous line of dialysis machine
Sucrofer may be administered during a haemodialysis session directly into the venous line of the dialysis machine under the same conditions as for intravenous injection.
4.3 Contraindications
The use of Sucrofer is contra-indicated in the following condition:
Hypersensitivity to the active substance, to Sucrofer or any of its excipients listed in section 6.1
Known serious hypersensitivity to other parenteral iron products
Anaemia not caused by iron deficiency
Evidence of iron overload or hereditary disturbance in utilization of iron.
4.4 Special warnings and precautions for use
Parenterally administered iron preparations can cause hypersensitivity reactions including serious and potentially fatal anaphylactic/anaphylactoid reactions. Hypersensitivity reactions have also been reported after previously uneventful doses of parenteral iron complexes including iron sucrose. There have been reports of hypersensitivity reactions which progressed to Kounis syndrome (acute allergic coronary arteriospasm that can result in myocardial infarction, see section 4.8). However, in several studies performed in patients who had a history of a hypersensitivity reaction to iron dextran or ferric gluconate, Iron Sucrose was shown to be well tolerated. For known serious hypersensitivity to other parenteral iron product see section 4.3.
The risk of hypersensitivity reactions is enhanced for patients with known allergies including drug allergies, including patients with a history of severe asthma, eczema or other atopic allergy.
There is also an increased risk of hypersensitivity reactions to parenteral iron complexes in patients with immune or inflammatory conditions (e.g. systemic lupus erythematosus, rheumatoid arthritis).
Iron Sucrose should only be administered when staff trained to evaluate and manage anaphylactic reactions is immediately available, in an environment where full resuscitation facilities can be assured. Each patient should be observed for adverse effects for at least 30 minutes following each Iron Sucrose injection. If hypersensitivity reactions or signs of intolerance occur during administration, the treatment must be stopped immediately. Facilities for cardio respiratory resuscitation and equipment for handling acute anaphylactic/anaphylactoid reactions should be available, including an injectable 1:1000 adrenaline solution. Additional treatment with antihistamines and/or corticosteroids should be given as appropriate.
In patients with liver dysfunction, parenteral iron should only be administered after careful risk/benefit assessment. Parenteral iron administration should be avoided in patients with hepatic dysfunction where iron overload is a precipitating factor, in particular Porphyria Cutanea Tarda (PCT). Careful monitoring of iron status is recommended to avoid iron overload.
Parenteral iron must be used with caution in case of acute or chronic infection. It is recommended that the administration of Iron Sucrose is stopped in patients with bacteraemia. In patients with chronic infection a risk/benefit evaluation should be performed.
Paravenous leakage must be avoided because leakage of Iron Sucrose at the injection site can lead to pain, inflammation, tissue necrosis and brown discoloration of the skin.
This medicinal product contains less than 1 mmol sodium (23 mg) per 5 ml ampoule, i.e. essentially “sodium-free”.
4.5 Interaction with other medicinal products and other forms of interaction
As with all parenteral iron preparations, Sucrofer should not be administered concomitantly with oral iron preparations since the absorption of oral iron is reduced.
4.6 Fertility, pregnancy and lactationPregnancy
There is no data from the use of iron sucrose in pregnant women in the first trimester. Data (303 pregnancy outcomes) from the use of Iron Sucrose in pregnant women in the second and third trimester showed no safety concerns for the mother or newborn.
A careful risk/benefit evaluation is required before use during pregnancy and Iron Sucrose should not be used during pregnancy unless clearly necessary (see section4.4).
Foetal bradycardia may occur following administration of parenteral irons. It is usually transient and a consequence of a hypersensitivity reaction in the mother. The unborn baby should be carefully monitored during intravenous administration of parenteral irons to pregnant women.
Iron deficiency anaemia occurring in the first trimester of pregnancy can in many cases be treated with oral iron. Treatment with Iron Sucrose should be confined to second and third trimester if the benefit is judged to outweigh the potential risk for both the mother and the foetus.
Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).
There is limited information on the excretion of iron in human milk following administration of intravenous iron sucrose. In one clinical study, 10 healthy breastfeeding mothers with iron deficiency received 100 mg iron in the form of iron sucrose. Four days after treatment, the iron content of the breast milk had not increased and there was no difference from the control group (n=5). It cannot be excluded that newborns/infants may be exposed to iron derived from Iron Sucrose via the mother's milk, therefore the risk/benefit should be assessed.
Preclinical data do not indicate direct or indirect harmful effects to the nursing child. In lactating rats treated with 59Fe-labelled iron sucrose, low secretion of iron into the milk and transfer of iron into the off spring was observed. Non metabolised iron sucrose is unlikely to pass into the mother's milk.
Preclinical studies did not show any effect of treatment at any dose level on fertility, mating performance.
