等待内容更新

Injectafer（美国商品名Ferinject，羧麦芽糖铁）已获得美国食品和药品监督管理局（FDA）批准用于治疗口服铁剂疗效不满意或不能耐受口服铁剂的缺铁性贫血（IDA）成年患者。
Injectafer?是第一个获得FDA批准用于治疗IDA的非右旋糖酐静脉铁剂，无论IDA患者的基础病因是什么，均可使用。
Injectafer也可以用于治疗非透析依赖的慢性肾脏病（ND-CKD）成年患者的缺铁性贫血。
INJECTAFER®（羧酸麦芽糖 ferric carboxymaltose）注射液
用于静脉使用
美国首次批准：2013年
作用机制
羧基麦芽糖是与羧基麦芽糖（一种释放铁的碳水化合物聚合物）复合的胶态铁（III）氢氧化物。
适应症和用法
Injectafer是一种铁替代产品，用于治疗成人患者的缺铁性贫血：
谁对口服铁不耐受或对口服铁有不满意的反应;
谁有非透析依赖慢性肾脏疾病。
剂量和给药
对于体重为50公斤（110磅）或以上的患者：给予Injectafer两次剂量，间隔至少7天。给每个剂量750毫克，每个疗程1500毫克铁的总累积剂量。
对于体重小于50公斤（110磅）的患者：以两次剂量给予Injectafer，间隔至少7天，每次剂量为15 mg / kg体重。
如果缺铁性贫血再次出现，可重复注射治疗。
剂量形式和强度
750毫克铁/15毫升一次性小瓶。
禁忌症
对Injectafer或其任何非活性组分的超敏反应。
警告和注意事项
超敏反应：观察Injectafer给药期间和之后超敏反应的体征和症状至少30分钟，并且在每次给药完成后直到临床稳定。
高血压：每次Injectafer给药后，密切监测患者的高血压征象和症状。
不良反应
最常见的不良反应（≥2％）是恶心，高血压，潮红，低磷血症和头晕。
要报告可疑的不良反应，请联系美国摄政1-800-734-9236或FDA 1-800-FDA-1088或www.fda.gov/medwatch。
在特定人群中使用
哺乳母亲：给护理妇女服用时要小心。

商品情報

 

販売名	欧文商標名	製造会社	規制区分
フェインジェクト静注500mg	Ferinject solution for injection/infusion 500mg	ゼリア新薬工業	処方箋医薬品

詳細情報

 

規格単位毎の明細 (フェインジェクト静注500mg)

販売名和名 : フェインジェクト静注500mg

規格単位 :

欧文商標名 : Ferinject solution for injection/infusion 500mg

規制区分

規制区分名称 : 処方箋医薬品注）

規制区分備考 : 注）注意−医師等の処方箋により使用すること

日本標準商品分類番号 : 873222

承認番号 : 23100AMX00290000

貯法及び期限等

貯法 : 室温保存（凍結を避けて保存）

有効期間 : 3年

規格単位毎の組成と性状

3.組成・性状_3.1　組成

販売名	フェインジェクト静注500mg
有効成分	1バイアル（10mL）中にカルボキシマルトース第二鉄を鉄として500mg含有する
添加剤	pH調整剤

添加物 : pH調整剤

3.組成・性状_3.2　製剤の性状

販売名	フェインジェクト静注500mg
性状	暗褐色の不透明な液
pH	5.0〜7.0
浸透圧比	1.0〜1.3（生理食塩液に対する比）

【色】
暗かっ色
【剤形】
／液剤／注射

規格単位毎の効能効果及び用法用量

効能効果対用法用量

4.効能又は効果

鉄欠乏性貧血

6.用法及び用量

通常、成人に鉄として1回あたり500mgを週1回、緩徐に静注又は点滴静注する。総投与量は、患者の血中ヘモグロビン値及び体重に応じるが、上限は鉄として1,500mgとする。

