Conditions: Mild and Moderate Iron-deficiency Anaemia
Keywords: Ferrum Lek® (iron (III) hydroxide polymaltosate) mild and moderate iron-deficiency anaemia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 267
Healthy volunteers: no

Brief summary:
The purpose of this study was to evaluate non-inferiority for efficacy and safety of Ferrum Lek® (iron (III) hydroxide polymaltosate), 100 mg chewable tablets (Lek d.d., Slovenia), compared to MALTOFER® (Vifor S.A., Switzerland), in the treatment of patients with mild and moderate iron-deficiency anaemia.

Detailed description:
This was a multi-centric, open-label, randomized, prospective, comparative, parallel-group, active-controlled, phase III clinical trial (in the Russian Federation).

The purpose of this study was to evaluate non-inferiority for efficacy and safety of Ferrum Lek® (iron (III) hydroxide polymaltosate), compared to MALTOFER®, in the treatment of patients with mild and moderate iron-deficiency anaemia.

Participants underwent screening for up to 7 days. Eligible participants were randomized in 1:1 ratio to two treatment arms.

Subjects in Group 1 received 2 tablets per day (200 mg) of chewable tablets Ferrum Lek® during or immediately after meals; once daily.

Subjects in Group 2 (reference product) received 2 tablets per day (200 mg) of chewable tablets Maltofer® during or immediately after meals; once daily.

The subjects received the medicinal products daily for 12 weeks. After the last scheduled study site visit, a follow-up visit (by phone) was scheduled 14 days after the completion of the active treatment period (day 98±2) to record any delayed adverse events.

Arms:
arm 1: Participants received Ferrum Lek® 2 tablets daily (200 mg) for 12 weeks arm 2: Participants received MALTOFER® 2 tablets daily (200 mg) for 12 weeks

Interventions: intervention 1: Ferrum Lek® (iron (III) hydroxide polymaltosate), 100 mg chewable tablets (Lek d.d., Slovenia) intervention 2: MALTOFER® (iron (III) hydroxide polymaltosate), 100 mg chewable tablets (Vifor S.A., Switzerland)
Intervention descriptions: intervention 1: Participants received Ferrum Lek® 2 tablets daily (200 mg) for 12 weeks intervention 2: Participants received MALTOFER® 2 tablets daily (200 mg) for 12 weeks

Protocol document:
Prot_000.pdf: 
Official Title: 
Multicenter, Open-label Active-controlled Randomized Study of Efficacy and 
Safety of Ferrum Lek® (Iron (III) Hydroxide Polymaltosate), 100 mg Chewable 
Tablets (Lek d.d., Slovenia) Compared With Maltofer® (Iron (III) Hydroxide 
Polymaltosate), 100 mg Chewable Tablets (Vifor S.A., Switzerland), in 
Treatment of Patients With Mild and Moderate Iron-deficiency Anaemia 
NCT Number: 
NCT03993288 
Document Date: 
Clinical Study Protocol Version 2.0: 20 March 2019 


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CLINICAL STUDY PROTOCOL 
 
Study title: Multicenter, open-label active-controlled randomized study of efficacy and safety of 
Ferrum Lek® (iron (III) hydroxide polymaltosate), 100 mg chewable tablets (Lek d.d., Slovenia) 
compared with Maltofer® (iron (III) hydroxide polymaltosate), 100 mg chewable tablets (Vifor 
S.A., Switzerland), in treatment of patients with mild and moderate iron-deficiency anaemia. 
ID: TE_005_FER_CHT 
Protocol version: 2.0 of March 20, 2019 
Study drug: Ferrum Lek® 
International non-proprietary name: iron (III) hydroxide polymaltosate 
Dosage Form: chewable tablets 
Study phase: III 
Study sponsored by: Sandoz CJSC  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notification of Confidentiality 
This document is intended for use by a party which it was addressed to, and includes non-public, 
confidential information and/or trade secrets protected from disclosure under applicable law. By 
accepting such documentation, the party acknowledges that such material is confidential and 
agrees not to disclose it to any third party without the prior written consent of Sandoz CJSC and 
not to use it for any other purpose than intended. 
 
 


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Sponsor's Protocol Approval Page 
Protocol Title: Multicenter, open-label active-controlled randomized study of efficacy and safety 
of Ferrum Lek® (iron (III) hydroxide polymaltosate), 100 mg chewable tablets (Lek d.d., Slovenia) 
compared with Maltofer® (iron (III) hydroxide polymaltosate), 100 mg chewable tablets (Vifor 
S.A., Switzerland), in treatment of patients with mild and moderate iron-deficiency anaemia. 
ID: TE_005_FER_CHT 
Protocol version: 2.0 of March 20, 2019 
Sponsor’s Representative: 
 
(Full name of the authorized person) 
   
(position) 
 
Name of organization: 
Sandoz CJSC, Russia 
Address: 
 
72 Leningradsky Prospekt, bld. 3, 125317 Moscow, Russia  
Telephone:  
 (ext.
) 
E-mail: 
 
 
 
 
_____________________________                   ___________ 201__   
          Signature                                     
 
 
Date 
 
 
 
 


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Investigator's Consent to the Study Protocol 
I confirm that I have read and understood this protocol, the Investigator's brochure, including 
potential risks and side effects of the drug, and other information on the product and study provided by the 
Sponsor.  
I agree to conduct this study in accordance with the requirements of this protocol, and also to protect 
the rights, safety, confidentiality and well-being of subjects' health in accordance with the ethical 
requirements set forth in the Declaration of Helsinki of the WMA, in Federal Law N 61-FZ of April 12, 
2010 On Circulation of Medicinal Products; requirements of the order of the Ministry of Health of the 
Russian Federation N 200n of April 01, 2016 On the Approval of the Rules of Good Clinical Practice; the 
principles of the National Standard of the Russian Federation GOST 52379-2005 Good Clinical Practice 
(GCP) and other regulatory requirements of the Russian Federation. 
I agree to make amendments to the protocol only after notifying the Sponsor, except where necessary 
to protect the safety, rights, and well-being of subjects. I fully understand that any changes made by the 
Investigator(s) without preliminary discussion with the Sponsor's representative will constitute a violation 
of the protocol (except for those procedures that are necessary to preserve the subjects' health). 
I agree to personally conduct or supervise the described study. 
I agree to inform subjects that the drugs are being used for research purposes; I will ensure 
compliance with the requirements for obtaining informed consent, after the approval of the Institutional 
Review Board and the local Independent Ethics Committee (IEC) and in accordance with the principles of 
GCP.  
I agree to report to the Sponsor adverse events that occur in the course of the study in accordance 
with the principles of GCP.  
I agree to ensure that all associates, colleagues, and employees engaged in the study are informed 
about their obligations to meet the above commitments. I agree to maintain adequate and accurate records, 
and to provide these records for analysis in accordance with the principles of GCP. 
I will ensure that the local IEC, which operates in accordance with the requirements of GCP, is 
responsible for carrying out the ethical review, as well as for approving the study. I also agree to promptly 
report to the local IEC all changes in the research activity and all unanticipated problems involving risks to 
subjects or other issues. Moreover, I will not make any changes to the study without IRB/local IEC, except 
for necessary cases to address the apparent sudden threats to the life and health of subjects.  
I am ready to provide direct access to the primary documents and agree to audit by the auditors from 
the Sponsor's representatives and the supervisory bodies. I guarantee that the study product(s) supplied by 
the Sponsor will be used only as described in this protocol. 
I agree to comply with all other requirements regarding the obligations of clinical investigators and 
all other pertinent requirements of Good Clinical Practice.  
Investigator:  
Signature: 
     
________________________________________________________________  
Date:   
 
___________ ____, 201__ 
Full Name (surname, name, patronymic): 
 
 
Position: 
   
 
 
Institution: 
 
 
 
Address: 
 
 
 
 
 
 


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Table of Contents 
Sponsor's Protocol Approval Page ............................................................................................... 2 
Investigator's Consent to the Study Protocol .............................................................................. 3 
List of abbreviations ...................................................................................................................... 7 
Synopsis .......................................................................................................................................... 9 
1 
General information ...................................................................................................... 18 
1.1 
Protocol name, Protocol ID, and date: ..................................................................................... 18 
1.2 
Study Sponsor: ........................................................................................................................... 18 
1.3 
Sponsor's representative for the medical questions: .............................................................. 18 
1.4 
Sponsor's representative for the medical questions (back up): ............................................. 19 
1.5 
Study Monitor: ........................................................................................................................... 19 
1.6 
Clinical laboratories and other organizations engaged in the study ..................................... 19 
2 
Study rationale ............................................................................................................... 21 
2.1 
Study drugs ................................................................................................................................. 21 
2.1.1 
Study drug: Ferrum Lek® ...................................................................................................... 21 
2.1.2 
Reference product: MALTOFER® ........................................................................................ 24 
2.2 
Summary of Non-Clinical Study Results ................................................................................. 30 
2.2.1 
Overview of the non-clinical study strategy .......................................................................... 30 
2.2.2 
Pharmacology ........................................................................................................................ 31 
2.2.3 
Pharmacokinetics ................................................................................................................... 37 
2.2.4 
Toxicology ............................................................................................................................. 43 
2.2.5 
Summary and Conclusions .................................................................................................... 49 
2.3 
Summary of Clinical Study Results ......................................................................................... 50 
2.3.1 
Product Development Rationale ............................................................................................ 50 
2.3.2 
Overview of Biopharmaceutics ............................................................................................. 51 
2.3.3 
Overview of Clinical Pharmacology ..................................................................................... 51 
2.3.4 
Review of efficacy ................................................................................................................. 55 
2.3.5 
Dosing ................................................................................................................................... 59 
2.3.6 
Safety review ......................................................................................................................... 60 
2.3.7 
Post-marketing data ............................................................................................................... 62 
2.3.8 
Conclusion of risks and benefits ............................................................................................ 63 
2.4 
Potential risk and benefit of the investigational drug products for the study participants 65 
2.5 
Description and rationale for the route of administration, dosing regimens, and duration 
of treatment ................................................................................................................................ 65 
2.6 
Description of the study population ......................................................................................... 65 
2.7 
Legal framework for the conduction of clinical study ............................................................ 65 
3 
Study goals and objectives ............................................................................................ 66 
3.1 
Study purpose ............................................................................................................................. 66 
4 
Study design ................................................................................................................... 66 
4.1 
Primary and secondary evaluated parameters ....................................................................... 66 
4.2 
Study design description and flowchart ................................................................................... 68 
4.2.1 
Number of centers and patients ............................................................................................. 68 
4.2.2 
Study population .................................................................................................................... 68 
4.2.3 
Design and treatment description .......................................................................................... 68 
4.2.4 
Duration of the study ............................................................................................................. 69 
4.2.5 
Study type .............................................................................................................................. 69 
4.2.6 
Study design flowchart .......................................................................................................... 69 
4.2.7 
Visit schedule ........................................................................................................................ 69 
4.2.8 
Study procedures ................................................................................................................... 73 


