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.

NAME OF THE MEDICINAL PRODUCT

QUALITATIVE AND QUANTITATIVE COMPOSITION

1 ml of solution contains 30 mg of iron as ferumoxytol. Each vial of 17 ml solution contains 510 mg of iron as ferumoxytol. For the full list of excipients, see section 6.1.

PHARMACEUTICAL FORM

Solution for injection. {Injection} Black to reddish brown solution Osmolality: 270-330 mosm/kg pH: 6.5 to 8.0

CLINICAL PARTICULARS

Posology and method of administration

Monitor carefully patients for signs and symptoms of hypersensitivity reactions during and following each administration of Rienso. Rienso 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 Rienso injection (see section 4.4).

The recommended course of Rienso is based on the patient's pre-treatment haemoglobin and body weight as provided in Table 1. Each 510 mg dose is administered as an intravenous injection. For patients receiving two doses, the second 510 mg intravenous injection is to be administered 2 to 8 days later.

Table 1: Recommended Dosing Table for Rienso Administration

The maximum dose is 1020 mg (2 vials) and the two doses of Rienso must not be administered at the same time.

Rienso should not be given to patients if their haemoglobin is greater than 12 g/dl, serum Transferrin Saturation (TSAT) is greater than 50% or Ferritin is greater than 800 ng/ml (see section 4.4).

Patients should be re-assessed at least one month after the completion of a course of Rienso and this should include laboratory testing of haematologic and blood iron parameters.

To maintain the target haemoglobin value, re-treatment with Rienso may be given after the patient has been re-assessed and confirmed to be iron deficient. For maintenance therapy and patient monitoring, the recommendations of current guidelines (e.g. Revised European Best Practice Guidelines) should be followed.

The safety and efficacy of Rienso in children and adolescents below the age of 18 years has not been established. No data are available. Therefore Rienso should not be administered to children and adolescents below the age of 18 years (see section 5.1).

For patients receiving haemodialysis, Rienso should be administered once the blood pressure is stable and the patient has completed at least one hour of haemodialysis.

Rienso has not been specifically studied in patients with hepatic impairment; clinical experience is

limited to 8 patients. In patients with liver dysfunction, parenteral iron should only be administered after careful risk/benefit assessment. No change in dosage is recommended from Table 1.

Intravenous use. Rienso is administered as an undiluted intravenous injection delivered at a rate of up to 1 ml/sec (30 mg/sec) resulting in at least 17 seconds for one vial. Follow the administration with a slow flush of sodium chloride 9 mg/ml (0.9%) solution for injection to clear the line.

Contraindications

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. 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). Rienso 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 Rienso 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 the post-marketing experience with Rienso, anaphylactic type reactions presenting with cardiac arrest/ cardiorespiratory arrest, clinically significant hypotension, syncope, and unresponsiveness have been reported (see section 4.8). In patients with multiple substance allergies, the need for Rienso or alternative treatment options should be carefully considered.

Severe adverse reactions of clinically significant hypotension have been reported. Hypotension may follow Rienso administration with or without accompanying signs of hypersensitivity (see section 4.8). Patients should be monitored for signs and symptoms of hypotension following each Rienso administration.

Rienso should not be administered to patients with iron overload. Rienso must not be given to patients if their haemoglobin is greater than 12 g/dl, serum Transferrin Saturation (TSAT) is greater than 50% or ferritin is greater than 800 ng/ml (see section 4.2).

Parenteral iron should be used with caution in cases of immunologic disease or acute or chronic infection. It is not recommended to administer Rienso to patients with ongoing bacteraemia.

Limited clinical study data is available regarding re-treatment with Rienso and no clinical study data is available for repeated long term use. For information on post-marketing experience see section 5.1.

This medicinal product contains small amounts of ethanol (alcohol), less than 100 mg per 17 ml vial. This medicinal product contains less than 23 mg sodium per 17 ml vial, i.e., is essentially "sodium free".

Administration of Rienso may transiently affect the diagnostic ability of MR imaging. Anticipated MR imaging studies should be conducted prior to the administration of Rienso. The effect on vascular MR imaging lasts approximately 1-2 days while tissue diagnostic imaging may be affected for up to 2-3 months. MR images are interpretable earlier by readers aware of the recent administration of Rienso or by the use of T1- or proton density-weighted MR pulse sequences. Rienso will not interfere with X-ray, computed tomography (CT), positron emission tomography (PET), single photon emission computed tomography (SPECT), ultrasound or nuclear medicine imaging.

