Rienso - patient leaflet, side effects, dosage

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• 4.6 Fertility, pregnancy and lactation

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Women of childbearing potential and pregnancy

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 be 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.

Fertility

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).

• 4.7 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.

♦

• 4.8 Undesirable effects

Summary of the safety profile

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.

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Tabulated list of adverse reactions

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

Description of selected adverse reactions

In clinical tri,.ls, 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.

Fatal and life-threatening hypersensitivity reactions have been observed with Rienso in the post marketing setting (see sections 4.3 and 4.4).

Reporting of suspected adverse reactions

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 the national reporting system listed in

4.9 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.

• 5. PHARMACOLOGICAL PROPERTIES

  • 5.1 Pharmacody­namic properties

Pharmacotherapeutic group: Not yet assigned, ATC code: Not yet assigned

Mechanism of Action

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 in

Clinical Efficacy and Safety

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)

* p<0.001 for main efficacy endpoint

Hgb = haemoglobin; TSAT = transferrin saturation; SD = standard deviation

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.

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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.

Post-Marketing Data from Dialysis Clinics in the United States

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.

Paediatric Population

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).

• 5.2 Pharmacoki­netic Properties

The pharmacokinetic (PK) behaviour of Rienso has been examined in healthy subj 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.

• 5.3 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 × 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.

• 6. PHARMACEUTICAL PARTICULARS

  • 6.1 List of excipients

Polyglucose-sorbitol carboxymethylether (PSC)

Mannitol

Water for Injections

Sodium hydroxide (for pH adjustment)

Hydrocholric acid (for pH adjustment)

• 6.2 Incompati­bilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products, except those mentioned in section 6.6.

• 6.3 Shelf life

48 months

Shelf-life after first opening and after dilution for infusion:

Chemical and physical in-use stability has been demonstrated for 96 hours at 25 °C.

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 and would not be longer than 4 hours at 25 °C.

• 6.4 Special precautions for storage

Rienso must only be mixed with sterile sodium chloride 9 mg/ml (0.9%) or sterile 5% glucose up to a final concentration of 2–8 mg iron per ml.

No other intravenous dilution solutions and therapeutic agents should be used. For dilution instructions, please see section 4.2.

Store in the original package in order to protect from light.

Do not freeze.

• 6.5 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.

• 6.6 Special precautions for disposal and other handling

Rienso Administration

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 infusion into a new or existing venous access site.

Administration should be performed as follows:

Haemodialysis patients:

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

For all patients:

• Administer Rienso as an infusion as follows:

o 510 mg (one vial) diluted in 50–250 ml of sterile 0.9% sodium chloride or sterile 5% glucose, administered for at least 15 minutes (concentration of 2–8 mg iron per ml).

• Patients should be carefully monitored for signs and symptoms of hypersensitivity reactions including monitoring of blood pressure and pulse during and for at least 30 minutes following each infusion of Rienso. In addition, patients should be placed in a reclining or semi-reclining position during infusion and for at least 30 minutes thereafter.
• Administer a single vial as an infusion. A second vial of the medicine should be administered as an infusion two to eight days later if indicated.
• Any unused product or waste material should be disposed of in accordance with local requirements.

• 7. MARKETING AUTHORISATION HOLDER

  
  

Takeda Pharma A/S Dybendal Alle 10 2630 Taastrup Denmark

P: +45 4677 1111

F: +45 4675 6640

NG AUTHORISATION NUMBER(S)

EU 74/001

EU 74/002

EU/1/12/774/003

EU/1/12/774/004

• 9. DATE OF FIRST AUTHORISATION/RE­NEWAL OF THE AUTHORISATION

Date of first authorisation: 15 June 2012

• 10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines

Agency

• A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE

• B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

  C.

  
  

OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION

CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND OF THE MEDICINAL PRODUCT

• A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer responsible for batch release Takeda Italia S.p.A.

Via Crosa 86

28065 Cerano (NO)

Italy

• B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

  
  

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Pro Characteristics, section 4.2).

• C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETIN AUTHORISATION

Periodic Safety Update Reports

The marketing authorisation holder shall submit periodic safety update reports for this product in accordance with the requirements set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web-portal.

• D. CONDITIONS OR RESTRICTIONS WITH R EFFECTIVE USE OF THE MEDICINAL PR

  Risk Management Plan (RMP)

  
  

  The MAH shall perform the required pha

  
  

igilance activities and interventions detailed in the

agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent updates of the RMP.