5.効能又は効果に関連する注意

本剤は経口鉄剤の投与が困難又は不適当な場合に限り使用すること。

7.用法及び用量に関連する注意

7.1　本剤の投与に際しては、以下を参考に、過量投与にならないよう、総投与量（投与回数）に注意すること。

本剤の鉄としての総投与量（投与回数）

		体重
		25kg以上 35kg未満	35kg以上 70kg未満	70kg以上
血中ヘモグロビン値	10.0g/dL未満	500mg （500mgを1回投与）	1,500mg （1回500mgを週1回、3回投与）	1,500mg （1回500mgを週1回、3回投与）
	10.0g/dL以上		1,000mg （1回500mgを週1回、2回投与）

7.2　本剤を希釈しないで使用する場合、5分以上かけて緩徐に静注すること。本剤を希釈して使用する場合は、6分以上かけて点滴静注すること。

7.3　35kg未満の患者には点滴静注とすること。

7.4　血中ヘモグロビン値は本剤投与終了後4週程度まで上昇するため、再治療の必要性は、投与終了後4週以降を目安に血中ヘモグロビン値、血清フェリチン値、患者の状態等から、鉄過剰に留意して慎重に判断すること。［12.2、17.1参照］

 

 

 

 

 

 

 

市场资料

 

 Ferinject (ferric carboxymaltose)

 

 

 

This information is intended for use by health professionals

 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

Ferinject 50 mg iron/mL solution for injection/infusion.

2. Qualitative and quantitative composition

One mL of solution contains 50 mg of iron as ferric carboxymaltose.

Each 2 mL vial contains 100 mg of iron as ferric carboxymaltose.

Each 10 mL vial contains 500 mg of iron as ferric carboxymaltose.

Each 20 mL vial contains 1,000 mg of iron as ferric carboxymaltose.

One mL of solution contains up to 5.5 mg (0.24 mmol) sodium, see section 4.4.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Solution for injection/infusion. Dark brown, non-transparent, aqueous solution.

4. Clinical particulars

4.1 Therapeutic indications

Ferinject is indicated for treatment of iron deficiency when oral iron preparations are ineffective or cannot be used. The diagnosis of iron deficiency must be based on laboratory tests.

4.2 Posology and method of administration

Monitor carefully patients for signs and symptoms of hypersensitivity reactions during and following each administration of Ferinject.

Ferinject 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 patient should be observed for adverse effects for at least 30 minutes following each Ferinject administration (see section 4.4).

Posology

The posology of Ferinject follows a stepwise approach: [1] determination of the individual iron need, [2] calculation and administration of the iron dose(s), and [3] post-iron repletion assessments. These steps are outlined below:

Step 1: Determination of the iron need

The individual iron need for repletion using Ferinject is determined based on the patient's body weight and haemoglobin (Hb) level. Refer to Table 1 for determination of the iron need:

Table 1: Determination of the iron need

Hb		Patient body weight
g/dL	mmol/L	below 35 kg	35 kg to <70 kg	70 kg and above
<10	<6.2	500 mg	1,500 mg	2,000 mg
10 to <14	6.2 to <8.7	500 mg	1,000 mg	1,500 mg
≥14	≥8.7	500 mg	500 mg	500 mg

Iron deficiency must be confirmed by laboratory tests as stated in 4.1.

Step 2: Calculation and administration of the maximum individual iron dose(s)

Based on the iron need determined above the appropriate dose(s) of Ferinject should be administered taking into consideration the following:

A single Ferinject administration should not exceed:

• 15 mg iron/kg body weight (for administration by intravenous injection) or 20 mg iron/kg body weight (for administration by intravenous infusion)

• 1,000 mg of iron (20 mL Ferinject)

The maximum recommended cumulative dose of Ferinject is 1,000 mg of iron (20 mL Ferinject) per week.

Step 3: Post-iron repletion assessments

Re-assessment should be performed by the clinician based on the individual patient's condition. The Hb level should be re-assessed no earlier than 4 weeks post final Ferinject administration to allow adequate time for erythropoiesis and iron utilisation. In the event the patient requires further iron repletion, the iron need should be recalculated using Table 1 above. (See section 5.1.)