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4.2.9 
Visit objectives ...................................................................................................................... 75 
4.2.10 
Early study termination ..................................................................................................... 77 
4.3 
Handling of the investigational drugs ...................................................................................... 77 
4.3.1 
Delivery of drugs to the center .............................................................................................. 77 
4.3.2 
Quality complaints................................................................................................................. 77 
4.3.3 
Dispensing and return of drugs .............................................................................................. 78 
4.3.4 
Drug records .......................................................................................................................... 78 
4.3.5 
Return and destruction of drugs ............................................................................................ 78 
4.4 
Subjectivity minimization measures ........................................................................................ 78 
4.4.1 
Randomization ....................................................................................................................... 78 
4.4.2 
Blinding ................................................................................................................................. 79 
4.5 
Dosing schedule for investigational products .......................................................................... 79 
4.6 
Dosage form, package and labeling of the investigational products ..................................... 79 
4.6.1 
Dosage form .......................................................................................................................... 79 
4.6.2 
Container ............................................................................................................................... 79 
4.6.3 
Labeling of the study drugs ................................................................................................... 79 
4.7 
Duration of patients participation in the study ....................................................................... 80 
4.8 
Rules of termination of clinical study parts or the study on the whole ................................. 80 
4.9 
Record keeping procedures for investigational drug products ............................................. 80 
4.10 
Storing and unblinding of randomization codes ..................................................................... 80 
4.11 
List of data registered in Case Report Form (without preliminary written or electronic 
record) and recognized as primary data .................................................................................. 80 
5 
Selection and exclusion of patients ............................................................................... 81 
5.1 
Inclusion criteria ........................................................................................................................ 81 
5.2 
Non-inclusion criteria ................................................................................................................ 81 
5.3 
Exclusion criteria ....................................................................................................................... 83 
5.3.1 
Terms and conditions for the subjects exclusion from the study ........................................... 83 
5.3.2 
Terms and conditions for suspension or discontinuation of the study therapy ...................... 83 
5.3.3 
Replacement of the excluded subjects ................................................................................... 83 
6 
Information on drug products used in this clinical study .......................................... 84 
6.1 
Administration of study and reference products .................................................................... 84 
6.2 
Duration of treatment: .............................................................................................................. 84 
6.3 
Compliance control .................................................................................................................... 84 
6.4 
Permitted concomitant therapy ................................................................................................ 84 
6.5 
Prohibited concomitant therapy ............................................................................................... 84 
7 
Assessment of efficacy ................................................................................................... 85 
7.1 
Methods and periods for registration of efficacy parameters ................................................ 85 
7.2 
Efficacy endpoints ...................................................................................................................... 85 
8 
Safety evaluation............................................................................................................ 86 
8.1 
Methods and periods for registration of safety parameters ................................................... 86 
8.2 
Safety parameters ...................................................................................................................... 86 
8.3 
Requirements for reporting, registration, and reporting of adverse events and 
intercurrent diseases .................................................................................................................. 86 
8.3.1 
Adverse Events / Serious Adverse Events Definitions ...................................................... 86 
8.3.2 
Severity of Adverse Events ................................................................................................... 87 
8.3.3 
Relation to the IMP ............................................................................................................... 87 
8.3.4 
Adverse Events Documentation ............................................................................................ 88 
8.3.5 
SAE Reporting ...................................................................................................................... 89 
8.3.6 
Pregnancy .............................................................................................................................. 91 
8.3.7 
Complaints related to IMP/medical device ........................................................................... 92 
8.3.8 
Special cases .......................................................................................................................... 92 
8.3.9 
Reconciliation ........................................................................................................................ 92 


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8.3.10 
Investigator Training ......................................................................................................... 93 
9 
Statistical methods description ..................................................................................... 94 
9.1 
Analysis methods description ................................................................................................... 94 
9.1.1 
Demographic and other baseline data (group comparability for the analysis) ...................... 94 
9.1.2 
Analysis of the primary efficacy endpoint ............................................................................ 94 
9.1.3 
Analysis of the secondary effecacy endpoints ....................................................................... 95 
9.1.4 
Safety parameteres analysis ................................................................................................... 95 
9.2 
Interim analysis .......................................................................................................................... 96 
9.3 
Target number of the clinical trial subjects with the sample size justification .................... 96 
9.4 
Applied significance level of the clinical trial .......................................................................... 98 
9.5 
Clinical study termination criteria ........................................................................................... 98 
9.6 
Accounting for missed, unanalyzable, and questionable data ............................................... 98 
9.7 
Procedures for reporting any deviations from the original statistical plan .......................... 98 
9.8 
Procedures for clinical trial participants selection with a view to analysis .......................... 98 
10 
Description of arrangements for quality control and quality assurance ............... 100 
10.1 
Trial monitoring and quality control ..................................................................................... 100 
10.2 
Amendments to the protocol ................................................................................................... 100 
10.3 
Protocol deviations ................................................................................................................... 101 
11 
Description of ethical aspects of the clinical trial ..................................................... 102 
11.1 
General provisions ................................................................................................................... 102 
11.2 
The informed consent receipt procedure ............................................................................... 102 
11.3 
Confidentiality and identification of the trial subjects ......................................................... 103 
11.4 
Enrollment of subjects from the vulnerable and special populations ................................. 103 
12 
Data processing and record keeping .......................................................................... 103 
13 
Direct access to primary data/documents ................................................................. 105 
14 
Finance and insurance ................................................................................................ 105 
14.1 
Funding ..................................................................................................................................... 105 
14.2 
Insurance .................................................................................................................................. 105 
15 
Publications .................................................................................................................. 106 
16 
Bibliography................................................................................................................. 106 
17 
Appendices ................................................................................................................... 114 
17.1 
Appendix 1. Claims .................................................................................................................. 114 
17.2 
Appendix 2. Patient diary ....................................................................................................... 115 
 
 


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List of abbreviations 
Abbreviation 
Explanation 
ANOVA 
Analysis of variance 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HFE 
Hemochromatosis gene 
ICH  
International Conference on Harmonization 
ITT 
Intention-to-treat 
LD100 
Lethal dose, the average dose of the substance in milligrams per 
kilogram of live weight, which causes the death of 100% of 
experimental animals 
LD50 
Half-lethal dose, the average dose of the substance in milligrams per 
kilogram of live weight, which causes the death of 50% of 
experimental animals 
MLE 
Maximum likelihood estimation 
PP 
Per protocol 
BP 
Blood pressure 
ALT 
Alanine aminotransferase 
JSC 
Joint-stock company 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical Classification System 
VAS 
Visual analogue scale 
HIV 
Human immunodeficiency virus 
IUS 
Intrauterine system 
IUD  
Intrauterine device 
Hb 
Hemoglobin 
GOST 
State standard 
GOST R 
State standard of the Russian Federation 
DBP 
Diastolic blood pressure 
ID 
Iron deficiency 
CI 
Confidence interval 
DMPO 
5,5-Dimethyl-1-pyrroline-N-oxide 
IDA 
Iron deficiency anemia 
GI 
Gastrointestinal 
GIT 
Gastrointestinal tract 
CRF 
Case record form 
CRO 
Contract research organization 
LDL 
Low-density lipoprotein 
MoH  
Ministry of Health 
MIC 
Minimum inhibitory concentration 
ICD 
International Classification of Diseases 
GCP 
Good Clinical Practice 
IEC 
Independent Ethics Committee  
AE 
Adverse event  
SPC 
Summary of Product Characteristics 
PVC 
Polyvinylchloride 
IHPC 
Iron(III)-hydroxide polymaltose complex 


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IPC 
Iron polymaltose complex 
PND 
Postnatal days 
PCR 
Polymerase chain reaction 
RMSAH/RSC 
The Russian Medical Society on Arterial Hypertension/the Russian 
Society of Cardiology 
ITP 
Iron transport proteins 1 and 2 
RE 
Reticuloendothelial (cells) 
RES 
Reticuloendothelial system 
SBP 
Systolic blood pressure 
SAE 
Serious adverse event  
SOD 
Superoxide dismutase 
SOP 
Standard operating procedure 
TF 
Transferrin 
TfR 
Transferrin receptor 
FL  
Federal law 
Full name 
First name, patronymic, last name 
CNS 
Central nervous system 
CP 
Ceruloplasmin 
RR 
Respiratory rate 
HR 
Heart rate 
ECG 
Electrocardiography 
 
 


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Synopsis 
Study title 
Multicenter, open-label active-controlled randomized study of 
efficacy and safety of Ferrum Lek® (iron (III) hydroxide 
polymaltosate), 100 mg chewable tablets (Lek d.d., Slovenia) 
compared with Maltofer® (iron (III) hydroxide polymaltosate), 100 
mg chewable tablets (Vifor S.A., Switzerland), in treatment of 
patients with mild and moderate iron-deficiency anaemia. 
Protocol No. 
No. TE_005_FER_CHT 
Study phase 
Phase III 
Study Sponsor 
Sandoz CJSC, Russia 
Country 
Russian Federation 
Study drug 
 
Ferrum Lek® (iron (III) hydroxide polymaltosate), 100 mg 
chewable tablets (Lek d.d., Slovenia) 
Marketing authorization 
status of the study drug 
The drug product is registered in the Russian Federation. 
Reference product  
MALTOFER® (iron (III) hydroxide polymaltosate), 100 mg 
chewable tablets (Vifor S.A., Switzerland) 
Marketing authorization 
status of the reference 
product 
The drug is registered for human use in the Russian Federation.  
Indication 
Iron-deficiency anemia  
Study purpose 
The purpose of this study is to evaluate non-inferiority and safety of 
Ferrum Lek® (iron (III) hydroxide polymaltosate), 100 mg chewable 
tablets (Lek d.d., Slovenia), compared to MALTOFER® (Vifor S.A., 
Switzerland), in the treatment of patients with mild and moderate 
iron-deficiency anaemia. 
Study objectives 
Main Objective: 
To assess the non-inferiority of the therapeutic efficacy of Ferrum 
Lek® 2 tablets daily (200 mg), via assessing the effect on hemoglobin 
level in the blood (g/l) after 12 weeks of treatment for patients with 
iron-deficiency anemia of mild and moderate severity compared with 
MALTOFER® 2 tablets daily (200 mg) during the same period. 
Secondary objectives: 
Assessment of safety of Ferrum Lek® 2 tablets daily (200 mg), 
compared with MALTOFER® 2 tablets daily (200 mg), via the 
frequency, characteristics, intensity and relationship to treatment 
received of AEs. 
Number of study sites 
20 sites in the Russian Federation. 