In the 24 hours following administration of Rienso, laboratory assays may overestimate serum iron and transferrin bound iron by also measuring the iron in the Rienso complex.

Interaction with other medicinal products and other forms of interaction

No drug-drug interaction studies have been performed. As with all parenteral iron preparations the absorption of oral iron is reduced when administered concomitantly.

Fertility, pregnancy and lactation

There are no adequate and well-controlled trials of Rienso in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). A careful risk/benefit evaluation is therefore required before use during pregnancy and Rienso 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 b e treated with oral iron. Treatment with Rienso 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. Rienso is not recommended in women of childbearing potential not using adequate contraception. Breastfeeding It is unknown whether Rienso is excreted in human milk. Available pharmacokinetic data in animals have shown excretion of Rienso in milk (see section 5.3). A risk to breastfeeding newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue Rienso therapy, taking into account the benefit of breast-feeding for the child and the benefit of the therapy for the mother.

No adverse effects on fertility or general reproductive performance were noted in adult rats (see Section 5.3). In a prenatal and postnatal developmental study in rats adverse effects on sexual maturation and on the ability to produce a litter were noted in the F1-generation (see section 5.3).

Effects on ability to drive and use machines

Rienso may have a minor influence on the ability to drive and use machines. In the case of symptoms of dizziness, confusion or light headedness following the administration of Rienso, patients should not drive or use machinery until the symptoms have ceased. No studies regarding effects on the ability to drive or operate machines have been performed.

Undesirable effects

Summaryofthesafetyprofile

In clinical trials involving 1562 subjects with CKD, adverse reactions were seen in 7.9% of patients who received Rienso, of which 0.2% were considered serious. The most frequently reported adverse reactions were gastrointestinal symptoms (diarrhoea, constipation, nausea and vomiting), headache, dizziness and hypotension, all occurring in less than 2.5% of patients. Serious hypersensitivity or hypotensive reactions are uncommon (less than 1 case per 100 patients) and were reported in 0.2% (3/1562) of subjects with CKD who received Rienso during the clinical studies. One of these three cases was also characterized as an anaphylactoid reaction.

Tabulatedlistofadversereactions

Table 2 presents all adverse experiences observed during the clinical studies in which 1562 subjects with CKD received two injections of 510 mg of Rienso separated by an interval of 2 to 8 days and post-marketing experience.

Table 2: Adverse reactions observed during clinical studies and post-marketing experience

SYSTEM	COMMON	UNCOMMON	RARE	FREQUENCY NOT
ORGAN	(>= 1/100 to	(>= 1/1,000 to	(>= 1/10,000 to	KNOWN (CANNOT BE
CLASS	< 1/10)	< 1/100)	< 1/1,000)	ESTIMATED FROM
CLASS	< 1/10)	< 1/100)	< 1/1,000)	AVAILABLE DATA)
Blood and lymphatic system disorders			Eosinophilia
Immune system disorders		Hypersensitivity including anaphylaxis		Life-threatening Anaphylactic/Anaphylactoid reactions
Metabolism and nutrition disorders		Decreased appetite Increased appetite	Dehydration Gout Hyperkalaemia
Nervous system disorders		Dizziness Dysgeusia Headache Somnolence Burning sensation	Paraesthesia	Syncope Unresponsiveness Loss of consciousness
Eye disorders			Lacrimation increased Vision blurred
Cardiac				Tachycardia/Arrhythmia, Cardiac arrest
SYSTEM ORGAN CLASS	COMMON (>= 1/100 to < 1/10)	UNCOMMON (>= 1/1,000 to < 1/100)	RARE (>= 1/10,000 to < 1/1,000)	FREQUENCY NOT KNOWN (CANNOT BE ESTIMATED FROM AVAILABLE DATA)
disorders				Cardio-respiratory arrest Myocardial infarction Cyanosis Congestive heart failure
Vascular disorders		Hypotension (hypotension, blood pressure decreased) Flushing (flushing, hot flush) Hypertension (hypertension, accelerated hypertension)		Vasodilation
Respiratory, thoracic and mediastinal disorders		Dyspnoea	Epistaxis	Bronchospasm Cough Hyperventilation Hypoxia Laryngeal oedema Pharyngeal oedema Respiratory arrest Respiratory failure Throat irritation Throat tightness Wheezing
Gastrointestinal disorders		Diarrhoea Constipation Nausea Abdominal pain (Abdominal distension, abdominal pain upper, abdominal discomfort) Vomiting Faeces discoloured	Dry mouth Dyspepsia Glossodynia	Lip swelling Swollen tongue
Hepatobiliary disorders			Hepatic function abnormal
Skin & subcutaneous tissue disorders		Rash (rash, rash generalised, rash pruritic, urticaria) Pruritus (pruritus generalised) Ecchymosis Sweating (hyperhidrosis, night sweats) Skin hyperpigmentation Skin reaction		Angioedema
Musculoskeletal and connective		Muscle/joint pain or stiffness
SYSTEM	COMMON	UNCOMMON	RARE	FREQUENCY NOT
ORGAN	(>= 1/100 to	(>= 1/1,000 to	(>= 1/10,000 to	KNOWN (CANNOT BE
CLASS	< 1/10)	< 1/100)	< 1/1,000)	ESTIMATED FROM
CLASS	< 1/10)	< 1/100)	< 1/1,000)	AVAILABLE DATA)
tissue disorders		(arthralgia, myalgia, muscular weakness, musculoskeletal stiffness) Back pain Muscle spasms
General disorders and administration site conditions	Injection site reactions (infusion/injection site bruising, pain, reaction, swelling, warmth, haemorrhage, irritation, rash)	Fatigue (asthenia, fatigue) Chest pain (chest discomfort, chest pain) Chills Fever (feeling hot, pyrexia)		Injection site discolouration Injection site pruritus
Investigations		Serum ferritin increased	Blood glucose decreased	Pulse absent Oxygen saturation decreased
Injury, poisoning and procedural complications		Contusion