Special Population – patients with haemodialysis-dependent chronic kidney disease

A single maximum daily dose of 200 mg iron should not be exceeded in haemodialysis-dependent chronic kidney disease patients (see also section 4.4).

Paediatric population

The use of Ferinject has not been studied in children, and therefore is not recommended in children under 14 years.

Method of administration

Ferinject must only be administered by the intravenous route:

• by injection, or

• by infusion, or

• during a haemodialysis session undiluted directly into the venous limb of the dialyser.

Ferinject must not be administered by the subcutaneous or intramuscular route.

Intravenous injection

Ferinject may be administered by intravenous injection using undiluted solution. The maximum single dose is 15 mg iron/kg body weight but should not exceed 1,000 mg iron. The administration rates are as shown in Table 2:

Table 2: Administration rates for intravenous injection of Ferinject

Volume of Ferinject required	Equivalent iron dose	Administration rate / Minimum administration time
2 to 4 mL	100 to 200 mg	No minimal prescribed time
>4 to 10 mL	>200 to 500 mg	100 mg iron / min
>10 to 20 mL	>500 to 1,000 mg	15 minutes

Intravenous infusion

Ferinject may be administered by intravenous infusion, in which case it must be diluted. The maximum single dose is 20 mg iron/kg body weight, but should not exceed 1,000 mg iron.

For infusion, Ferinject must only be diluted in sterile 0.9% m/V sodium chloride solution as shown in Table 3. Note: for stability reasons, Ferinject should not be diluted to concentrations less than 2 mg iron/mL (not including the volume of the ferric carboxymaltose solution).

Table 3: Dilution plan of Ferinject for intravenous infusion

Volume of Ferinject required	Equivalent iron dose	Maximum amount of sterile 0.9% m/V sodium chloride solution	Minimum administration time
2 to 4 mL	100 to 200 mg	50 mL	No minimal prescribed time
>4 to 10 mL	>200 to 500 mg	100 mL	6 minutes
>10 to 20 mL	>500 to 1,000 mg	250 mL	15 minutes

4.3 Contraindications

The use of Ferinject is contraindicated in cases of:

• hypersensitivity to the active substance, to Ferinject or any of its excipients listed in section 6.1.

• known serious hypersensitivity to other parenteral iron products.

• anaemia not attributed to iron deficiency, e.g. other microcytic anaemia.

• evidence of iron overload or disturbances in the utilisation of iron.

4.4 Special warnings and precautions for use

Hypersensitivity reactions

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.

The risk 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).

Ferinject should only be administered when staff trained to evaluate and manage anaphylactic reactions are 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 Ferinject administration. 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.

Hypophosphataemia

Parenterally administered iron preparations can cause hypophosphataemia which in most cases is transient and without clinical symptoms. Cases of hypophosphataemia requiring medical attention were reported, mainly in patients with existing risk factors and after prolonged exposure to high-dose intravenous iron.

Hepatic or renal impairment

In patients with liver dysfunction, parenteral iron should only be administered after careful benefit/risk 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.

No safety data on haemodialysis-dependent chronic kidney disease patients receiving single doses of more than 200 mg iron are available.

Infection

Parenteral iron must be used with caution in case of acute or chronic infection, asthma, eczema or atopic allergies. It is recommended that the treatment with Ferinject is stopped in patients with ongoing bacteraemia. Therefore, in patients with chronic infection a benefit/risk evaluation has to be performed, taking into account the suppression of erythropoiesis.

Extravasation

Caution should be exercised to avoid paravenous leakage when administering Ferinject. Paravenous leakage of Ferinject at the administration site may lead to irritation of the skin and potentially long lasting brown discolouration at the site of administration. In case of paravenous leakage, the administration of Ferinject must be stopped immediately.