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Number of subjects 
It is planned to randomize 336 patients (168 patients in each 
treatment group) considering that no more than 15% of them will 
drop out before the end of study per protocol. 
Randomization will be stratified by two factors: 
- 
Gender (male vs female); 
- 
Hb level (80–94 g/L vs 95–110 g/L) 
Thus, it is necessary to receive data from at least 286 patients (143 
patients in each treatment group) who completed the study according 
to protocol. 
Duration of the study 
Subject enrollment – not longer than 9 months. 
Treatment – 3 months (12 weeks). 
Follow-up visit (by phone) – 14 days after the last planned visit to the 
study cite. 
Total study duration – not more than 12 months. 
Study design 
A phase III, open-label, active-controlled, randomized, multicenter, 
prospective, comparative, parallel-group study (in the Russian 
Federation). 
Study population – 336 adult outpatients of both sexes with 
diagnosed mild and moderate iron-deficiency anemia (hemoglobin 
level below 110 g/L (in men and women), but above 80 g/L), who are 
iron-naive patients. Up to 480 subjects will be screened in order to 
achieve 336 randomizations of patients that meet inclusion/exclusion 
criteria per protocol. 
Upon signing of the informed consent for participation in the study, 
the subjects undergo screening for up to 7 days. The subjects who 
meet entry criteria will be randomized into two treatment groups at 
the ratio 1:1:  
The subjects in the first group (168 subjects; study drug) will receive 
Ferrum Lek® chewable tablets – 2 tablets daily (200 mg), during or 
right after meal; the daily dose administered once daily. The subjects 
in the second group (168 subjects; reference drug) will receive 
MALTOFER® chewable tablets – 2 tablets daily (200 mg), during or 
right after meal; the daily dose administered once daily. The subjects 
will take the drugs daily for 12 weeks and keep a Diary, where they 
will record administration of the study drugs and the concomitant 
therapy. 
Complete blood count and blood chemistry will be performed on all 
subjects. During the treatment period three visits are planned:  
I. 
Week 4: Day 29±2 from the therapy start,  
II. 
Week 8: Day 57±2 from the therapy start, 
III. 
Week 12: Day 84±2 final visit after therapy course 
completion. 
After the last planned visit to the study site, a Follow-up visit 
(by telephone) is to be made 14 days after the end of the active 


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therapy period for the registration of delayed adverse events 
(98±2 days). 
Inclusion criteria 
1) The signed and dated written informed consent prior to 
participation in the study. 
2) Men and women aged 18 and older (by the time of screening). 
3) Outpatients. 
4) Diagnosed iron-deficiency anemia, based on two criteria: 
a) hemoglobin level below 110 g/L (in men and women), but 
above 80 g/L, 
b) serum ferritin levels below 30 µg/L. 
5) Women are eligible for enrollment if they are: 
a)  not fertile (i.e., women in postmenopause or after surgical sterilization). 
Surgically sterile women are considered as female subjects with 
documented hysterectomy and/or bilateral ovariectomy and/or tubal 
ligation. Women in postmenopause are considered as women with 
menostasia for more than 1 year, with the corresponding clinical profile, 
e.g. older than 45 years, in absence of hormonal replacement therapy. 
However, in case of doubt, a blood sample shall be taken, where FSH 
content shall be above 40 IU/ml, and estradiol content – below 40 pg/ml 
(below 
140 
pmol/L), 
in 
order 
to 
confirm 
postmenopause. 
OR 
b) fertile, but the result of pregnancy test at screening is negative, and the 
subject agrees to use one of the following contraception methods 
constantly and properly (i.e. in accordance with the approved prescribing 
information and the doctor's orders) during the whole period of 
participation in the study: 
i) 
Total sexual abstinence  
ii) Oral contraceptives (combination drugs containing progestogen, or 
progestogen alone) 
iii) Injectable progestogen 
iv) Levonorgestrel implants 
v) Estrogen-containing vaginal ring 
vi) Transdermal contraceptive patches 
vii) Intrauterine device or intrauterine system 
viii) A male partner has been sterile (vasectomy with documented 
azoospermia) prior to enrollment of a woman, provided that he is 
the only partner of the female subject. For the purpose of this 
definition, "documented" is related to the result of a subject's medical 
examination by an investigator/responsible person or a subject's past 
medical history review for assessment of eligibility for enrollment, 
obtained during the interview with a subject or from his/her medical 
records.  
ix) Double barrier method: a condom or an occlusive cap (diaphragm or 
cervical/vault 
caps) 
with 
a 
spermicide 
(foam/gel/film/cream/suppository).  
Exclusion criteria 
1) Administration of any iron-containing drugs during the last 3 
months. 
2) History of erythropoietin drugs administration. 
3) Hypersensitivity to iron therapy (both Oral and/or IV 
administration) and other components of the study drugs. 
4) Hormone therapy (including the use of androgens/anabolic 
steroids) or administration of drugs that inhibit blood formation, 
less than 3 months before the start of the study. 
5) History of severe allergic reactions or drug intolerance. 


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6) Fructose intolerance, glucose-galactose malabsorption syndrome, 
and sucrase-isomaltase deficiency. 
7) Pregnant or lactating women, or women intending to become 
pregnant during the study. 
8) Failure of iron therapy for iron-deficiency anaemia in a subject's 
past medical history.  
9) Heme metabolism disorders (e.g., sideroachrestic anaemia, lead 
anaemia, thalassaemia). 
10) Iron overload including haemochromatosis and hemosiderosis 
11) Other causes of anemia, apart from iron deficiency, including: 
a) Haemolysis (determined as per analyses results at screening, 
or as per anamnestic data),  
b) Vitamin B12 and folic acid deficiency (as per the screening 
data),  
c) Chronic kidney disease (creatinine clearance at screening is 
below 90 ml/min (based on Cockcroft-Gault Formula)), 
d) Systemic connective tissue diseases, chronic infectious 
diseases requiring regular therapy (as per the past medical 
history), and other conditions which may, in the investigator's 
opinion, be accompanied by anaemia of chronic diseases.  
12)  Dysfunction of the thyroid gland (based on the data obtained at 
screening). 
13) Laboratory and clinical signs of an active inflammatory process 
for 10 days before screening.  
14) AST, ALT, and total bilirubin levels exceeding the upper limit of 
normal 1.5 times and more.  
15) Clinically apparent hypothyroidism, in the investigator's opinion. 
16) Malignant diseases, including blood and lymphoid tissue 
disorders 
(leukemia, 
Hodgkin 
disease, 
myelodysplastic 
syndrome, myeloma, etc.) at screening or in the past medical 
history, provided that the remission was less than 5 years before 
screening.  
17) Signs of bone marrow aplasia at screening or history of bone 
marrow aplasia. 
18) The necessity of parenteral iron therapy, i.e. the following cases:  
a) impaired absorption in case of an intestinal pathology 
(enteritis, coeliac disease, malabsorption, small intestinal 
resection, stomach resection, including the duodenum);  
b) exacerbation of gastric or duodenal ulcer;  
c) the necessity of quick iron saturation, e.g. in patients with 
iron-deficiency anaemia with upcoming surgery; 
d) continuous vast blood loss and other causes, at the discretion 
of the investigator.  
19) Known presence of an active infection caused by Helicobacter 
pylori. In case of presence of Helicobacter pylori, a subject may 
be enrolled after eradicative therapy.  
20) Concomitant diseases and conditions, which, in the investigator's 
opinion, pose risk to a subject's safety in case of his/her 
participation in the study, or able to affect the safety data analysis 


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in case of exacerbation of this disease/condition during the study, 
including: 
a) Myocardial infarction or stroke within 6 months before 
screening. 
b) Unstable angina; 
c) Severe arrhythmia, not controlled by drug therapy; 
d) Decompensated diabetes mellitus; 
e) Nephrological disorders; 
f) Other significant diseases, at the discretion of the investigator.  
21) HIV infection (as per the screening data or the results of analysis 
performed within 6 months before screening).  
22) Known or suspected drug or alcohol abuse for the last 2 years. 
23) Suspected poor adherence of a subject (e.g., due to mental 
disorders). 
24) Participation in any clinical drug studies less than 3 months 
before the study.  
25) Blood donation / blood transfusion within 30 days prior to 
screening or planned blood transfusion at time of screening. 
26) History of smoking, unless leave off smoking > 6 months. 
 
Study endpoints: 
Primary endpoint: 
• Changes in blood haemoglobin level (g/L) after 12-weeks of iron-
deficiency anaemia treatment, a non-inferiority comparison, as 
compared with the baseline value (screening visit) between 
Ferrum Lek® and MALTOFER® groups. 
Secondary endpoints: 
• Absolute values and changes of blood hemoglobin level (g/L) 
after 4, 8 and 12-weeks of treatment in the study groups. 
• Changes in average values of iron metabolism parameters 
(ferritin, transferrin, percent transferrin saturation, serum iron) 
after 4, 8 and 12 weeks of iron-deficiency anaemia treatment, as 
compared with the baseline value in the study groups. 
• The frequency of response to therapy, determined as an increase 
in haemoglobin level by 20 g/L and more after 12-weeks of iron-
deficiency anemia treatment in the study groups.  
• Frequency and severity of all adverse events observed during the 
study therapy in the study groups. 
 