In clinical trials, adverse reactions leading to treatment discontinuation and occurring in >= 2 Rienso-treated patients included hypotension, infusion site swelling, increased serum ferritin levels, chest pain, diarrhoea, dizziness, ecchymosis, pruritis, chronic renal failure and urticaria.

Reportingofsuspectedadversereactions

Reporting suspected adverse reactions is an important way to gather more information to continuously monitor the benefit/risk balance of the medicinal product. Any suspected adverse reactions should be reported via .

thenationalreportingsystemlistedinAppendixV

Overdose

No data from clinical trials are available regarding overdose of Rienso in humans. During the post-marketing phase, several patients received an overdose of Rienso ranging from 1 g in 1 day to 2.5 g over 21 days. Only one case of minor rash was observed. Excessive administration of Rienso may lead to accumulation of iron in storage sites potentially leading to haemosiderosis. Periodic monitoring of laboratory parameters of iron storage, such as serum ferritin and transferrin saturation, enables recognition of iron accumulation. However, caution should be exercised in interpreting serum iron levels in the 24 hours following administration of Rienso as laboratory assays may overestimate serum iron and transferrin bound iron by also measuring the iron in Rienso. Please see the iron overload section 4.4 and for dosing guidance, see section 4.2. Overdose should be treated, if required, with an iron chelating agent.

PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

Pharmacotherapeutic group: Not yet assigned, ATC code: Not yet assigned MechanismofAction Rienso is a colloidal iron-carbohydrate complex. It includes iron oxide particles with an iron oxide core surrounded by a polyglucose sorbitol-carboxymethylether shell. The shell isolates the bioactive iron from plasma components until the iron-carbohydrate complex enter reticuloendothelial system macrophages of the liver, spleen and bone marrow. The iron is then released intracellularly from the iron-carbohydrate complex within vesicles in macrophages. Iron then either enters the intracellular storage iron pool (e.g., ferritin) or is transferred to plasma transferrin for transport to erythroid precursor cells for incorporation into haemoglobin.

The safety and efficacy of Rienso (cumulative dose of 1.02 grams) for the treatment of iron deficiency in CKD patients with IDA were assessed in three randomized, open-label, controlled clinical studies (Studies 1, 2 and 3). The principal efficacy results at Day 35 from the controlled phase of each study are shown in Table 3. This includes the Baseline and mean change to Day 35 in haemoglobin (Hgb, g/dl), transferrin saturation (TSAT, %) and ferritin (ng/ml) as well as the proportion of subjects who were Hgb Responders at Day 35 (defined as proportion of subjects with an increase in Hgb of at least 1.0 g/dl) in each treatment group for Studies 1, 2, and 3.

