- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
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.
PosologyThe cumulative dose of Venofer must be calculated for each patient individually and must not be exceeded.
Calculation of dosageThe total cumulative dose of Venofer, equivalent to the total iron deficit (mg), is determined by the haemoglobin level (Hb) and body weight (BW). The dose of Venofer must be individually calculated for each patient according to the total iron deficit calculated with the following Ganzoni formula, for example:
Total iron deficit [mg] = BW [kg] x (target Hb - actual Hb) [g/dl] x 2.4* + storage iron [mg]
|• Below 35 kg BW: • 35 kg BW and above:||Target Hb = 13 g/dl and storage iron = 15 mg/kg BW Target Hb = 15 g/dl and storage iron = 500 mg|
|BW||Total amount of Venofer (20 mg iron per ml) to be administered|
|Hb 6.0 g/dl||Hb 7.5 g/dl||Hb 9.0 g/dl||Hb 10.5 g/dl|
|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 ml||97.5 ml||82.5 ml||67.5 ml|
|85 kg||117.5 ml||102.5 ml||85 ml||70 ml|
|90 kg||122.5 ml||107.5 ml||90 ml||72.5 ml|
|* Below 35 kg BW:||Target Hb = 13 g/dl|
|35 kg BW and above:||Target Hb = 15 g/dl|
Adults5 - 10 ml of Venofer (100 - 200 mg iron) 1 to 3 times a week. For administration time and dilution ratio see Method of administration.
Paediatric populationThe use of Venofer has not been adequately studied in children and, therefore, Venofer is not recommended for use in children.
Method of administrationVenofer 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 infusionVenofer 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:
|Venofer dose (mg of iron)||Venofer dose (ml of Venofer)||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|
Intravenous injectionVenofer may be administered by slow intravenous injection at a rate of 1 ml undiluted solution per minute and not exceeding 10 ml Venofer (200 mg iron) per injection.
Injection into venous line of dialysis machineVenofer may be administered during a haemodialysis session directly into the venous line of the dialysis machine under the same conditions as for intravenous injection.
PregnancyThere is no data from the use of iron sucrose in pregnant women in the first trimester. Data (303 pregnancy outcomes) from the use of Venofer 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 Venofer should not be used during pregnancy unless clearly necessary (see section 4.4).Iron deficiency anaemia occurring in the first trimester of pregnancy can in many cases be treated with oral iron. Treatment with Venofer 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).
Breast-feedingThere is limited information on the excretion of iron in human milk following administration of intravenous iron sucrose. In one clinical study, 10 healthy breast-feeding 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 Venofer 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 offspring was observed. Non metabolised iron sucrose is unlikely to pass into the mother's milk.FertilityNo effects of iron sucrose treatment were observed on fertility and mating performance in rats.
|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, somnolence||Depressed level of consciousness, confusional state, loss of consciousness, anxiety, tremor|
|Cardiac disorders||Palpitations||Bradycardia, tachycardia|
|Vascular disorders||Hypotension, hypertension||Flushing, phlebitis||Circulatory collapse, thrombophlebitis|
|Respiratory, thoracic and mediastinal disorders||Dyspnoea||Bronchospasm|
|Renal and urinary disorders||Chromaturia|
|Gastrointestinal disorders||Nausea||Vomiting, abdominal pain, diarrhoea, constipation|
|Skin and subcutaneous tissue disorders||Pruritus, rash||Urticaria, erythema|
|Musculoskeletal and connective tissue disorders||Muscle spasm, myalgia, arthralgia, pain in extremity, back pain|
|General disorders and administration site conditions||Injection/infusion site reaction2)||Chills, asthenia, fatigue, oedema peripheral, pain||Chest pain, hyperdrosis, pyrexia||Cold sweat, malaise, pallor|
|Investigations||Alanine aminotransferase increased, aspartate aminotransferase increased, gamma-glutamyltransferase increased, serum ferritin increased||Blood lactate dehydrogenase increased|
Reporting of suspected adverse reactionsReporting 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 at: www.mhra.gov.uk/yellowcard.
Mechanism of actionIron sucrose, the active ingredient of Venofer, 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 diseaseStudy LU98001 was a single arm study to investigate the efficacy and safety of 100 mg iron as Venofer 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 μg/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 Venofer (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 μg/l, and TSAT ≤25%) with or without rHuEPO. A clinical response (defined as Hb increase ≥1.0 g/dl and serum ferritin increase ≥160 μg/l) was more frequently observed in patients treated with Venofer (31/79; 39.2%) compared to oral iron (1/82; 1.2%); p<0.0001.
Inflammatory Bowel DiseaseA randomised, controlled study compared Venofer (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 Venofer group had an increase in Hb ≥2.0 g/dl compared to 47% in the oral iron group (p=0.07).
PostpartumA randomised, controlled trial in women with postpartum iron deficiency anaemia (Hb <9 g/dl and serum ferritin <15 μg/l at 2448 hours post-delivery) compared 2 × 200 mg iron given as Venofer 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 Venofer group and 0.7 g/dl in the oral iron group (p<0.01).
PregnancyIn 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 µg/l) were randomised to Venofer (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 Venofer group compared to the oral iron group at Day 28 and at delivery (p<0.01).
DistributionThe ferrokinetics of iron sucrose labelled with 52Fe and 59Fe were assessed in 6 patients with anaemia and chronic renal failure. In the first 68 hours, 52Fe was taken up by the liver, spleen and bone marrow. The radioactive uptake by the macrophage-rich 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 µmol/l. The volume of distribution of the central compartment corresponded well to the volume of plasma (approximately 3 litres).
BiotransformationUpon 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%.
EliminationThe 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 a Venofer 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.
Shelf life of the product as packaged for sale3 years.
Shelf life after first opening of the containerFrom a microbiological point of view, the product should be used immediately.
Shelf life after dilution with sterile 0.9% m/V sodium chloride (NaCl) solutionFrom a microbiological point of view, the product should be used immediately after dilution with sterile 0.9% m/V sodium chloride solution.
Vifor Pharma UK Limited
The Old Stables, Bagshot Park, Surrey, GU19 5PJ, UK
+44 (0)1276 452 341
+44 (0)1276 452 341
+44 (0)1276 853 600
+44 (0)1276 853 633
+44 (0)1276 853 633