Examinations 
Baseline data (demography, past medical history and laboratory data) 
will be collected for all subjects at screening. 
The parameters for the study therapy efficacy evaluation will be 
collected prior to treatment and after 12-weeks of treatment: 
• 
Haemoglobin (complete blood count), 
• 
Iron metabolism parameters (serum ferritin, serum iron, 
transferrin, percent transferrin saturation). 
Safety evaluation of the study therapy will be performed throughout 
the study and will be based on detection of any adverse events 
occurring during the study. The following will be performed: 


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• 
Physical examination, including BP and heart rate 
measurement, and identification of complaints on digestive system 
disorders (at screening, during Visit 2 and the final visit).  
• 
Complete blood count (at screening and after 12-weeks of 
treatment), 
• 
Blood chemistry (at screening), 
• 
Urinalysis, pregnancy test (at screening), 
• 
Concomitant therapy recording (during each visit). 
 
Statistical analysis 
 
Efficacy evaluation: 
Primary efficacy endpoint: 
• Changes in blood haemoglobin level (g/L) after 12-weeks of 
iron-deficiency anaemia treatment (during the final visit), as 
compared with the baseline value (the screening visit) 
between the study groups.  
Analysis of covariance (ANCOVA) will be used as the main method 
of assessment of the primary endpoint, with baseline haemoglobin 
value being a covariate and four fixed factors (treatment group, 
gender, weight and baseline Hb level (80–94 g/L vs 95–110 g/L). 
Unrestricted least significant differences (LSD) method will be 
applied to the ANCOVA results with the calculation of least-square 
(LS) means with 95% CI for LS means for the difference between the 
study groups. 
Non-inferiority will be confirmed if the upper limit of the two-sided 
95% confidence interval for LS mean will not exceed the pre-defined 
non-inferiority margin of 5 g/L. 
 
Secondary efficacy endpoints: 
All secondary efficacy analysis will be considered explorative, 
therefore, no multiplicity correction will be done for any tests, and no 
formal power calculation will be provided for the test results. 
• Absolute values and changes (compared to baseline) of blood 
hemoglobin level (g/L) after 12 weeks of treatment (during 
the final visit) between the study groups. 
Values at individual time points and values of change between the 
individual time points will be compared using the t-test or Mann-
Whitney test depending on the normality of the distribution (which 
will be tested using Shapiro-Wilk test). 
Additionally, it is planned to use ANCOVA for analysis of changes 
in the assessed parameters over time where group will be a fixed 
factor, screening hemoglobin level will be a covariate , and 
hemoglobin level at Week 12 will be a response variable.  
• Changes in average values of iron metabolism parameters 
(ferritin, transferrin, percent transferrin saturation, serum 
iron) during the treatment period (from screening till the final 
visit) in the study groups. 
 Values at individual time points (baseline and Week 12) and values 
of change between the individual time points (baseline and Week 12) 
will be compared using the t-test or Mann-Whitney test depending on 


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the normality of the distribution (which will be tested using Shapiro-
Wilk test). 
• The percentage (%) of subjects with response to the therapy, 
determined as an increase in hemoglobin level by 20 g/L and 
more after 12-weeks of treatment (from screening till the final 
visit) in the study groups.  
Comparison between the two groups will be performed using the 
Fisher’s exact test or chi-square test depending on the number of 
expected observations per cell (<5 or ≥5). Two-sided 95% confidence 
interval will be calculated using exact Clopper-Pearson method. 
These changes will be compared between the groups using the t-test 
or Mann-Whitney test depending on the normality of the distribution 
(which will be tested using Shapiro-Wilk test). 
Safety evaluation: 
Safety evaluation will include: 
1)determination of the total number, frequency and severity of: 
I. 
adverse events (AEs) irrespective of their relation to 
treatment;  
II. 
AEs related or possibly related to the treatment received;  
III. 
AEs requiring termination of the therapy.  
2) Complaints on digestive system disorders (defined through 
MedDRA SMQ for the corresponding symptoms), considered as 
related to the study therapy by the investigator, will be analyzed 
separately.  
Descriptive statistics will be used for presentation of the result. 
Comparison of all AE incidence between the study groups will be 
performed using the Fisher’s exact test or chi-square test depending 
on the number of expected observations per cell (<5 or ≥5), and 
comparison of intensity (and possible causal relationship between the 
treatment received and the AE) will be performed using Cochrane-
Armitage trend test for the ordered categorical data. 
3) Changes in laboratory test results (assessed in central laboratory) 
over time and frequency of abnormal test results (according to the 
normal ranges of central laboratory) will be summarized by group 
and also compared by group using corresponding tests for 
quantitative data and qualitative data (see below). 
4) Changes in vital signs over time and frequency of abnormal 
physical examination findings will be summarized by group and also 
compared by group using corresponding tests for quantitative data 
and qualitative data (see below). 
Quantitative data will be compared using the t-test or Mann-Whitney 
test depending on the normality of the distribution (which will be 
tested using Shapiro-Wilk test). 
Qualitative data will be compared using the Fisher’s exact test or chi-
square test depending on the number of expected observations per 
cell (<5 or ≥5). 
 
Interim analysis 
One formal Interim analysis to assess the primary and secondary 
endpoints of efficacy is planned when the population of patients with 


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available primary efficacy endpoint data is at least 240 patients (120 
patients in each group treatment: the main group is Ferrum Lek® (iron 
(III) 
hydroxide 
polymaltosate) 
and 
the 
reference 
group 
MALTOFER® (iron (III) hydroxide polymaltosate). Safety and 
Efficacy will be assessed for all patients who received at least one 
dose of the randomized treatment at the time of the interim analysis. 
Based on the results of the interim analysis of the primary and 
secondary statistical endpoints of the efficacy and safety of the study 
Sponsor may decide to stop the study if study endpoints have been 
met as per protocol based on the results of interim analyses or sample 
size might be recalculated using results of interim analyses. 
 
Justification of the 
sample size 
Calculation of the sample size is based on published works focusing 
on iron (III) hydroxide polymaltosate efficacy: 
1) Maltofer 
Product 
Information 
leaflet 
(http://www.aspenpharma.com.au/product_info/pi/PI_Malto
fer.pdf) 
2) Santiago P. Ferrous versus iron oral iron formulations for the 
treatment of iron deficiency: a clinical overview. Scientific 
World Journal. 2012;2012:846824. 
3) Geisser P. Safety and efficacy of iron(III)-hydroxide 
polymaltose complex / a review of over 25 years' experience. 
Arzneimittelforschung. 2007;57(6A):439-52;  
4) Toblli JE, Brignoli R. Iron(III)-hydroxide polymaltose 
complex in iron deficiency anemia / review and meta-
analysis. Arzneimittelforschung. 2007;57(6A):431-8); 
5) Reinisch 
W, 
Staun 
M, 
Tandon 
RK, 
Altorjay 
I, 
Thillainayagam AV, Gratzer C, Nijhawan S, Thomsen LL. A 
randomized, open-label, non-inferiority study of intravenous 
iron isomaltoside 1,000 (Monofer) compared with oral iron 
for treatment of anemia in IBD (PROCEED). Am J 
Gastroenterol. 2013 Dec;108(12):1877-88.  
6) Zaim M, Piselli L, Fioravanti P, Kanony-Truc C. Efficacy and 
tolerability of a prolonged release ferrous sulphate 
formulation in iron deficiency anaemia: a non-inferiority 
controlled trial. Eur J Nutr. 2012 Mar;51(2):221-9. 
Based on the data of these publications, during 12-weeks of oral 
administration of iron (III) hydroxide polymaltosate the hemoglobin 
level can increase on average by 8-15 g/L with a standard deviation 
up to 15 g/L. As similar efficacy is expected in both groups, zero 
difference in primary efficacy parameter will be used for calculation 


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of sample size. Maximum value of standard deviation was used – 15 
g/L to take a maximum variability of the primary endpoint variable 
into account for properly powered study. 
The value of 5 g/L was selected as the non-inferior efficacy limit (in 
accordance with the limit stated and justified in the above mentioned 
works. 
Thus, the following assumptions were proposed for calculations: 
1) Changes in blood hemoglobin level (g/L) after 12-weeks of 
iron-deficiency anemia treatment (during the final visit), as 
compared with the baseline value (the screening visit 0) are 
expected to be similar for the investigational and reference 
drug groups (i.e. expected difference between the two groups 
is set to zero). 
2) The pooled standard deviation for the changes in hemoglobin 
level was 15 g/L. 
3) Non-inferiority margin is 5 g/L. 
4) The significance level (two-sided, in accordance with FDA 
recommendations) is 95%, which corresponds to the type I 
one-sided error 0.05. 
5) Power of the study is 80%, which corresponds to the type II 
error 0.20. 
6) Statistical hypotheses – evidence of a non-inferior efficacy: 
H0: μA−μB≤5.0  
H1 :μA−μB>5.0 
 
7) The ratio between the study and control group sizes is 1:1 
8) Interim analysis will be performed at 70% of the total sample 
size 
9) O’Brien-Fleming alpha-spending function will be used with 
80% power for efficacy boundary that will correspond to the 
following critical values for t-test: 2,628 for interim analysis 
(corresponds to p=0,005) and 1,976 for final analysis 
(corresponds to p= 0,0245); 
Calculation was performed using the clinfun package of Microsoft R 
Open software (available at https://mran.microsoft.com – Microsoft 
R Application network), that uses the group sequential design 
approach for the calculation of fixed sample sizes for the interim and 
final analysis. 
 
According to the output from the clinfun package, 143 subjects per 
group (286 subjects in total) should complete the study in order to 


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1 General information 
1.1 Protocol name, Protocol ID, and date:  
Name: A multicenter, open-label, randomized, active-controlled study to evaluate the efficacy and 
safety of Ferrum Lek® (iron (III) hydroxide polymaltosate), 100 mg chewable tablets (Lek d.d., 
Slovenia), as compared with Maltofer® (iron (III) hydroxide polymaltosate), 100 mg chewable 
tablets (Vifor S.A., Switzerland), in subjects with mild and moderate iron deficiency anemia.  
ID: TE_005_FER_CHT 
Protocol version: 2.0  
Date: March 20, 2019 
1.2 Study Sponsor: 
Study Sponsor: 
Name of organization: 
Sandoz CJSC, Russia 
Address: 
 
72 Leningradsky Prospekt, bld. 3, 125317 Moscow, Russia 
Telephone:  
 
E-mail: 
sandoz.russia@sandoz.com 
 
Sponsor’s representative: 
 
 
 
Full name:
Phone:
Fax:
E-mail:  
 
 
 Novartis Pharma 
 
Full name:
Address:
Phone:
Mobile:
 (24h) 
Fax:
E-mail:
1.3 Sponsor's representative for the medical questions: 
Full name: 
 
Position: 
confirm non-inferiority. 200 (100 per group) subjects should have 
evaluable data to perform interim analysis. Taking 15% withdrawal 
rate into account, one need to randomize 336 subjects (168 subjects 
per group). Taking 30% screening failure rate, up to 480 subjects 
should be screened to achieve target randomization. 
 