Excipients

One mL of undiluted Ferinject contains up to 5.5 mg (0.24 mmol) of sodium. This has to be taken into account in patients on a sodium-controlled diet.

Paediatric population

The use of Ferinject has not been studied in children.

4.5 Interaction with other medicinal products and other forms of interaction

The absorption of oral iron is reduced when administered concomitantly with parenteral iron preparations. Therefore, if required, oral iron therapy should not be started for at least 5 days after the last administration of Ferinject.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are limited data from the use of Ferinject in pregnant women (see section 5.1). A careful benefit/risk evaluation is required before use during pregnancy and Ferinject should not be used during pregnancy unless clearly necessary.

Iron deficiency occurring in the first trimester of pregnancy can in many cases be treated with oral iron. Treatment with Ferinject should be confined to the second and third trimester if the benefit is judged to outweigh the potential risk for both the mother and the foetus.

Animal data suggest that iron released from Ferinject can cross the placental barrier and that its use during pregnancy may influence skeletal development in the fetus (see section 5.3).

Breast-feeding

Clinical studies showed that transfer of iron from Ferinject to human milk was negligible (≤1%). Based on limited data on breast-feeding women it is unlikely that Ferinject represents a risk to the breast-fed child.

Fertility

There are no data on the effect of Ferinject on human fertility. Fertility was unaffected following Ferinject treatment in animal studies (see section 5.3).

4.7 Effects on ability to drive and use machines

Ferinject is unlikely to impair the ability to drive and use machines.

4.8 Undesirable effects

Table 4 presents the adverse drug reactions (ADRs) reported during clinical studies in which >8,000 subjects received Ferinject, as well as those reported from the post-marketing experience (see table footnotes for details).

The most commonly reported ADR is nausea (occurring in 2.9% of the subjects), followed by injection/infusion site reactions, hypophosphataemia, headache, flushing, dizziness and hypertension. Injection/infusion site reactions comprise several ADRs which individually are either uncommon or rare.

For subjects in clinical trials that showed a decrease in serum phosphorous, the minimum values were obtained after approximately 2 weeks, and in most cases returned to baseline values by 12 weeks following Ferinject treatment . The most serious ADR is anaphylactoid/anaphylactic reactions (rare); fatalities have been reported. See section 4.4 for further details.

Table 4: Adverse drug reactions observed during clinical trials and post-marketing experience

System Organ Class	Common (≥1/100 to <1/10)	Uncommon (≥1/1,000 to <1/100)	Rare (≥1/10,000 to <1/1,000)
Immune system disorders		Hypersensitivity	Anaphylactoid/anaphylactic reactions
Metabolism and nutritional disorders	Hypophosphataemia
Nervous system disorders	Headache, dizziness	Paraesthesia, dysgeusia	Loss of consciousness(1)
Psychiatric disorders			Anxiety(2)
Cardiac disorders		Tachycardia
Vascular disorders	Flushing, hypertension	Hypotension	Phlebitis, syncope(2), presyncope(2)
Respiratory, thoracic and mediastinal disorders		Dyspnoea	Bronchospasm(2)
Gastrointestinal disorders	Nausea	Vomiting, dyspepsia, abdominal pain, constipation, diarrhoea	Flatulence
Skin and subcutaneous tissue disorders		Pruritus, urticaria, erythema, rash(3)	Angioedema(2), pallor(2), and face oedema(1)
Musculoskeletal and connective tissue disorders		Myalgia, back pain, arthralgia, pain in extremity, muscle spasms
General disorders and administration site conditions	Injection/infusion site reactions(4)	Pyrexia, fatigue, chest pain, oedema peripheral, chills	Malaise, influenza like illness (whose onset may vary from a few hours to several days) (2)
Investigations		Alanine aminotransferase increased, aspartate aminotransferase increased, gamma-glutamyltransferase increased, blood lactate dehydrogenase increased, blood alkaline phosphatase increased

1 ADRs exclusively reported in the post-marketing setting.

2 ADRs reported in the post-marketing setting which are also observed in the clinical setting.

3 Includes the following preferred terms: rash (individual ADR determined to be uncommon) and rash erythematous, -generalised, -macular, -maculo-papular, -pruritic (all individual ADRs determined to be rare).