An updated RMP should be submitted:

• At the request of the European Medicines Agency;
• Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached.

If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the same time.

• Additional risk minimisation measures

Prior to the use of Rienso in each Member State the Marketing Authorisation Holder (MAH) must agree about the content and format of the educational programme, including communication media, distribution modalities, and any other aspects of the programme, with the National Competent Authority.

The educational programme is aimed at highlighting the risks and warnings on hypersensitivity reactions and the monitoring of patients during and after administration.

The MAH shall ensure that in each Member State where Rienso is marketed, all healthcare professionals and patients/carers who are expected to use Rienso have access to/are provided with the following educational package:

• Healthcare professional checklist
• Patient alert card

The healthcare professional checklist shall contain the following messages:

The checklist should include tick-boxes to check and document:

o Confirmation on appropriate settings (emergency resuscitation equipment available ) prior to administration of ferumoxytol

o Patient’s e­ligibility

o Contraindications and warnings

o Duration of administration

o Semi-reclined position during administration

o Duration of monitoring of patients after administration.

The patient alert card shall contain the following key messages:

• Information regarding the increased risk of serious including fatal hypersensitivity reactions: contraindications, special patient populations (e.g. pregnant women, elderly), warnings, symptoms of hypersensitivity reactions, monitoring by health care professionals during 30 minutes after administration, warning on late onset of allergic reactions.

Obligation to conduct post-authorisation measures

The MAH shall complete, within the stated timeframe, the below measures:

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

Carton Label (1, 2, 6 or 10 vial pack)

• 1. NAME OF THE MEDICINAL PRODUCT

Rienso 30 mg/ml solution for infusion Iron as ferumoxytol

• 2. STATEMENT OF ACTIVE SUBSTANCE(S) 1 ml contains 30 mg of iron. 510 mg iron/17 ml

  3. LIST OF EXCIPIENTS

  
  

Excipients:

Polyglucose-sorbitol carboxymethylether (PSC)

Mannitol

Water for injections

Sodium hydroxide (for pH adjustment)

Hydrochloric acid (for pH adjustment)

4. PHARMACEUTICAL FORM AND CONTENTS

Solution for infusion

1 vial

2 vials

6 vials

10 vials

OUTE(S) OF ADMINISTRATION

For intravenous use only.

Read the package leaflet before use.

• 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

• 7. OTHER SPECIAL WARNING(S), IF NECESSARY

• 8. EXPIRY DATE

EXP:

• 9. SPECIAL STORAGE CONDITIONS

Store in the original package in order to protect from light. Do not freeze.

• 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODU OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, I APPROPRIATE

• 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOlDER

  
  

Takeda Pharma A/S Dybendal Alle 10 2630 Taastrup Denmark

• 12. MARKETING AUTHORISATION NUMBER(S

  
  

EU/1/12/774/001

EU/1/12/774/002

EU/1/12/774/003

EU/1/12/774/004

• 14. GENERAL Cl ASSIFICATION FOR SUPPLY

  Medicinal product subject to medical prescription.

  16. INFORMATION IN BRAILLE

  
  

Justification for not including Braille is accepted

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

Vial Label

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Rienso 30 mg/ml infusion

Iron as ferumoxytol

For intravenous use only

Package leaflet: Information for the patient

Rienso 30 mg/ml solution for infusion Iron as ferumoxytol

This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects.

Read all of this leaflet carefully before you are given this medicine because it contains important information for you.

• – Keep this leaflet. You may need to read it again.

• – If you have any further questions, ask your doctor, pharmacist or nurse.

• – If you get any side effects talk to your doctor, pharmacist or nurse. This includes any possible

side effects not listed in this leaflet. See section 4.

What is in this leaflet

• 1. What Rienso is and what it is used for

• 2. What you need to know before you receive Rienso

• 3. How Rienso is given

• 4. Possible side effects

• 5. How to store Rienso

• 6. Contents of the pack and other information

1. What Rienso is and what it is used for

Rienso is an iron preparation, containing the active substance ferumoxytol, which is given by infusion into a vein. It is used to treat iron deficiency anaemia resulting from a lack of stored iron, in adult patients with reduced kidney function.

Iron is an essential element required to make haemoglobin, a molecule in red blood cells that enables oxygen to be carried around the body. When there is insufficient iron in the body, haemoglobin cannot be formed, resulting in anaemia (low levels of haemoglobin).

The aim of Rienso therapy is to replenish the body’s iron stores.