Table 3: Summary of Efficacy Endpoints at Day 35 (Intent to Treat Population)

In all three studies, patients with CKD and iron deficiency anaemia were randomized to treatment with Rienso or oral iron. Rienso was administered as two 510 mg intravenous injections (separated by 2 to 8 days) and oral iron (ferrous fumarate) was administered at a total daily dose of 200 mg elemental iron for 21 days. The major study outcomes assessed the change in haemoglobin from Baseline to Day 35. Studies 1 and 2 enrolled patients with non-dialysis dependent CKD and Study 3 enrolled patients who were undergoing haemodialysis. In Study 1, the mean age of patients was 66 years (range, 23 to 95); 60% were female; 65% were Caucasian, 32% were Black, and 2% were other races. In the Rienso and oral iron groups, 42% and 44% of patients, respectively, were receiving erythropoiesis stimulating agents (ESAs) at Baseline. In Study 2, the mean age of patients was 65 years (range, 31 to 96); 61% were female; 58% were Caucasian, 35% were Black, and 7% were other races. In the Rienso and oral iron groups, 36% and 43% of patients, respectively, were receiving ESAs at Baseline. In Study 3, the mean age of patients was 60 years (range, 24 to 87); 43% were female; 34% were Caucasian, 59% were Black, and 7% were other races. All patients were receiving ESAs at Baseline. Following completion of the controlled phase of each of the Phase 3 trials, patients who were iron deficient and anaemic could be optionally retreated and receive two additional 510 mg intravenous injections of Rienso for a total cumulative dose of 2.04 g. Overall, 69 patients received a total cumulative dose of 2.04 g. Adverse reactions following this repeat Rienso dosing were similar in character and frequency to those observed following the first two intravenous injections. In a placebo-controlled, cross-over trial, 713 patients with CKD received a single 510 mg dose of Rienso and placebo. Adverse reactions reported in these patients were similar in character and frequency to those observed in the other clinical trials.

Retrospective observational data from three large haemodialysis clinics in the US over a 1 year period included the treatment of over 8,600 patients with more than 33,300 administered doses of Rienso; nearly 50% of patients received repeat dosing with 4 or more doses. Mean haemoglobin increased (0.5-0.9 g/dl) post-treatment and stabilised in the range of 11-11.7 g/dl over the 10 month post-dose period; no new safety signals were identified with repeat dosing.

The European Medicines Agency has deferred the obligation to submit the results of studies with Rienso in one or more subsets of the paediatric population in the treatment of iron deficiency anaemia (see section 4.2 for information on paediatric use).

Pharmacokinetic Properties

The pharmacokinetic (PK) behaviour of Rienso has been examined in healthy subjects and in patients with CKD stage 5D on haemodialysis. Rienso exhibited dose-dependent, capacity-limited elimination from plasma with a half life of approximately 16 hours in humans. The clearance (CL) was decreased with increased doses of Rienso. Volume of distribution (Vd) was consistent with plasma volume, and the mean maximum observed plasma concentration (Cmax) and terminal half-life (t1/2) values increased with dose. The estimated values of CL and Vd following two 510 mg doses of Rienso administered intravenously within 24 hours were 69.1 ml/hr and 3.3 l, respectively. The Cmax and time of maximum concentration (tmax) were 206 mcg/ml and 0.32 hr, respectively. Rate of infusion had no influence on Rienso PK parameters. No gender differences in Rienso PK parameters were observed. Rienso is not removed by haemodialysis.

Preclinical Safety Data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, local tolerance and immunotoxicity. In a 4 week repeated dose toxicity study in rats after a recovery of 26 weeks hepatic changes (focal or multifocal haemorrhage, hemorrhagic necrosis, chronic inflammation, and/or bile duct hyperplasia) were seen in the female animals (the cumulative HED of the dose groups compares to a safety multiple of 5.1 and 10.5 to the cumulative human therapeutic dose (2 x 510 mg Fe) in a 60 kg human). Such effects were not seen in the male animals of that study or in the 13 weeks repeated dose toxicity study in rats (without recovery). As seen from clinical data there is no evidence that these effects seen in female rats are relevant for humans. No carcinogenicity studies were performed with Rienso. No adverse effects on fertility or general reproductive performance were noted in rats given IV Rienso at doses up to 18 mg Fe/kg/day (Human Equivalent Dose of 2.9 mg Fe/kg/day). Administration of Rienso during organogenesis in rats at maternally toxic doses of 100 mg Fe/kg/day caused a decrease in foetal weights. In rabbits administration of Rienso during organogenesis induced decreased foetal weights and external and/or soft tissue malformations (malrotated or flexed fore- and malrotated hindlimbs, internal hydrocephaly, absent brains, cleft palate and microglossia) at the high dose of 45.3 mg Fe/kg/day (HED of 14.6 mg Fe/kg/day), a dose which induced only minimal maternal toxicity. In a pre-natal and post-natal development study in rats sexual maturation was delayed in male pups in the high dose of 60 mg Fe/kg/day (HED of 9.7 mg Fe/kg/day). In female pups of the mid and high dose groups of 30 mg Fe/kg/day and 60 mg Fe/kg/day respectively (HED of 4.8 mg Fe/kg/day and 9.7 mg Fe/kg/day, respectively) sexual maturation was delayed and a disruption of the oestrus cycle was noted in some females. The ability to produce a litter (reproductive competence) was reduced in high dose males and in mid and high dose females, irrespective of whether F1 males were mated with F1 females or F1 males were mated with naive females and vice versa. In a lactation study in rats, there was minimal excretion of Rienso or Rienso-derived radioactivity into milk following single IV administration of approximately 100 mg Fe/kg (HED of 16.1 mg Fe/kg, approximately 2 times the recommended 510 mg human dose on a mg/m2 basis) of either the unlabelled, 59Fe or 14C-labelled product to lactating rats 10-11 days post-parturition, which peaked at 8 to 24 hours post-administration.