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Name of organization: 
Sandoz CJSC, Russia 
Address: 
 
72 Leningradsky Prospekt, bld. 3, 125317 Moscow, Russia 
Telephone:  
Phone: 
 
Fax: 
 
E-mail: 
 
1.4 Sponsor's representative for the medical questions (back up): 
Full name: 
Position: 
Name of organization: 
Sandoz CJSC, Russia 
Address: 
 
72 Leningradsky Prospekt, bld. 3, 125317 Moscow, Russia 
Telephone:  
T.:
ext
Fax: 
 
Mobile:
 
E-mail: 
 
 
1.5 Study Monitor: 
Contract research organization (CRO) responsible for study conduct  
Address:
T.:
; Fax:
Email address
 
1.6 Clinical laboratories and other organizations engaged in the 
study 
Name of organization: 
Address: 
 
Telephone:  
E-mail: 
 
 


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2 Study rationale 
2.1 Study drugs  
2.1.1 Study drug: Ferrum Lek® 
Trade name: Ferrum Lek® 
International non-proprietary name or generic name: iron [III] hydroxide polymaltosate. 
Chemical name: iron [III] hydroxide polymaltosate  
Dosage Form: chewable tablets 
Composition: 
1 chewable tablet contains: 
Active substance: iron (III) hydroxide polymaltosate 400 mg (equivalent to 100 mg of iron). 
Excipients: macrogol 6000 — 37.0 mg; aspartame — 1.5 mg; chocolate flavoring — 0.6 mg; talc 
— 21.0 mg; dextrates to 730.0 mg. 
Appearance: 
Dark brown, round, flat tablets with light brown impregnations and a bevel edge. 
Pharmacotherapeutic group: iron drug. 
ATC code: В03АВ05.  
Pharmacodynamic properties 
Pharmacodynamics 
Polynuclear iron (III) hydroxide is surrounded by a number of covalently bound polymaltose 
molecules from the outside in iron (III) hydroxide polymaltosate, which gives a total average 
molecular weight of about 50 kDa.  
The polynuclear iron (III) hydroxide polymaltosate core has a structure similar to that of the core 
of the physiological iron storage protein ferritin. Iron (III) hydroxide polymaltosate is stable and 
under physiological conditions does not emit a large number of iron ions. Due to its size, iron (III) 
hydroxide polymaltosate diffusion degree through the mucosa is approximately 40 times less than 
that of the iron (II) hexahydrate complex. Iron from iron (III) hydroxide polymaltosate is actively 
absorbed in the intestine.  
The efficacy of iron (III) hydroxide polymaltosate for normalizing the hemoglobin content and 
iron pool replenishment was demonstrated in numerous randomized controlled clinical studies 
using placebo or an active comparator in adults and children with different iron pool status. 
Pharmacokinetics 
Absorption 
Iron from iron (III) hydroxide polymaltosate is absorbed in accordance with the controlled 
mechanism. The increase in serum iron content after the drug administration does not correlate 
with total iron absorption, measured as incorporation into hemoglobin (Hb). Studies with a labeled 
radioisotope of iron (III) hydroxide polymaltosate revealed a strong correlation between the 
inclusion of iron in erythrocytes and the iron content throughout the body. The maximum activity 
of iron absorption from iron (III) hydroxide polymaltosate occurs in the duodenum and small 
intestine. As in case of other oral iron drugs, the relative absorption of iron from iron (III) 
hydroxide polymaltosate defined as incorporation into hemoglobin, decreases with increasing 
doses of iron. In addition, a correlation was observed between the degree of iron deficiency (in 
particular serum ferritin concentration) and the relative amount of absorbed iron (i.e., the greater 
the iron deficiency, the better the relative absorption). In subjects with anemia, absorption of iron 
from iron (III) hydroxide polymaltosate, in contrast to iron salts, increased in the presence of food. 
 
 


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Distribution 
Distribution of iron from iron (III) hydroxide polymaltosate after absorption was studied in a study 
using the technique of double isotopes (55Fe and 59Fe). 
Biotransformation 
The absorbed iron binds to transferrin and is used to synthesize hemoglobin in the bone marrow 
or is stored, mainly in the liver, where it binds to ferritin. 
Excretion 
Non-absorbed iron is excreted by the intestine (with feces). 
Therapeutic indications 
• 
treatment of latent iron deficiency (iron deficiency without anemia); 
• 
treatment of symptomatic iron deficiency anemia; 
• 
increased need for iron during pregnancy and lactation, blood donation, intensive 
growth, vegetarians and the elderly. 
Contraindications 
• 
iron overload (e.g., hemosiderosis, hemochromatosis); 
• 
impairment of iron utilization (e.g., lead anemia, sideroachrestic anemia, thalassemia); 
• 
anemia other than iron deficiency anemia (e.g., haemolytic anemia, megaloplastic 
anemia due to vitamin B12 deficiency); 
• 
children under 12 years old (due to the need to prescribe small doses in this age group 
it is recommended to use Ferrum Lek® syrup 10 mg/ml). 
Administration during pregnancy and lactation 
Pregnancy 
Until now, there have been no reports of serious adverse reactions after oral administration of iron 
(III) hydroxide polymaltosate at therapeutic doses for the treatment of anemia during pregnancy. 
The data obtained from animal studies showed no danger to the fetus or the mother. There is no 
clinical data on the use of Ferrum Lek® in the first trimester of pregnancy. 
The studies conducted in pregnant women after the end of the first trimester of pregnancy revealed 
no adverse effects of iron (III) hydroxide polymaltosate in mothers and/or newborns. 
Consequently, adverse effect on the fetus is unlikely following the administration of iron (III) 
hydroxide polymaltosate.  
Lactation 
Woman breast milk contains iron bound to lactoferrin. The amount of iron that passes from iron 
(III) hydroxide polymaltosate to breast milk is unknown. It is unlikely that the administration of 
iron (III) hydroxide polymaltosate in lactating women can lead to adverse effects in the child. As 
a precaution to women of childbearing age and women during pregnancy and lactation, Ferrum 
Lek® should be administered only after consultation with the doctor. The benefit/risk ratio should 
be evaluated. 
Posology and method of administration 
Oral dosage form. 
The daily dose can be divided into several doses or taken at a time. Ferrum Lek® should be 
administered during or immediately after meals. Ferrum Lek®, 100 mg chewable tablets, can be 
chewed or swallowed whole.  
The daily dose of the drug depends on the degree of iron deficiency (see table of daily doses). 
 
 
 


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Table of daily doses 
Patient populations 
Treatment of iron 
deficiency anemia 
Treatment of iron 
deficiency without 
anemia 
Increased iron 
requirement 
Children older than 
12 years, adults and 
lactating women 
1–3 chewable tablets 
(100–300 mg of iron) 
1 chewable tablet 
(50–100 mg of iron) 
-- 
Pregnant women 
2–3 chewable tablets 
(200–300 mg of iron) 
1 chewable tablet 
(100 mg of iron) 
1 chewable tablet 
(100 mg of iron) 
 
Treatment of iron deficiency anemia in children older than 12 years and adults  
100 to 300 mg of iron (1–3 tablets) per day for 3–5 months until the normal hemoglobin (Hb) level 
is reached. After this, treatment should be continued for several weeks at the dose described for 
iron deficiency without anemia in order to replenish iron stores. 
Treatment of iron deficiency anemia during pregnancy 
200 to 300 mg of iron (2–3 tablets) per day until the normal hemoglobin (Hb) level is reached. 
After this, treatment should be continued at least until the end of pregnancy at a dose described for  
iron deficiency without anemia in order to replenish iron stores and meet the increased 
requirements for iron due to pregnancy. 
Treatment and prevention of iron deficiency without anemia in children older than 12 years and 
adults 
100 mg (1 tablet) per day for 1–2 months.  
Paediatric use 
Ferrum Lek® 100 mg chewable tablets are contraindicated for children under 12 years old.  
Side effects 
Ferrum Lek® is generally well tolerated. Side effects are mainly mild and transient. 
Side effects are mainly mild and transient. According to the World Health Organization (WHO), 
adverse reactions are classified depending on their incidence as follows: very common (> 1/10), 
common (> 1/100, < 1/10), uncommon (> 1/1,000, < 1/100), rare (> 1/10,000, < 1/1,000), very 
rare (< 1/10,000), not known (cannot be estimated using the available data).  
Nervous system disorders 
uncommon: headache.  
Gastrointestinal disorders 
very common: feces discolored (in 23% of patients, this is a known adverse reaction to iron drugs);  
common: diarrhea, nausea, indigestion;  
uncommon: vomiting, constipation, abdominal pain, discoloration of tooth enamel (in 0.6% of 
patients, this is a known adverse reaction to iron drugs); 
Skin and subcutaneous tissue disorders  
uncommon: rash, including exanthema, itching. 
Overdose 
In case of an overdose of Ferrum Lek®, iron overload or intoxication is unlikely due to the low 
toxicity of iron (III) hydroxide polymaltosate and controlled iron uptake. No cases of fatal 
unintentional poisoning were reported. 
Interaction with other medicinal products 
Interactions of iron (III) hydroxide polymaltosate with tetracycline or aluminum hydroxide have 
been studied. No significant decrease in tetracycline absorption has been observed. Plasma 
concentrations of tetracycline did not drop below the effective level. Absorption of iron from iron 
(III) hydroxide polymaltosate did not decrease under the influence of aluminum hydroxide or 
tetracycline. Thus, concomitant administration of iron (III) hydroxide polymaltosate with 


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tetracycline and other phenolic compounds, as well as aluminum hydroxide, is allowed. The 
studies in rats using tetracycline, aluminum hydroxide, acetylsalicylic acid, sulfasalazine, calcium 
carbonate, calcium acetate and calcium phosphate in combination with vitamin D3, bromazepam, 
magnesium aspartate, D-penicillamine, methyldopa, paracetamol and auranofin revealed no 
interactions with iron (III) hydroxide polymaltosate. 
No interaction of iron (III) hydroxide polymaltosate with food components such as phytic acid, 
oxalic acid, tannin, sodium alginate, choline and choline salts, vitamin A, vitamin D3, and vitamin 
E, soybean oil and soybean flour was observed either. These results indicate that iron (III) 
hydroxide polymaltosate can be administered during or immediately after meals.  
The administration of the drug does not affect the results of the detection of hidden blood (with a 
selective determination of hemoglobin), therefore, treatment interruption is not necessary. 
Concomitant use of parenteral and oral iron drugs should be avoided, since the absorption of iron 
taken orally slows down. 
Special warnings 
Ferrum Lek® is not expected to have an effect on the daily insulin requirement in patients with 
diabetes mellitus. 1 chewable tablet contains 0.04 bread units. 
Anemia can be caused by infectious diseases or malignant neoplasms. Since iron can only be taken 
after the root cause of the disease has been eliminated, the benefit/risk ratio of treatment should be 
determined. 
During treatment with Ferrum Lek®, dark discoloration of feces can be noted, but this is not 
clinically significant. 
Effects on ability to drive and use machines 
No data available. It is unlikely that Ferrum Lek® influences the ability to drive or use mechanisms. 
Pharmaceutical form 
100 mg chewable tablets. 
 