4 Includes, but is not limited to, the following preferred terms: injection/infusion site -pain, -haematoma, -discolouration, -extravasation, -irritation, -reaction, (all individual ADRs determined to be uncommon) and -paraesthesia (individual ADR determined to be rare).

Note: ADR = Adverse drug reaction.

Reporting of suspected adverse reactions

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:

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9 Overdose

Administration of Ferinject in quantities exceeding the amount needed to correct iron deficit at the time of administration may lead to accumulation of iron in storage sites eventually leading to haemosiderosis. Monitoring of iron parameters such as serum ferritin and transferrin saturation may assist in recognising iron accumulation. If iron accumulation has occurred, treat according to standard medical practice, e.g. consider the use of an iron chelator.

5. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Iron trivalent, parenteral preparation, ATC code: B03AC

Ferinject solution for injection/infusion is a colloidal solution of the iron complex ferric carboxymaltose.

The complex is designed to provide, in a controlled way, utilisable iron for the iron transport and storage proteins in the body (transferrin and ferritin, respectively).

Red cell utilisation of 59Fe from radio-labelled Ferinject ranged from 91% to 99% in subjects with iron deficiency (ID) and 61% to 84% in subjects with renal anaemia at 24 days post-dose.

Ferinject treatment of patients with ID anaemia results in an increase in reticulocyte count and serum ferritin levels to within normal ranges.

Clinical efficacy and safety

The efficacy and safety of Ferinject has been studied in different therapeutic areas necessitating intravenous iron to correct iron deficiency. The main studies are described in more detail below.

Cardiology

Chronic heart failure

Study CONFIRM-HF was a double-blind, randomised, 2-arm study comparing Ferinject (n=150) vs. placebo (n=151) in subjects with chronic heart failure and ID for a treatment period of 52 weeks. At Day 1 and Week 6 (correction phase), subjects received either Ferinject according to a simplified dosing grid using baseline Hb and body weight at screening (see section 4.2), placebo or no dose. At Weeks 12, 24, and 36 (maintenance phase) subjects received Ferinject (500 mg iron) or placebo if serum ferritin was <100 ng/mL or 100-299 ng/mL with TSAT <20%, or no dose. The treatment benefit of Ferinject vs. placebo was demonstrated with the primary efficacy endpoint, the change in the 6-minute walk test (6MWT) from baseline to Week 24 (p=0.002). This effect was sustained throughout the study to Week 52 (p<0.001).

Nephrology

Haemodialysis-dependent chronic kidney disease

Study VIT-IV-CL-015 was an open-label, randomised parallel group study comparing Ferinject (n=97) to iron sucrose (n=86) in subjects with ID anaemia undergoing haemodialysis. Subjects received Ferinject or iron sucrose 2-3 times per week in single doses of 200 mg iron directly into the dialyser until the individually calculated cumulative iron dose was reached (mean cumulative dose of iron as Ferinject: 1,700 mg). The primary efficacy endpoint was the percentage of subjects reaching an increase in Hb of ≥1.0 g/dL at 4 weeks after baseline. At 4 weeks after baseline, 44.1% responded to treatment with Ferinject (i.e. Hb increase of ≥1.0 g/dL) compared to 35.3% for iron sucrose (p=0.2254).

Non-dialysis-dependent chronic kidney disease

Study 1VIT04004 was an open-label, randomised active-control study, evaluating the safety and efficacy of Ferinject (n=147) vs. oral iron (n=103). Subjects in the Ferinject group received 1,000 mg of iron at baseline and 500 mg of iron at days 14 and 28, if TSAT was <30% and serum ferritin was <500 ng/mL at the respective visit. Subjects in the oral iron arm received 65 mg iron TID as ferrous sulphate from baseline to day 56. Subjects were followed-up until day 56. The primary efficacy endpoint was the percentage of subjects achieving an increase in Hb of ≥1.0 g/dL anytime between baseline and end of study or time of intervention. This was achieved by 60.54% of subjects receiving Ferinject vs. 34.7% of subjects in the oral iron group (p<0.001). Mean haemoglobin change to day 56/end of study was 1.0 g/dL in the Ferinject group and 0.7 g/dL in the oral iron group (p=0.034, 95% CI: 0.0, 0.7).