4.7 Effects on ability to drive and use machines
In the case of symptoms of dizziness, confusion or light headedness following the administration of Sucrofer, patients should not drive or use machinery until the symptoms have ceased.
4.8 Undesirable effects
The most commonly reported adverse drug reaction in clinical trials with iron sucrose injection was dysgeusia, which occurred with a rate of 4.5 events per 100 subjects. The most important serious adverse drug reactions associated with iron sucrose injection are hypersensitivity reactions, which occurred with a rate of 0.25 events per 100 subjects in clinical trials (see section 4.4).
The adverse drug reactions reported after the administration of iron sucrose injection in 4,064 subjects in clinical trials as well as those reported from the post marketing setting are presented in table below:
| System Organ Class | Common (>1/100, <1/10) | Uncommon (>1/1,000, <1/100) | Rare (>1/10,000, <1/1,000) | Frequency not known1) |
| Immune system disorders | Hypersensitivity | Anaphylactoid reactions, angioedema | ||
| Nervous system disorders | Dysgeusia | Headache, dizziness, paraesthesia, hypoaesthesia | Syncope, somnolenc e | Depressed level of consciousness, confusional state, loss of consciousness, anxiety, tremor |
| Cardiac disorders | Palpitation s | Bradycardia, tachycardia Kounis syndrome | ||
| Vascular disorders | Hypotension, hypertension | Flushing, phlebitis | Circulatory collapse, thrombophlebit is superficial | |
| Respiratory, thoracic and mediastinal disorders | Dyspnoea | Bronchospasm |
| System Organ Class | Common (>1/100, <1/10) | Uncommon (>1/1,000, <1/100) | Rare (>1/10,000, <1/1,000) | Frequency not known1) |
| Renal and urinary disorders | Chromaturi a | |||
| Gastrointestina l disorders | Nausea | Vomiting, abdominal pain, diarrhoea, constipation | ||
| Skin and subcutaneous tissue disorders | Pruritus, rash | Urticaria, erythema | ||
| Musculoskelet al and connective tissue disorders | Muscle spasm, myalgia, arthralgia, pain in extremity, back pain | |||
| General disorders and administration site conditions | Injection/infusi on site reaction2) | Chills, asthenia, fatigue, oedema peripheral, pain | Chest pain, hyperdrosis , pyrexia | Influenza like illness whose onset may vary from a few hours to several days, Cold sweat, malaise, pallor |
| Investigations | Alanine aminotransferase increased, aspartate aminotransferase increased, gamma-glutamyltransfera se increased, serum ferritin increased | Blood lactate dehydrogenase increased |
1) Spontaneous reports from the post-marketing setting
2)The most frequently reported are: injection/infusion site pain, extravasation, irritation, reaction, discolouration, haematoma, pruritus.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard.
4.9 Overdose
4.9 OverdoseOverdosage can cause acute iron overloading which may manifest itself as haemosiderosis. Overdosage should be treated, as deemed necessary by the treating physician, with an iron chelating agent or according to standard medical practice.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Anti-anaemic preparation, iron, parenteral preparation,
ATC code: B03AC
Mechanism of action
Iron sucrose, the active ingredient of Sucrofer, is composed of a polynuclear iron(III)-hydroxide core surrounded by a large number of non-covalently bound sucrose molecules. The complex has a weight average molecular weight (Mw) of approximately 43 kDa. The polynuclear iron core has a structure similar to that of the core of the physiological iron storage protein ferritin. The complex is designed to provide, in a controlled manner, utilisable iron for the iron transport and storage proteins in the body (i.e., transferrin and ferritin, respectively).
Following intravenous administration, the polynuclear iron core from the complex is taken up predominantly by the reticuloendothelial system in the liver, spleen, and bone marrow. In a second step, the iron is used for the synthesis of Hb, myoglobin and other iron-containing enzymes, or stored primarily in the liver in the form of ferritin.
Clinical efficacy and safety
Chronic kidney disease
Study LU98001 was a single arm study to investigate the efficacy and safety of 100 mg iron as Iron sucrose injection for up to 10 sessions over 3–4 weeks in haemodialysis patients with iron deficiency anaemia (Hb >8 and <11.0 g/dl, TSAT <20%, and serum ferritin <300 jig/l) who were receiving rHuEPO therapy. A Hb >11 g/dl was attained in 60/77 patients. The mean increase in serum ferritin and TSAT was significant from baseline to the end of treatment (Day 24) as well as to the 2 and 5 weeks follow-up visit.
Study 1VEN03027 was a randomised study comparing Iron sucrose injection (1000 mg in divided doses over 14 days) and oral ferrous sulphate (325 mg 3 times daily for 56 days) in non-dialysis dependent chronic kidney disease patients (Hb <11.0 g/dl, serum ferritin <300 jig/l, and TSAT <25%) with or without rHuEPO. A clinical response (defined as Hb increase >1.0 g/dl and serum ferritin increase >160 jrg/l) was more frequently observed in patients treated with Iron sucrose injection (31/79;
39.2%) compared to oral iron (1/82; 1.2%); p<0.0001.