2. What you need to know before you receive Rienso

Before you were prescribed Rienso, the doctor will have carried out a blood test to make sure that you have iron deficiency anaemia.

You must not receive Rienso:

• – if you are allergic (hypersensitive) to the product or any of the other ingredients of this medicine (listed in section 6).

• – if you have a history of medicine allergy or have experienced serious allergic (hypersensitive) reactions to other injectable iron preparations.

• – if you have iron overload (too much iron in your body).

• – if your anaemia is not caused by iron deficiency.

Warnings and precautions

Talk to your doctor, pharmacist or nurse before receiving Rienso:

• – if you have a history of medicine allergy.

• – if you have systemic lupus erythematosus.

• – if you have rheumatoid arthritis.

• – if you have severe asthma, eczema or other allergies.

• – if you have a problem with your liver.

• – if you have problems with your immune system.

• – if you have any infections, including infections which have spread to your blood stream.

• – if you are scheduled for magnetic resonance imaging (an MRI scan), as this medicine may interfere with the interpretation of the scan. For the same reason also talk to your doctor or radiographer if you have been given Rienso within the past 6 months and an MRI is subsequently arranged.

Rienso can affect the interpretation of your blood iron test results.

Children and adolescents

Rienso should not be given to children and adolescents under 18 years old.

Other medicines and Rienso

Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other medicines.

Pregnancy

Rienso has not been tested in pregnant women. Studies in animals have shown reproductive toxicity.

If you are pregnant, you should not receive Rienso.

It is important to tell your doctor if you are pregnant, think you may be pregnant, or are planning to have a baby.

If you are able to become pregnant, you must use birth control during treatment.

If you become pregnant during treatment, you must ask your doctor for advice.

Your doctor will decide whether or not you should be given this medicine.

Breast-feeding

It is not known whether the active substance in this medicine can pass into breast milk. If you are breast-feeding, ask your doctor for advice before you are given Rienso.

Driving and using machines

Some people may feel dizzy, confused or lightheaded after receiving treatment. If this happens to you, do not drive or use any tools or machinery.

Rienso contains ethanol and sodium

This medicine contains small amounts of ethanol (alcohol), less than 100 mg per 17 ml vial.

than 23 mg sodium per 17 ml vial, i.e., it is essentially “sodium free”.

• 3. How Rienso is given

Your doctor will decide how much Rienso to give you based on your weight and blood test results. The treatment you will receive can be 1 or 2 vials of Rienso (510 mg each) by infusion and each dose will be infused into a vein. For patients receiving two vials, the second one will be infused two to eight days after the first infusion. Your doctor will decide if additional doses of Rienso are needed and for how long. He or she will also monitor your blood test results to avoid iron accumulation.

Your doctor or nurse will administer Rienso by infusion into a vein. You will be lying down and your blood pressure and pulse will be monitored. Rienso will be administered in an environment where any allergic event can receive appropriate and prompt treatment.

You will be carefully observed during the infusion and for at least 30 minutes after each infusion by your doctor or nurse. Please immediately tell the doctor or nurse if you start to feel unwell. They may decide to stop the infusion.

If you are on haemodialysis, you may receive Rienso via infusion over 15 minutes during a dialysis session.

If you receive more Rienso than you should

Overdose can cause accumulation of iron in your body. Your doctor will monitor iron levels to avoid iron accumulation.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Serious side effects:

Tell your doctor or nurse immediately if you experience any of the following signs and symptoms indicating serious side effects during or shortly after treatment:

rash, itching, (sudden) dizziness, light-headedness, (increasing) swelling, difficulty breathing, wheezing or any other problems you may have.

In some patients these allergic reactions can become severe or life-threatening (known as anaphylactic reactions). These reactions can be associated with heart and circulation complications, loss of consciousness and may result in death. If you are older than 65 years or have an underlying condition, such as liver or heart disease, the risk of having severe consequences including death may be higher after a serious allergic reaction.

Doctors are aware of these possible side effects and will monitor you during the infusion and for at least 30 minutes after the infusion, and also have emergency treatment available if required.