Primary packaging 
10 tablets in an Al/Al strip or in an Al/Al blister. 
Secondary packing 
3, 5 or 9 strips or blisters in a carton pack along with the Patient Information Leaflet. 
Storage Conditions 
At a temperature below 25 °С.  
Keep out of reach of children. 
Shelf life 
5 years. 
Do not use after the expiry date. 
Pharmacy purchasing terms 
By prescription. 
Manufacturer 
PL Holder: Sandox d.d. Verovskova 57, 1000 Ljubljana, Slovenia 
Manufacturer: Lek d. d. Verovskova 57, 1526 Ljubljana, Slovenia 
Send customer complaints to 
Sandoz CJSC, 72 Leningradsky Prospekt, bld. 3, 125315 Moscow; 
telephone: 
 fax: 
. 
 
2.1.2 Reference product: MALTOFER®  
Trade name: MALTOFER® (Maltofer®) 
International non-proprietary name or generic name: iron [III] hydroxide polymaltosate 


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Chemical name: iron [III] hydroxide polymaltosate  
Dosage Form: chewable tablets 
Composition: 
1 tablet contains: 
active substance: 
 
iron [III] hydroxide polymaltosate 
357.0 mg 
equivalent to iron 
100.0 mg 
excipients: 
 
dextrates 
232.0 mg 
macrogol 6000 
37.0 mg 
purified talc 
21.0 mg 
sodium cyclamate 
9.0 mg 
vanillin 
2.9 mg 
cocoa powder 
29.0 mg 
chocolate flavor 
0.6 mg 
microcrystalline cellulose 
up to 730.0 mg 
 
Appearance 
Dark brown, round, flat scored tablets with white impregnations. 
Pharmacotherapeutic group: iron drug.  
ATC code: В03АВ05 
Pharmacodynamic properties 
Pharmacodynamics 
Polynuclear iron (III) hydroxide is surrounded by a number of covalently bound polymaltose 
molecules from the outside in iron (III) hydroxide polymaltosate, which gives a total average 
molecular weight of about 50 kDa. The polynuclear iron (III) hydroxide polymaltosate core has a 
structure similar to that of the core of the physiological iron storage protein ferritin. Iron (III) 
hydroxide polymaltosate is stable and under physiological conditions does not emit a large number 
of iron ions. Due to its size, iron (III) hydroxide polymaltosate diffusion degree through the mucosa 
is approximately 40 times less than that of the iron (II) hexahydrate complex. Iron from iron (III) 
hydroxide polymaltosate is actively absorbed in the intestine. The efficacy of MALTOFER® for 
normalizing the hemoglobin content and iron pool replenishment was demonstrated in numerous 
randomized controlled clinical studies using placebo or an active comparator in adults and children 
with different iron pool status. 
Pharmacokinetics 
Absorption 
Iron from iron (III) hydroxide polymaltosate is absorbed in accordance with the controlled 
mechanism. The increase in serum iron content after the drug administration does not correlate 
with total iron absorption, measured as incorporation into hemoglobin (Hb). Studies with a labeled 
radioisotope of iron (III) hydroxide polymaltosate revealed a strong correlation between the 
inclusion of iron in erythrocytes and the iron content throughout the body. The maximum activity 
of iron absorption from iron (III) hydroxide polymaltosate occurs in the duodenum and small 
intestine. As in case of other oral iron drugs, the relative absorption of iron from iron (III) 
hydroxide polymaltosate defined as incorporation into hemoglobin, decreases with increasing 
doses of iron. In addition, a correlation was observed between the degree of iron deficiency (in 
particular serum ferritin concentration) and the relative amount of absorbed iron (i.e., the greater 
the iron deficiency, the better the relative absorption). In subjects with anemia, absorption of iron 
from iron (III) hydroxide polymaltosate, in contrast to iron salts, increased in the presence of food. 
 
 


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Distribution 
Distribution of iron from iron (III) hydroxide polymaltosate after absorption was studied in a study 
using the technique of double isotopes (55Fe and 59Fe). 
Biotransformation 
The absorbed iron binds to transferrin and is used to synthesize hemoglobin in the bone marrow 
or is stored, mainly in the liver, where it binds to ferritin. 
Excretion 
Non-absorbed iron is excreted by the intestine (with feces). 
Therapeutic indications 
• 
Treatment of iron deficiency without anemia (latent iron deficiency) and treatment of 
symptomatic  iron deficiency anemia. 
• 
Increased need for iron during pregnancy and lactation, blood donation, intensive 
growth, vegetarians and the elderly. 
Contraindications 
• 
The established hypersensitivity to iron (III) hydroxide polymaltosate or to any 
excipient. 
• 
Iron overload (e.g., hemosiderosis, hemochromatosis). 
• 
Impairment of iron utilization (e.g., lead anemia, sideroachrestic anemia, thalassemia). 
• 
Anemia other than iron deficiency anemia (e.g., haemolytic anemia, megaloplastic 
anemia due to vitamin B12 deficiency). 
• 
Children under 12 years old (due to the need to prescribe small doses in this age group 
it is recommended to use MALTOFER® 50 mg/ml oral drops, or MALTOFER® 10 
mg/ml syrup). 
Administration during pregnancy and lactation 
Pregnancy 
Until now, there have been no reports of serious adverse reactions after oral administration of 
MALTOFER® at therapeutic doses for the treatment of anemia during pregnancy. Animal data 
showed no 
danger to the fetus or mother. There is no clinical data on the use of MALTOFER® in the first 
trimester of pregnancy. 
The studies conducted in pregnant women after the end of the first trimester of pregnancy revealed 
no adverse effects of MALTOFER® in mothers and/or newborns. Consequently, adverse effect on 
the fetus is unlikely following the administration of MALTOFER®. Lactation 
Woman breast milk contains iron bound to lactoferrin. The amount of iron that passes from iron 
(III) hydroxide polymaltosate to breast milk is unknown. It is unlikely that the administration of 
MALTOFER® in lactating women can lead to adverse effects in the child. As a precaution to 
women of childbearing age and women during pregnancy and lactation, MALTOFER® should be 
administered only after consultation with the doctor. The benefit/risk ratio should be evaluated. 
Posology and method of administration 
Oral dosage form. 
The daily dose can be divided into several doses or taken at a time. MALTOFER® should be 
administered during or immediately after meals. MALTOFER®, 100 mg chewable tablets, can be 
chewed or swallowed whole. The daily dose of the drug depends on the degree of iron deficiency 
(see table of daily doses). 
 
 


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Table of daily doses 
Patient populations 
Treatment of iron 
deficiency anemia 
Treatment of iron 
deficiency without 
anemia 
Increased iron 
requirement 
Children older than 
12 years, adults and 
lactating women 
1–3 tablets (100–300 
mg of iron) 
1 tablet (50–100 mg 
of iron) 
⃰ 
Pregnant women 
2–3 tablets (200–300 
mg of iron) 
1 tablet (100 mg of 
iron) 
1 tablet (100 mg of 
iron) 
*Due to the need to prescribe small doses according to these indications, it is recommended to use MALTOFER® 50 
mg/ml oral drops, or MALTOFER® 10 mg/ml syrup). 
 
Treatment of iron deficiency anemia in children older than 12 years and adults  
100 to 300 mg of iron (1–3 tablets) per day for 3–5 months until the normal hemoglobin (Hb) level 
is reached. After this, treatment should be continued for several weeks at the dose described for 
iron deficiency without anemia in order to replenish iron stores. 
Treatment of iron deficiency anemia during pregnancy 
200 to 300 mg of iron (2–3 tablets) per day until the normal hemoglobin (Hb) level is reached. 
After this, treatment should be continued at least until the end of pregnancy at a dose described for  
iron deficiency without anemia in order to replenish iron stores and meet the increased 
requirements for iron due to pregnancy. 
Treatment and prevention of iron deficiency without anemia in children older than 12 years and 
adults 
100 mg (1 tablet) per day for 1–2 months. If a smaller dose is required for prevention, 
MALTOFER® 50 mg/ml oral drops, or MALTOFER® 10 mg/ml syrup can be used. Paediatric use 
MALTOFER® 100 mg chewable tablets are contraindicated for children under 12 years old. The 
dosage form and the concentration of MALTOFER® 50 mg/ml oral drops, and MALTOFER® 10 
mg/ml syrup are mor suitable for taking the recommended dose in this age group. 
Side effects 
Safety and tolerability of MALTOFER® was evaluated in numerous clinical studies. The main 
adverse drug reactions (ADRs), noted in these studies, occurred in the following three classes of 
systems and organs. 
Adverse drug reactions reported in clinical studies 
System organ class 
Very common 
(>1/10) 
Common (> 1/100, < 
1/10) 
Uncommon (> 
1/1000, < 1/100) 
Nervous system 
disorders 
-- 
-- 
Headache 
Gastrointestinal 
disorders 
Feces discolouration1 
Diarrhea, nausea, 
indigestion 
Vomiting, 
constipation, 
abdominal pain, 
discoloration of tooth 
enamel2 
Skin and 
subcutaneous tissue 
disorders 
-- 
-- 
Rash3, pruritus 
                                                 
 
1 Often registered as an adverse event (in 23% of patients), this is a well-known ADR for oral iron drugs. 
2 Registered as an adverse event in 0.6 % of patients, this is a well-known ADR for oral iron drugs. 
3 Including exanthema. 