In flammatory Bowel Disease
A randomised, controlled study compared Iron sucrose injection (single IV dose of 200 mg iron once per week or every second week until the cumulative dose was reached) with oral iron (200 mg twice daily for 20 weeks) in patients with inflammatory bowel disease and anaemia (Hb <11.5 g/dl). At the end of treatment, 66% of patients in the Iron sucrose injection group had an increase in Hb >2.0 g/dl compared to 47% in the oral iron group (p=0.07).
Postpartum
A randomised, controlled trial in women with postpartum iron deficiency anaemia (Hb <9 g/dl and serum ferritin <15 jrg/l at 24–48 hours post-delivery) compared 2 × 200 mg iron given as Iron sucrose injection on Days 2 and 4 (n=22) and 200 mg of oral iron given as ferrous sulphate twice daily for 6 weeks (n=21). The mean increase in Hb from baseline to Day 5 was 2.5 g/dl in the Iron sucrose injection group and 0.7 g/dl in the oral iron group (p<0.01).
Pregnancy
In a randomised, controlled study, women in their third trimester of pregnancy with iron deficiency anaemia (Hb 8 to 10.5 g/dl and serum ferritin <13 jLLg/l) were randomised to Iron sucrose injection (individually calculated total dose of iron administered over 5 days) or oral iron polymaltose complex (100 mg 3× daily until delivery). The increase in Hb from baseline was significantly greater in the Iron sucrose injection group compared to the oral iron group at Day 28 and at delivery (p<0.01).
5.2 Pharmacokinetic properties
Distribution
The ferrokinetics of iron sucrose labelled with 52Fe and 59Fe were assessed in 6 patients with anaemia and chronic renal failure. In the first 6–8 hours, 52Fe was taken up by the liver, spleen and bone marrow. The radioactive uptake by the macrophagerich spleen is considered to be representative of the reticuloendothelial iron uptake.
Following intravenous injection of a single 100 mg iron dose of iron sucrose in healthy volunteers, maximum total serum iron concentrations were attained 10 minutes after injection and had an average concentration of 538 ^mol/l. The volume of distribution of the central compartment corresponded well to the volume of plasma (approximately 3 litres).
Biotransformation
Upon injection, sucrose largely dissociates and the polynuclear iron core is mainly taken up by the reticuloendothelial system of the liver, spleen, and bone marrow. At 4 weeks after administration, red cell iron utilization ranged from 59 to 97%.
Elimination
The iron sucrose complex has a weight average molecular weight (Mw) of approximately 43 kDa, which is sufficiently large to prevent renal elimination. Renal elimination of iron, occurring in the first 4 hours after injection of Iron Sucrose dose of 100 mg iron, corresponded to less than 5% of the dose. After 24 hours, the total serum iron concentration was reduced to the pre-dose level. Renal elimination of sucrose was about 75% of the administered dose.
5.3 Preclinical safety data
5.3 Preclinical safety dataNon-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity, genotoxicity and toxicity to reproduction and development.
6.1 List of excipients
Water for injections
Sodium hydroxide (for pH adjustment)
Nitrogen (inert gas)
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6. There is the potential for precipitation and/or interaction if mixed with other solution or medicinal products. The compatibility with containers other than glass, polyethylene and PVC is not known.
6.3
Shelf life
Shelf life of the product as packaged for sale:
3 years.
Shelf life after first opening of the container:
From a microbiological point of view, the product should be used immediately.
Shelf life after dilution with sterile 0.9% sodium chloride solution:
From a microbiological point of view, the product should be used immediately after dilution with sterile 0.9% m/V sodium chloride solution.
6.4 Special precautions for storage
Do not store above 25°C. Do not freeze. Keep the ampoule in the outer carton in order to protect from light.
For storage conditions after dilution or first opening of the medicinal product, see section 6.3.
6.5 Nature and contents of container
5 ml solution in one ampoule (type I glass) in pack sizes of 5, 10 or 25. Not all pack sizes may be marketed.
6.6 Special precautions for disposal
6.6 Special precautions for disposalAmpoules should be visually inspected for sediment and damage before use. Use only those with sediment free and homogenous solution.
Sucrofer must not be mixed with other medicinal products except sterile 0.9% m/v sodium chloride solution for dilution. For instructions on dilution of the product before administration, see section 4.2
The diluted solution must appear as brown and clear.
Each ampoule of Sucrofer is intended for single use only.
Any unused product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
Baxter Healthcare Limited
Caxton Way
Thetford, Norfolk IP24 3SE, United Kingdom.
8 MARKETING AUTHORISATION NUMBER(S)
PL 00116/0690
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION
22/06/2018