Other side effects that you should tell your doctor, pharmacist or nurse about if they become serious:

Common side effects (may affect up to 1 in 10 people):

• – bleeding, swelling, bruising, pain, rash, irritation or warmth at infusion/injec­tion site

Uncommon side effects (may affect up to 1 in 100 people):

• – dizziness

• – low blood p

• – feeling weak or tired

feeling drowsy or sleepy

flushing, hot flush

feeling hot, fever

sweating (including night sweats) chills

high blood pressure (sudden increase in blood pressure)

skin rash, itching, darkening of an area of skin or nails, bruising, hives

burning sensation of skin

shortness of breath

diarrhoea

constipation

stomach pain/discomfort

stomach distension or bloating

nausea, vomiting

discoloured stools

changes in taste

increased or decreased appetite

muscle/joint pain, weakness or stiffness, muscle spasms

headache

chest pain/discomfort

back pain

changes in blood test results (e.g. iron parameters)

allergic reaction including severe allergic reaction (see paragraph „serious side effects“)

Rare side effects (may affect up to 1 in 1,000 people):

• – burning, prickling, numbness or tingling sensation of skin

• – dehydration

• – upset stomach/indigestion

• – nose bleed

• – dry mouth

• – burning or tingling sensation of tongue/mouth

• – increased tearing

• – blurred vision

• – gout

abnormal blood tests (decreased glucose, elevated potassium, abnormal liver function, elevated type of white blood cell i.e. eosinophilia)

Side effects of unknown frequency (frequency cannot be estimated from the available data)

The following serious side effects have been reported shortly after receiving Rienso:

• – life-threatening and fatal allergic reactions (anaphylactic/a­naphylactoid hypersensitivity)

• – cardiovascular complications (affecting the heart and blood vessels) including heart attack, congestive heart failure, palpitations, blood vessel dilation, changes in your pulse rate including

weak/absent pulse, heart stops beating, heart and breathing stop, blue discolouration of skin

and/or mucous membranes due to lack of oxygen in the blood (cyanosis)

fainting/loss of consciousness/un­responsiveness

sudden swelling up of skin or mucous membranes (angioedema), skin rash

wheezing (bronchospasm), cough, upper airway swelling, difficulty breathing (change to

breathing rate), inability to breathe

throat irritation, throat tightness, lip swelling, tongue swelling injection site discolouration, injection site itching and discolouration

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report any side effects directly to the national reporting system via the national reporting system listed in By reporting side effects you can help provide more information on the safety of this medicine.

5. How to store Rienso

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the label after EXP. The expiry date refers to the last day of that month.

Store in the original package in order to protect from light.

Do not freeze.

Before administration, the vials will be inspected by the person administering the medicine for signs of damage or deterioration.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help to protect the environment.

• 6. Content of the pack and other information
  
  What Rienso contains

  
  

• – The active substance is iron as ferumoxytol 30 mg/ml.

• – 1 ml solution for infusion contains 30 mg of iron as ferumoxytol.

• – 17 ml solution for infusion contains 510 mg of iron as ferumoxytol.

• – The other ingredients are mannitol, Polyglucose-sorbitol carboxymethylether (PSC), Sodium hydroxide (for pH adjustment, Hydrochloric acid (for pH adjustment) and water for injections.

What Rienso looks like and contents of the pack

Interference with Magnetic Resonance Imaging (MRI)

No spontaneous post-marketing reports of MRI interference have been received to date. Within this PSUR, a further literature review has been provided by the MAH identifying 9 relevant publications addressing ferumoxytol and MRI. Four case reports have been published describing the supraparamagnetic effects of ferumoxytol on MR imaging and emphasized the importance for the radiologists to be aware if a patient received ferumoxytol recently. Based on a limited number of case reports, the influence of ferumoxytol on the interpretation of MRIs, due to its unique crystalline structure appears to be primarily noted in the first few weeks after administration and, based on animal data, dissipated within 3 months. The MAH is of the opinion that the current EU SmPC accurately reflects the current literature and provides appropriate guidance to EU practitioners. However, the MAH acknowledges that Rostoker and Cohen recommend a minimum of 6 months between ferumoxytol’s ad­ministration, which they base on the study with 6 healthy volunteers published by Storey et al. Therefore the MAH proposed as part of this PSUR to amend the current warning in section 4.4 of the SmPC to reflect that interference with MRI can occur up to 6 months after administration of ferumoxytoll which was agreed by the PRAC.

Therefore, in view of available data regarding hypersensitivity reactions and interference with Magnetic Resonance Imaging (MRI), the PRAC considered that changes to the product information were warranted.

The CHMP agrees with the scientific conclusions made by the PRAC.

Grounds recommending the variation to the terms of the Marketing Authorisation

On the basis of the scientific conclusions for Rienso, the CHMP is of the opinion that the benefit-risk balance of the medicinal product containing the active substance ferumoxytol is favourable subject to the proposed changes to the product information.

The CHMP recommends that the terms of the Marketing Authorisation should be varied.

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