PHARMACEUTICAL PARTICULARS

List of excipients

Polyglucose-sorbitol carboxymethylether (PSC) Mannitol Water for Injections Sodium hydroxide (for pH adjustment) Hydrocholric acid (for pH adjustment)

Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Shelf life

48 months Shelf-life after first opening: From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.

Special precautions for storage

Nature and contents of container

17 ml of solution in a vial (type I glass) with a stopper (chlorobutyl rubber) and an aluminium crimp-on seal. Available in packs sizes of 1, 2, 6 or 10 vials. Not all pack sizes may be marketed.

Special precautions for disposal and other handling

The vials are for single use only. The vials should be inspected visually to ensure the absence of particulate matter and damage prior to administration. Rienso should be administered as an intravenous injection into a new or existing venous access site. Administration should be performed as follows:

Dosing should begin when blood pressure is stable and the patient has completed at least one hour of haemodialysis.

MARKETING AUTHORISATION HOLDER

Takeda Pharma A/S Langebjerg 1 DK-4000 Roskilde Denmark P: +45 4677 1111 F: +45 4677 6560

MARKETING AUTHORISATION NUMBER(S)

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu

	Total Amount of Rienso to Administer mg of Iron (Number of vials)
Haemoglobin	<= 50 kg Body Weight	> 50 kg Body Weight
> 10-12 g/dl	510 mg iron (1 vial)	2 x 510 mg iron (2 vials)
<= 10 g/dl	2 x 510 mg iron (2 vials)	2 x 510 mg iron (2 vials)

Endpoint	Study 1 Non-dialysis CKD		Study 2 Non-dialysis CKD		Study 3 CKD on Haemodialysis
Endpoint	Rienso n = 226	Oral Iron n = 77	Rienso n = 228	Oral Iron n = 76	Rienso n = 114	Oral Iron n = 116
Baseline Hgb	9.9	9.9	10.0	10.0	10.6	10.7
(mean +- SD, g/dl)	+- 0.8	+- 0.7	+- 0.7	+- 0.8	+- 0.7	+- 0.6
Hgb change from Baseline at Day 35 (mean +- SD, g/dl)	1.2 * +- 1.3	0.5 +- 1.0	0.8 * +- 1.2	0.2 +- 1.0	1.0 * +- 1.1	0.5 +- 1.1
Proportion of Hgb Responders (%)	51.8	19.5	39.0	18.4	49.1	25.0
Baseline TSAT	9.8	10.4	11.3	10.1	15.7	15.9
(mean +- SD, %)	+- 5.4	+- 5.2	+- 6.1	+- 5.5	+- 7.2	+- 6.3
TSAT change from Baseline at Day 35 (mean +- SD, %)	9.2 +- 9.4	0.3 +- 4.7	9.8 +- 9.2	1.3 +- 6.4	6.4 +- 12.6	0.6 +- 8.3
Baseline ferritin	123.7	146.2	146.1	143.5	340.5	357.6
(mean +- SD, ng/ml)	+- 125.4	+- 136.3	+- 173.6	+- 144.9	+- 159.1	+- 171.7
Ferritin change from Baseline at Day 35 (mean +- SD, ng/ml)	300.7 +- 214.9	0.3 +- 82.0	381.7 +- 278.6	6.9 +- 60.1	233.9 +- 207.0	-59.2 +- 106.2

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS