Traisengasse 5, 1200 Wien

CMDh/223/2005
February 2014

Public Assessment Report

Scientific discussion

Esnogutan 50 mg Eisen/ml Dispersion zur Injektion/Infusion

FERRIC CARBOXYMALTOSE

AT/H/1322/001/DC

Date: 02.05.2024

This module reflects the scientific discussion for the approval of Esnogutan 50 mg
Eisen/ml Dispersion zur Injektion/Infusion. The procedure was finalised on 15.02.2024.
For information on changes after this date, please refer to the module ‘Update’.

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I. INTRODUCTION
Based on the review of the quality, safety and efficacy data, the Member States have granted a
marketing authorisation for Esnogutan 50 mg Eisen/ml Dispersion zur Injektion/Infusion, from Day
Zero ehf.. In this Assessment Report, the name Esnogutan is used.

The product is indicated in the treatment of iron deficiency when

• oral iron preparations are ineffective.
• oral iron preparations cannot be used.
• there is a clinical need to deliver iron rapidly.
The diagnosis of iron deficiency must be based on laboratory tests.
A comprehensive description of the indications and posology is given in the SmPC.

The marketing authorisation has been granted pursuant to Article 10(3), “hybrid application”, of
Directive 2001/83/EC.
Esnogutan dispersion 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).
Conditions pursuant to Article 21a of Directive 2001/83/EC have been agreed. For details, please refer
to section VI of this assessment report.

II. QUALITY ASPECTS

Introduction
Esnogutan is a dispersion for injection/infusion which is presented in a glass vial (Type I) with a
stopper (bromobutyl rubber) and an aluminium seal cap with a plastic cover.

Drug Substance
The active substance in Esnogutan is iron (as ferric carboxymaltose). The specification of the active
substance meets the current scientific requirements. The adequate quality of the active substance has
been shown by submitting the appropriate control data. The stability of the active substance has been
tested under ICH conditions. The results of the stability studies support the established retest-period.

Medicinal Product
Esnogutan contains the following excipients:
One mL of dispersion contains 4.23 mg sodium.
Sodium hydroxide (for pH adjustment)
Hydrochloric acid (for pH adjustment)
Water for injections
The development of the product has been sufficiently made and deemed appropriate. The usage of all
the excipients has been described.
The release specification includes the check of all parameters relevant to this dispersion for
injection/infusion. Appropriate data concerning the control of the finished product support the
compliance with the release specifications.
The packaging of the medicinal product complies with the current legal requirements.
Stability studies under ICH conditions have been performed and data presented support the shelf life
claimed in the SmPC, with a shelf life (of the product as packaged for sale) of 2 years when not stored
above 30ºC.
Shelf life after first opening of the container:

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From a microbiological point of view, unless the method of opening precludes the risk of microbial
contamination, the product should be used immediately. If not used immediately, in-use storage times
and conditions are the responsibility of the user.
Shelf life after dilution with sterile 0.9% m/V sodium chloride solution:
Chemical and physical in-use stability has been demonstrated for 24 hours at 15 to 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 normally not be longer than 24 hours at 15 to 25°C, unless dilution has taken place in
controlled and validated aseptic conditions.
The pharmaceutical quality of Esnogutan has been adequately shown.

Discussion on chemical, pharmaceutical and biological aspects

Information on development, manufacture and control of active substance and medicinal product has
been presented in a satisfactory manner. The results of tests carried out indicate satisfactory
consistency and uniformity of important product quality characteristics.

III. NON-CLINICAL ASPECTS

Introduction
Pharmacodynamic, pharmacokinetic and toxicological properties of ferric carboxymaltose are well
known. The applicant has provided an overview based on literature review which is, thus, appropriate.

Pharmacokinetics/toxicology
In agreement with the Reflection paper on the data requirements for intravenous iron-based nano-
colloidal products developed with reference to an innovator medicinal product
(EMA/CHMP/SWP/620008/2012), the nonclinical development program that consists of in vitro studies
and two in vivo comparative pharmacokinetic studies in female Sprague-Dawley rats was done to
show the comparability between Esnogutan and reference drug product Ferinject.

For assurance of similarity with the reference product, the applicant submitted the following non-
clinical pharmacokinetic studies:

• Exploratory In vitro feasibility studies that evaluated iron uptake into THP-1 cells (human monocytic
cell line derived from an acute monocytic leukaemia):
o Iron uptake from Ferrlecit (sodium ferric gluconate complex in sucrose injection).
o Iron uptake from Ferrlecit and Ferinject dispersion.
• A non-GLP Pilot comparative pharmacokinetic single-dose study with 6-week follow up period of
Esnogutan and Ferinject following intravenous (bolus) route of administration in female Sprague-
Dawley rats.
• A GLP Single dose comparative pharmacokinetic study of Esnogutan and reference drug product
Ferinject in female Sprague Dawley rats.

In the in vitro studies no time or concentration correlation for iron uptake could be established. In
addition, variability was very high and signal-to-noise ratio was very low rendering the employed in
vitro systems not suitable to detect PK differences between different products. Thus, the applicant
performed a comparative in vivo PK evaluation.
A pilot comparative non-GLP PK and biodistribution study was conducted in female Sprague Dawley
(SD) rats in order to confirm the required bioanalytical range and the dose selection of 30 mg/kg.
Based on the results of the pilot study the pivotal study was conducted in compliance to GLP. The
bioanalytical method (ICP-MS) was adequately validated for all matrices analysed. Female SD rats
received single administrations of 30 mg/kg of the test formulation or two different batches of
reference drug product Ferinject. Plasma, blood, bone marrow, liver and spleen were analysed for up
to 8 weeks post-dose. In addition, liver, kidneys, spleen, lungs, heart, bone marrow and draining
lymph nodes were analysed for toxicological effects. Peak concentrations (Cmax) and overall exposure

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(AUC0-t) ratios, tmax values, iron exposure profiles over time as well as the toxicological profiles of
the test and reference substance batches were comparable.
The recommendations given in the Reflection Paper and in the Scientific Advice
(EMA/CHMP/SAWP/135996/2020) on the in vivo studies have been considered by the applicant.
Overall, and despite certain limitations of the in vivo study design, i.e. predominantly the small groups
size which is, however, acknowledged in the light of 3R recommendations, the results point towards
similar PK and biodistribution profiles of Esnogutan and the reference product Ferinject.

Ecotoxicity/environmental risk assessment (ERA)

Since the API of Esnogutan is regarded a naturally occurring substance, the use of Esnogutan is not
considered to pose a risk to the environment.
An environmental risk assessment is therefore not deemed necessary.

Discussion on the non-clinical aspects

The non-clinical overview on the pre-clinical pharmacology, pharmacokinetics and toxicology is
adequate.

IV. CLINICAL ASPECTS

Introduction
The application contains an adequate review of published clinical data.

Pharmacokinetics
To support the application, the applicant has submitted as report one bioequivalence study.
The primary objective of the study was to assess the bioequivalence of Ferric carboxymaltose
dispersion for injection/infusion, 50 mg/mL compared to that of Ferinject (ferric carboxymaltose),
50 mg iron/mL dispersion for injection/infusion following a single intravenous dose (1 × 20 mL i.e.,
total dose of 1000 mg iron) in healthy adult subjects.
The secondary objective of the study was to assess the safety and tolerability.

The study was open label, randomized, single dose, two treatment (test product or reference
product), parallel design in healthy human, adult subjects under fasting conditions.
96 subjects were enrolled, 95 subjects completed the study and were included in pharmacokinetic and
statistical analysis.
The 90% CI for Cmax and AUC0-72 for total iron (TI) baseline corrected and uncorrected were compared
using the acceptance range 80-125%.
The point estimate (90% CI) for baseline-corrected total iron AUC0-72 and Cmax were 101.42% (95.26 -
107.98%) and 104.21% (100.14 - 108.45%), respectively.
The point estimate (90% CI) for baseline-uncorrected total iron AUC0-72 and Cmax were 101.32%
(95.18% - 107.86%) and 104.19% (100.12% - 108.42%), respectively.
To conclude, bioequivalence of the test product Esnogutan with the reference product Ferinject has
been sufficiently demonstrated. Both the test and reference products were found to be safe and well
tolerated.
Biowaiver
The proposed medicinal product has only one strength (50 mg/mL) and the product is available in 3
different fill volumes (2 mL, 10 mL and 20 mL). For the bioequivalence study, the 20 mL fill volume
was selected. No separate studies are required for additional fill volumes.
Conclusion on bioequivalence studies:
Based on the submitted bioequivalence study, Esnogutan is considered bioequivalent with Ferinject.

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Pharmacodynamics
Pharmacotherapeutic group: Antianemic preparations, iron, parenteral preparation, ATC code: B03AC
The pharmacodynamics profile of ferric carboxymaltose is well established. No additional
pharmacodynamics study has been submitted by the applicant and none is required.

Clinical efficacy
No efficacy studies were submitted.

Clinical safety
Efficacy and safety of ferric carboxymaltose in the proposed indications are known and assessed as
being scientifically based considering recent knowledge, guidelines, and recommendations.
The safety profile of the test product is comparable with the safety profile of the reference product.

Risk Management Plan and Summary of the Pharmacovigilance System

Master File
Risk Management Plan
The MAH has submitted a risk management plan, in accordance with the requirements of Directive
2001/83/EC as amended, describing the pharmacovigilance activities and interventions designed to
identify, characterise, prevent or minimise risks relating to Esnogutan.
Summary table of safety concerns as approved in RMP:
Important identified risks Hypersensitivity/anaphylactic reaction
Hypophosphataemic osteomalacia
Important potential risks None
Missing information Use in pregnant or lactating women
Use in patients with hepatic impairment
Use in patients with infectious diseases
Long-term usage

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Summary of important risks

Important risks of Esnogutan are risks that need special risk management activities
to further investigate or minimise the risk, so that the medicinal product can be safely administered.
Important risks can be regarded as identified or potential. Identified risks are concerns for which there
is sufficient proof of a link with the use of Esnogutan. Potential risks are concerns for
which an association with the use of this medicine is possible based on available data, but this
association has not been established yet and needs further evaluation. Missing information refers to
information on the safety of the medicinal product that is currently missing and needs to be collected
(e.g. on the long-term use of the medicine).

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Summary of the Pharmacovigilance System Master File

The applicant submitted the summary of the pharmacovigilance system in the scope of this procedure.
The summary includes the following elements:
• Proof that the applicant has at his disposal a qualified person responsible for
pharmacovigilance
• The Member States in which the qualified person resides and carries out his/her tasks
• The contact details of the qualified person
• A statement signed by the applicant to the effect that the applicant has the necessary means
to fulfil the tasks and responsibilities listed in Title IX of Directive 2001/83/EC
• The Pharmacovigilance System Master File (PSMF), sign off date 03.02.2022 is located at the
offices of Day Zero ehf, Hafnarfjörður, Iceland.

Discussion on the clinical aspects

The dossier contains an adequate review of published clinical data and bioequivalence has been
shown.

V. USER CONSULTATION
The package leaflet has been evaluated via a user consultation study in accordance with the
requirements of Articles 59(3) and 61(1) of Directive 2001/83/EC. The language used for the purpose
of user testing the PIL was English.
The results show that the package leaflet meets the criteria for readability as set out in the Guideline
on the readability of the label and package leaflet of medicinal products for human use.
The test consisted of a pilot test, followed by two rounds with 10 participants each. The questions
covered the following areas sufficiently: traceability, comprehensibility and applicability.

VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION

Conditions pursuant to Article 21a or 22 of Directive 2001/83/EC were agreed, namely additional risk
minimisation measures (including educational material):
Key messages of the additional risk minimisation measures
>Prescriber Guide
BEFORE each administration of Intravenous (IV) iron, you should inform your patient so that they are
aware that…
parenterally administered iron preparations can cause hypersensitivity reactions including serious and
potentially fatal anaphylactic/anaphylactoid reactions.
these reactions have also been reported after previously uneventful doses of IV iron.
they may have an increased risk of experiencing a hypersensitivity reaction if they have:
known allergies including drug allergies*
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a history of severe asthma*, eczema* or other atopic allergies* or immune or inflammatory conditions
(e.g. rheumatoid arthritis, lupus erythematosus)*.
*In these patients, IV iron products should only be used if the benefit is clearly judged to outweigh
the potential risk.
IV iron should not be used during pregnancy unless clearly necessary. Treatment should be confined
to the 2nd-3rd trimester if the benefit is judged to outweigh the potential risk for both the mother and
the foetus.
They should report any signs or symptoms suggestive of a hypersensitivity reaction (e.g.: hives,
pruritus, dyspnoea, wheezing, swelling of the lips, tongue, throat or body) to their doctor/nurse
immediately.
The patient should also be given a copy of the patient information leaflet provided with the individual
IV iron product to be administered.
And remember that IV iron is contraindicated and should not be administered if your patient has
known hypersensitivity to the IV iron product, the active substance or to any of its excipients.
has previously experienced a serious hypersensitivity reaction to any IV iron preparations.
has anaemia not caused by iron deficiency.
has evidence of iron overload or disturbances in the utilisation of iron.
BEFORE each administration of IV iron make sure that…
staff trained to evaluate and manage anaphylactic reactions are immediately available.
cardio-pulmonary resuscitation facilities and equipment for handling
acute anaphylactic/anaphylactoid reactions, including an injectable 1:1000 adrenaline solution, are
immediately available onsite. Additional treatment with antihistamines and/or corticosteroids should
be given as appropriate.
DURING administration of IV iron remember that…
if hypersensitivity reactions or signs of intolerance occur during administration,
the treatment must be stopped immediately, and appropriate management initiated.
IV iron products should be administered in accordance with the posology and method of
administration described in the product information for each individual product.
AFTER you have administered IV iron
the patient must be closely observed for signs and symptoms of a hypersensitivity reactions for at
least 30 minutes after each administration.
>Patient Guide
IV Iron is used to treat iron deficiency when oral preparations are ineffective or cannot be used.
IV Iron can cause allergic reactions and must be administered by persons trained to
evaluate and manage these reactions.
In some patients these allergic reactions can become severe or life-threatening (known as
anaphylactic reactions) and can cause problems with your heart and blood pressure and/or cause you
to faint or lose consciousness.
You may have an increased risk of having an allergic) reaction if you have: known allergies including
drug allergies a history of severe asthma, eczema or other allergies (for example dust, pollen, pet
dander) or immune or inflammatory conditions (e.g. rheumatoid arthritis, lupus erythematosus and
others)
You should tell your doctor before they prescribe or give you IV Iron if you have any of these allergies
or conditions.
Your Doctor will decide whether the benefit to you is greater than the risk.
You should not be prescribed or given an IV Iron if:
- you are allergic (hypersensitive) to the product or any of the other ingredients of this medicine
- you have experienced serious allergic (hypersensitive) reactions to other IV iron treatments in the
past*

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- you have iron overload (too much iron in your body)

- your anaemia is not caused by iron deficiency
You should tell your doctor before they prescribe/administer an IV Iron if you have any of these
allergies or conditions.
* It is important to know that a reaction can still happen even if you have not had any problems in the
past with IV iron.
Pregnancy:
IV iron should not be used during pregnancy unless clearly necessary. If you are pregnant or think
you could be pregnant, it is important to discuss this with your doctor.
You should contact your Doctor or Nurse immediately if:
You have any signs or symptoms of an allergic reaction during or shortly after treatment with IV Iron
For example: hives or rash, itching, dizziness, light-headedness, swelling of the lips, tongue, throat or
body, difficulty breathing, shortness of breath or wheezing.
Your Doctor will monitor you for signs and symptoms of an allergic reaction for at least 30 minutes
after each time IV iron is given to you.

The pharmaceutical quality of Esnogutan has been adequately shown, and no new non-clinical or
clinical concerns have been identified.

The application contains an adequate review of published non-clinical and clinical data.
The Applicant followed the ‘Reflection paper on the data requirements for intravenous iron-based nano-
colloidal products developed with reference to an innovator medicinal product’,
EMA/CHMP/SWP/620008/2012, 26 March 2015. The totality of data, i.e. quality comparison, non-clinical
studies and human PK study, demonstrate sufficient evidence of similarity between the proposed generic
ferric carboxymaltose and the reference product Ferinject, Vifor France SA.

All issues raised during this procedure have been resolved. The benefit-risk relation is considered
positive.

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Public Assessment Report

Update

Esnogutan 50 mg Eisen/ml Dispersion zur

Injektion/Infusion

FERRIC CARBOXYMALTOSE

This module reflects the procedural steps and scientific information after
the finalisation of the initial procedure.

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Procedure Scope Product Information Date of end of Approval/ Summary/ Justification for refuse
number* affected procedure
non approval

*Only procedure qualifier, chronological number and grouping qualifier (when applicable)

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