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Spontaneous post-marketing reports about adverse drug reactions  
No additional adverse drug reactions were reported. 
Laboratory abnormalities 
No data available. 
Overdose 
In case of an overdose of MALTOFER®, iron overload or intoxication is unlikely due to the low 
toxicity of iron (III) hydroxide polymaltosate and controlled iron uptake. No cases of fatal 
unintentional poisoning were reported. 
Interaction with other medicinal products 
Interactions of iron (III) hydroxide polymaltosate with tetracycline or aluminum hydroxide have 
been studied. No significant decrease in tetracycline absorption has been observed. Plasma 
concentrations of tetracycline did not drop below the effective level. Absorption of iron from iron 
(III) hydroxide polymaltosate did not decrease under the influence of aluminum hydroxide or 
tetracycline. Thus, concomitant administration of iron (III) hydroxide polymaltosate with 
tetracycline and other phenolic compounds, as well as aluminum hydroxide, is allowed. The 
studies in rats using tetracycline, aluminum hydroxide, acetylsalicylic acid, sulfasalazine, calcium 
carbonate, calcium acetate and calcium phosphate in combination with vitamin D3, bromazepam, 
magnesium aspartate, D-penicillamine, methyldopa, paracetamol and auranofin revealed no 
interactions with iron (III) hydroxide polymaltosate. 
No interaction of iron (III) hydroxide polymaltosate with food components such as phytic acid, 
oxalic acid, tannin, sodium alginate, choline and choline salts, vitamin A, vitamin D3, and vitamin 
E, soybean oil and soybean flour was observed either. These results indicate that iron (III) 
hydroxide polymaltosate can be administered during or immediately after meals. The 
administration of the drug does not affect the results of the detection of hidden blood (with a 
selective determination of hemoglobin), therefore, treatment interruption is not necessary. 
Concomitant use of parenteral and oral iron drugs should be avoided, since the absorption of iron 
taken orally slows down. 
Special warnings 
MALTOFER® is not expected to have an effect on the daily insulin requirement in patients with 
diabetes mellitus. 1 chewable tablet contains 0.04 bread units. 
Anemia can be caused by infectious diseases or malignant neoplasms. Since iron can only be taken 
after the root cause of the disease has been eliminated, the benefit/risk ratio of treatment should be 
determined. 
During treatment with MALTOFER®, dark discoloration of feces can be noted, but this is not 
clinically significant. 
Effects on ability to drive and use machines 
No data available. It is unlikely that MALTOFER® influences the ability to drive or use 
mechanisms. 
Pharmaceutical form 
100 mg chewable tablets. 
10 tablets in polyethylene laminated aluminum foil blisters. 1 or 3 blisters per carton pack along 
with the Patient Information Leaflet. 
Storage Conditions 
In a place protected from light at a temperature below 25°C. Keep out of reach of children. 
Shelf life 
5 years. 
Do not use after the expiry date indicated on the package. 
Pharmacy purchasing terms 
By prescription. 


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Marketing authorization holder / company that performs release quality control 
Vifor (International) Inc. 
Rechenstrasse 37, CH-9014 St. Gallen, Switzerland  
Vifor (International) Inc. 
Rechenstrasse 37, CH-9014 St. Gallen, Switzerland 
Manufacturer 
Vifor S.A. 
Route de Moncor 10, CH-1752 Villars-sur-Glane, Switzerland  
Vifor S.A. 
Route de Moncor 10, CH-1752 Villars-sur-Glane, Switzerland 
Organization for customer complaints 
Takeda Pharmaceutical Co., Ltd.  
2, Usacheva st., bld. 1, 119048 Moscow  
Tel. +7 (495) 933 55 11. Fax: +7 (495) 502 16 25.  
E-mail: russia@takeda.com  
Internet: www.takeda.com.ru  
 
 


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2.2 Summary of Non-Clinical Study Results 
Introduction 
This non-clinical review contains information regarding the composition of Ferrum Lek®, which 
is marketed the EU. 
In order to provide brief and up-to-date information, this review is devoted to a medicinal product 
containing iron (III) hydroxide polymaltosate as the active substance.  
In particular, the review will be based on data published in recent literature, taking into account 
any new information on the safety and efficacy of the drug.  
According to the above provisions, non-clinical data of the active substance of the drug, iron (III) 
hydroxide polymaltosate, will be highlighted first of all. The next part will contain all reports and 
publications in accordance with the updated edition of November 2003 (the first edition was 
published in 1979) of the Uniform requirements for manuscripts submitted to biomedical journals 
of the International Committee of Medical Journal Editors (ICMJE). 
In the sections printed in italics, a critical assessment of safety pharmacology will be presented as 
part of a comparison of non-clinical data and a number of well-known clinical indicators. In 
general, non-clinical studies showed that non-clinical pharmacokinetic and pharmacodynamic 
parameters are similar to those found in clinical studies. 
2.2.1 Overview of the non-clinical study strategy 
Iron is a natural component of the body, and it is necessary for the formation of hemoglobin and 
oxidative processes occurring in living tissues. It is a component of hemoglobin, myoglobin and a 
number of enzymes. A third part of the total iron in the body is stored in the form of ferritin and 
hemosiderin.  
The body contains about 4 g of iron, most of which is contained in hemoglobin. Ionized iron is a 
component of certain enzymes necessary for energy transfer (such as cytochrome oxidase, 
xanthine oxidase, succinate dehydrogenase). Prescription of iron drugs allows you to correct 
hematopoietic disorders, associated with iron deficiency. However, iron does not activate 
hematopoiesis and does not eliminate structural changes in hemoglobin that are not associated with 
iron deficiency.  
Iron is also not used to treat anemia, the cause of which is not associated with its deficiency. Iron 
can be bivalent or trivalent. Unlike Fe (II) ions, Fe (III) ions form a high-molecular-weight 
polynuclear Fe (III) hydroxide in a weakly acidic medium (at pH of about 2). Water-soluble 
complexes of polynuclear Fe (III) hydroxide polymaltose or polysomaltose are iron dextrin or iron 
dextran. In addition to parenteral administration, polynuclear iron(III) hydroxide complexes are 
also effective when administered orally [1]. 
Iron(III) hydroxide polymaltose complex (IPC) is an organic complex comprising trivalent iron, 
which is used as an antianemic food additive.  
One chewable tablet contains 100 mg of iron in the form of iron (III) hydroxide polymaltose 
complex.  
One teaspoon (5 ml) of syrup contains 50 mg of iron in the form of iron (III) hydroxide polymaltose 
complex.  
Each ampoule of the solution for intramuscular injection (2 ml) contains 100 mg of iron in the 
form of iron polymaltosate, whereas each ampoule of the solution for intravenous injection (5 ml) 
contains 100 mg of iron in the form of iron sucrose. 
The iron polymaltose complex for oral use is a water-soluble, non-ionized polynucleated iron 
hydroxide polymaltose complex with a molecular weight of more than 150.00.  
This drug is intended to treat iron deficiency anemia (sideropenia) or blood loss.  


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2.2.2 Pharmacology 
2.2.2.1 Primary pharmacodynamics  
Iron is an integral component of hemoglobin formation in vivo, an adequate amount of which is 
required to maintain effective erythropoiesis, and the resulting ability of blood to carry oxygen. 
Iron contained in myoglobin demonstrated the same function. Iron is also a co-factor for a number 
of natural enzymes, including cytochromes involved in electron transport. Iron is essential for 
catecholamine metabolism and the adequate functioning of neutrophils. When administered with 
food or as an additive, iron passes through the cells of the mucosa in the glandular state in a 
complex with transferrin protein. Iron is transported in this form to the bone marrow in the body, 
where it participates in the formation of red blood cells. Iron participates in the formation of 
hemosiderin and ferritin in a protein-bound form, replenishes depleted body stores or incorporates 
into hemoglobin. The body iron store is divided between the natural iron-containing compounds 
and the excess iron stored in the tissues. Hemoglobin predominates among the natural iron-
containing fractions. This protein with a molecular weight of 64,500 Da includes 4 iron atoms per 
molecule. About 73% of iron in the body is contained in hemoglobin, the circulation of which 
continuously occurs in the body as red blood cells form. Of the total amount of iron in the body, 
12–17% is stored in the form of two molecules, ferritin and hemosiderin, each of which can bind 
a large number of iron atoms. Ferritin is a protein the function of which is to deposit iron. It can 
exist in the form of individual molecules or form aggregates. Iron can occupy more than 30% of 
the ferritin mass (4000 iron atoms per ferritin molecule). Ferritin in the aggregated form, known 
as hemosiderin, contains about one third of the total amount of iron in normal condition and 
becomes visible under light microscopy. The predominant sites of iron deposition are the 
reticuloendothelial system and hepatocytes, despite the fact that a part of the iron is stored in the 
muscles. Apoferritin has a molecular weight of about 450,000 Da and includes 24 polypeptide 
subunits, inside of which there is a cavity for storing polynuclear phosphorylated iron hydroxide. 
Myoglobin contains 5 to 15% of iron, and acts as an oxygen reservoir for muscle cells [2,3] 
Other forms of natural iron include various iron-dependent and non-gem-containing enzymes. 
Small but highly significant amounts of iron (0.2%) are represented in the body in a transferrin-
bound form. The internal charge of iron is compensated by a plasma protein, known as transferrin. 
This β1-glycoprotein has a molecular weight of about 76,000 Da [4] 
Iron is transported from transferrin into the cells via specific plasma membrane transferrin 
receptors. Iron transferrin complexes bind to receptors, resulting in a tertiary complex, which is 
captured by receptor-mediated endocytosis. After that, iron dissociates in an pH-dependent 
mechanism in the acid vesicular compartment inside the cell, and the receptors return 
apotransferrin to the cell surface, from which it is released into the extracellular space [5].  
When the body is saturated with iron, the synthesis of transferrin receptors slows down, and the 
production of transferrin is activated. In case of iron deficiency, the cells express more transferrin 
receptors, and the concentration of ferritin is reduced, which allows to maximize the level of iron 
absorption by cells and prevent its deposition. Isolation of human transferrin receptor genes and 
ferritin provided an opportunity to further study the molecular basis of the regulation of the 
described processes. Lactoferrin, a component of breast milk, mucosal tissues and white blood 
cells, or leukocytes, also binds some amount of iron in the body. Small amounts of iron, not 
included in the listed compounds, are included in a large number of enzymes involved in 
metabolism.  These include oxidases, catalases, reductases, peroxidases and dehydrogenases. Each 
enzyme has the important function of electron reversing donor or acceptor during cellular 
metabolism. Iron-sensitive binding elements control the rate of translation and the stability of 
messenger RNA, which encodes ferritin and transferrin receptor [6]. 