Gastroenterology

Inflammatory bowel disease

Study VIT-IV-CL-008 was a randomised, open-label study which compared the efficacy of Ferinject vs. oral ferrous sulphate in reducing ID anaemia in subjects with inflammatory bowel disease (IBD). Subjects received either Ferinject (n=111) in single doses of up to 1,000 mg iron once per week until the individually calculated iron dose (per Ganzoni formula) was reached (mean cumulative iron dose: 1,490 mg), or 100 mg iron BID as ferrous sulphate (n=49) for 12 weeks. Subjects receiving Ferinject showed a mean increase in Hb from baseline to Week 12 of 3.83 g/dL, which was non-inferior to 12 weeks of twice daily therapy with ferrous sulphate (3.75 g/dL, p=0.8016).

Study FER-IBD-07-COR was a randomised, open-label study comparing the efficacy of Ferinject vs. iron sucrose in subjects with remitting or mild IBD. Subjects receiving Ferinject were dosed according to a simplified dosing grid using baseline Hb and body weight (see section 4.2) in single doses up to 1,000 mg iron, whereas subjects receiving iron sucrose were dosed according to individually calculated iron doses using the Ganzoni formula in doses of 200 mg iron until the cumulative iron dose was reached. Subjects were followed-up for 12 weeks. 65.8% of subjects receiving Ferinject (n=240; mean cumulative iron dose: 1,414 mg) vs. 53.6% receiving iron sucrose (n=235; mean cumulative dose 1,207 mg; p=0.004) had responded at Week 12 (defined as Hb increase ≥2 g/dL). 83.8% of Ferinject-treated subjects vs. 75.9% of iron sucrose-treated subjects achieved a Hb increase ≥2 g/dL or had Hb within normal limits at Week 12 (p=0.019).

Women's health

Post partum

Study VIT-IV-CL-009 was a randomised open-label non-inferiority study comparing the efficacy of Ferinject (n=227) vs. ferrous sulphate (n=117) in women suffering from post-partum anaemia. Subjects received either Ferinject in single doses of up to 1,000 mg iron until their individually calculated cumulative iron dose (per Ganzoni formula) was reached, or 100 mg of iron as oral ferrous sulphate BID for 12 weeks. Subjects were followed-up for 12 weeks. The mean change in Hb from baseline to Week 12 was 3.37 g/dL in the Ferinject group (n=179; mean cumulative iron dose: 1,347 mg) vs. 3.29 g/dL in the ferrous sulphate group (n=89), showing non-inferiority between the treatments.

Pregnancy

Intravenous iron medicines should not be used during pregnancy unless clearly necessary. Treatment with Ferinject should be confined to the second and third trimester if the benefit is judged to outweigh the potential risk for both the mother and the foetus, see section 4.6.

Limited safety data in pregnant women are available from study FER-ASAP-2009-01, a randomised, open-label, study comparing Ferinject (n=121) vs. oral ferrous sulphate (n=115) in pregnant women in the second and third trimester with ID anaemia for a treatment period of 12 weeks. Subjects received Ferinject in cumulative doses of 1,000 mg or 1,500 mg of iron (mean cumulative dose: 1,029 mg iron) based on Hb and body weight at screening, or 100 mg of oral iron BID for 12 weeks. The incidence of treatment related adverse events was similar between Ferinject treated women and those treated with oral iron (11.4% Ferinject group; 15.3% oral iron group). The most commonly reported treatment-related adverse events were nausea, upper abdominal pain and headache. Newborn Apgar scores as well as newborn iron parameters were similar between treatment groups.

Ferritin monitoring after replacement therapy

There is limited data from study VIT-IV-CL-008 which demonstrates that ferritin levels decrease rapidly 2-4 weeks following replacement and more slowly thereafter. The mean ferritin levels did not drop to levels where retreatment might be considered during the 12 weeks of study follow up. Thus, the available data does not clearly indicate an optimal time for ferritin retesting although assessing ferritin levels earlier than 4 weeks after replacement therapy appears premature. Thus, it is recommended that further re-assessment of ferritin should be made by the clinician based on the individual patient's condition.

5.2 Pharmacokinetic properties

Positron emission tomography demonstrated that 59Fe and 52Fe from Ferinject was rapidly eliminated from the blood, transferred to the bone marrow, and deposited in the liver and spleen.

After administration of a single dose of Ferinject of 100 to 1,000 mg of iron in ID subjects, maximum total serum iron levels of 37 µg/mL up to 333 µg/mL are obtained after 15 minutes to 1.21 hours respectively. The volume of the central compartment corresponds well to the volume of the plasma (approximately 3 litres).

The iron injected or infused was rapidly cleared from the plasma, the terminal half-life ranged from 7 to 12 hours, the mean residence time (MRT) from 11 to 18 hours. Renal elimination of iron was negligible.

5.3 Preclinical safety data

Preclinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeat dose toxicity and genotoxicity. Preclinical studies indicate that iron released from Ferinject does cross the placental barrier and is excreted in milk in limited, controlled amounts. In reproductive toxicology studies using iron replete rabbits Ferinject was associated with minor skeletal abnormalities in the fetus. In a fertility study in rats, there were no effects on fertility for either male or female animals. No long-term studies in animals have been performed to evaluate the carcinogenic potential of Ferinject. No evidence of allergic or immunotoxic potential has been observed. A controlled in-vivo test demonstrated no cross-reactivity of Ferinject with anti-dextran antibodies. No local irritation or intolerance was observed after intravenous administration.

6. Pharmaceutical particulars

6.1 List of excipients

Sodium hydroxide (for pH adjustment)

Hydrochloric acid (for pH adjustment)

Water for injections

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

The compatibility with containers other than polyethylene and glass 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, preparations for parenteral administration should be used immediately.

Shelf life after dilution with sterile 0.9% m/V sodium chloride solution:

From a microbiological point of view, preparations for parenteral administration should be used immediately after dilution with sterile 0.9% m/V sodium chloride solution.

6.4 Special precautions for storage

Store in the original package in order to protect from light. Do not store above 30 °C. Do not freeze.

6.5 Nature and contents of container

Ferinject is supplied in a vial (type I glass) with a stopper (bromobutyl rubber) and an aluminium cap as:

- 2 mL solution containing 100 mg iron. Available in pack sizes of 1, 2 and 5 vials.

- 10 mL solution containing 500 mg iron. Available in pack sizes of 1, 2 and 5 vials.

- 20 mL solution containing 1,000 mg iron. Available in a pack size of 1 vial.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Inspect vials visually for sediment and damage before use. Use only those containing sediment-free, homogeneous solution.

Each vial of Ferinject is intended for single use only. Any unused product or waste material should be disposed of in accordance with local requirements.

Ferinject must only be mixed with sterile 0.9% m/V sodium chloride solution. No other intravenous dilution solutions and therapeutic agents should be used, as there is the potential for precipitation and/or interaction. For dilution instructions, see section 4.2.

7. Marketing authorisation holder

Vifor France

100-101 Terrasse Boieldieu

Tour Franklin La Défense 8

92042 Paris La Défense Cedex

France

Tel. +33 (0)1 41 06 58 90

Fax +33 (0)1 41 06 58 99

8. Marketing authorisation number(s)

PL 15240/0002

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 19.07.2007

Date of latest renewal: 18.06.2012

10. Date of revision of the text

November 2018