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Absorption is considered to be regulated by a single hematopoietic transcription factor (NF-E2), 
which binds intestinal transport and erythropoiesis by global control of genes in chromosomes 
[6,7] 
A lot of studies investigated the often expressed opinion that iron (II) is more efficiently absorbed 
and utilized following oral administration in comparison with iron (III).  
As a result, it was concluded that iron (II) and iron (III) do not differ in terms of therapeutic 
efficacy. 
In vivo studies 
Bioavailability of iron valence forms 
Rats 
No difference in the bioavailability of iron forms of different valencies was observed 
in  experiments on animals. A prerequisite was the administration of iron in the ionized state. The 
results were confirmed by in vivo studies in healthy and iron deficient rats after intragastric 
administration of radioactively labeled 59Fe (FeSO4), 59Fe (FeCl3) and 59Fe-(Fe (III)-polymaltose) 
organic complex. Utilization of iron obtained in the form of an organic complex was somewhat 
less active in iron-deficient rats than in animals treated with FeSO4. In addition to detecting 59Fe-
radioactivity 6 days after the administration of the drug, the level of 59Fe-radioactivity in the blood 
of iron-deficient rats was higher than that detected in healthy animals. The proportion of 
radioactivity present in the liver, in contrast, was higher in healthy animals compared with iron-
deficient rats. In other words, this means that the 59Fe-labeled iron of all three compounds studied 
is equivalently utilized. 
Experiments were also conducted in healthy and iron-deficient rats that received food containing 
small amounts of iron. The animals were taken several samples for blood test. The hemoglobin 
content in the blood of healthy rats ranged 12 to 14 g/dL, and in iron deficient rats it was 6 to 8 
g/dL. Iron was injected with a probe into the stomach, and traces of radioactivity of compounds 
labeled with 59Fe-ion were detected on day 6 after the administration of the drug. No differences 
in the absorption level of divalent and trivalent ions were detected provided that iron was used in 
the ionized state. A similar effect can be achieved while maintaining pH of the prescribed solution 
at a level of less than 2.5. The administration of two- or trivalent ionized iron with food to healthy 
rats led to a slight decrease in the amount of iron absorbed. This difference disappeared after the 
administration of ionized iron with food to iron-deficient animals. The level of iron accumulation 
in the body of rats was investigated after its simultaneous administration with a mixture of amino 
acids and increasing amounts of HPO-42 anions. While the level of absorption of iron iron in 
healthy animals decreased slightly, the accumulation activity of divalent ions in the body has 
increased dramatically [9]. 
Pigs 
When testing these drugs in the treatment of iron deficiency or iron deficiency anemia in the 
models of anemia or sideropenia in 4-day piglets, the following results were obtained. Studies 
performed in newborn piglets can be compared with clinical data, as piglets manage to create 
typical models of anemia, most similar to the  pathophysiological pattern observed in humans. The 
therapeutic result was evaluated on the basis of the analysis of the following parameters: serum 
iron content, iron total binding capacity (TBC), hemoglobin, hematocrit, the number and diameter 
of red blood cells. The equivalent efficacy of both groups of drugs was confirmed [10]. 
Bioavailability of iron contained in salts and complexes 
Rats 
A comparison of the absorption level was carried out in mature rats which were orally administered 
iron at doses of 5, 25, 50, and 250 μg. The effect of activated erythropoiesis was studied in 50 and 
250 μg dose groups after sampling of 20 ml of blood by venesection two weeks before the 
beginning of the tests. The comparative bioavailability of iron sulfate and iron polymaltose 
complex was evaluated in hemoglobin synthesis processes. Iron from the salt and the complex was 


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equally accessible for hemoglobin synthesis in rats  after venesection, administered a dose of 250 
μg (41.2 and 35.6%) (0.7 < р < 0.6).  In these bioavailability studies in rats, the absorption of doses 
of 5 and 25 μg was evident for salt. However, the differences disappeared after the preliminary 
erythropoiesis stimulation by phlebotomy, as a result of which a dose of 250 μg of iron was 
absorbed with equal efficiency both from the polymaltose complex and ferrous sulfate. Such 
differences are inexplicable, and since salts and high-molecular complexes can use  different 
transport routes in enterocytes, further studies are required to study these mechanisms [11] 
Radioactively marked ferrous sulfate and an iron hydroxide polymaltose complex were used to 
study the mechanisms of iron utilization after oral administration to healthy rats and anemic rats. 
Measurements of the radioactivity of blood serum, compact red cells, whole blood, liver,  kidneys, 
spleen, bone tissue and, in some cases, gastrointestinal tract tissues were performed for doses of 
0.84 to 41.9 mg Fe/kg. No significant differences in bioavailability and ways of iron utilization 
between the two studied drugs were observed. Differences in pharmacokinetic behavior after oral 
administration, especially in non-anemic rats, were confirmed by demonstrating the same level of 
increase in serum iron content after 10–20 times  lower dose of FeSO4  in comparison with the 
iron-polymaltose complex. A significant difference between the two studied drugs is the kinetics 
of serum release and excretion, especially in non-anemic rats. Also, they have a different volume 
of distribution and clearance [12]. 
A comparative bioavailability study of the correlated amounts of iron ascorbate and iron 
polymaltose complex was also carried out in rats. The studies were conducted in healthy animals 
under standard conditions or with insufficient or excessive iron content, which was achieved by  
manipulation with its stores or erythropoietic activity. No significant differences were noted 
between the total amount of iron absorbed from the salt or complex under any of the conditions 
studied, suggesting that the mechanism of regulation of the absorption process at the mucosal level 
is the same for both drugs [13]. 
It was also established that the iron-polymaltose complex and iron sulfate are  equally available 
for the hemoglobin recovery process. The 12-week study demonstrated by evaluating serum 
ferritin levels that the recovery of this metal in the body was more effective with ferrous sulfate. 
Effects in iron deficiency anemia 
Experiments in rats demonstrated that the morbidity of animals was associated more with  the level 
of iron deficiency in the body than with a slowdown in hemoglobin synthesis. Pharmacological 
tests were developed to demonstrate the effect of Fe +++ complex in animals with experimentally 
induced iron deficiency anemia. The following three paragraphs provide an overview of these 
tests.  
Rats 
Experiments on the treadmill were carried out in healthy rats and animals with iron deficiency. 
Anemia was compensated as a variable by optimizing the hemoglobin level of all animals to the 
same concentration. At a level of hemoglobin necessary for carrying an adequate load, a significant 
impairment of the ability to run was observed in iron deficient animals in comparison with the 
control. 
Iron therapy helped to restore the deficiency in 4 days. The cytochrome and myoglobin pigments 
concentration, as well as the activity of the processes of oxidative phosphorylation of substrates 
such as pyruvate malate, succinate and alpha-glycerophosphate in mitochondria preparations from 
skeletal muscles in rats with iron deficiency were reduced. A significant increase in the activity of 
only alpha-glycerophosphate phosphorylation alongside with productivity recovery occurred in 
iron-deficient rats receiving iron dextran. 
Another group of authors from UCLA studied the effect of moderate to severe anemia on  
biochemical tissue parameters in adult male rats over time. Having formed 9 groups of Sprague-
Dawley rats, the authors held 8 of them in a state of moderate anemia (8 g of hemoglobin/dL) for 
different periods of time from 3 to 360 days, and one group in severe anemia (4 g hemoglobin/dL) 


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for 30 days. The plasma iron concentration was reduced in the groups of moderate and severe 
anemia  throughout the experiment in comparison with healthy control animals. As a result, the 
following conclusions were made: 1) moderate iron deficiency anemia does not cause a change in 
oxidative and glycolytic activity in skeletal muscles, whereas in severe iron deficiency anemia a 
rapid change in the mitochondrial component of skeletal muscles is observed; 2) blood analysis 
and biochemical study of muscles in the group of  moderate anemia suggest the manifestation of 
hypochromic, microcytic iron-deficient anemia, while in the severe anemia group hypochromic, 
microcytic symptomatic iron deficiency anemia is observed. 
The state of iron deficiency in young rats was obtained by feeding the animals with low-iron food 
for 8 weeks. The lack of iron led to a 50% decrease in the activity of cytochrome C, cytochrome 
oxidase and a 26% decrease in mitochondrial glycerol-3-phosphate dehydrogenase activity in 
skeletal muscles. The respiratory capacity of the muscle homogenates was reduced by 55%. After 
8 days of iron administration, the respiratory capacity, activity of cytochrome C,  cytochrome 
oxidase, and glycerol-3-phosphate dehydrogenase were approximately 50% closer to normal.  The 
maximum level of oxygen consumption with a limb muscle contraction, on average, was 8 μmol 
O2 / (min * g) in the control; 4.3 μmol O2 / (min x g) in the iron deficiency group and 6.2 μmol O2 
/ (min * g) in the 8-day iron balance recovery group. The level of muscle fatigue after 10 minutes 
of stimulation was higher in the iron-deficient group. Lactate concentration in the red musculature 
after stimulation was also higher in iron-deficient rats  compared to the control. The levels of 
muscular fatigue and lactate response by 50% returned to normal after 8 days of iron therapy. The 
investigators concluded that the lack of iron in the body leads to a decrease in the  activity of 
aerobic metabolism in the skeletal muscles, resulting in  increased susceptibility of the muscle to 
fatigue [17].                                                                                                                                                       
Sheep 
A rapid increase in the mass of red blood cells was noted with intra-amniotic administration of 
iron to the progeny of anemic sheep. This study tested the hypothesis that with the daily intra-
amniotic administration of iron preparations to non-anemic sheep, in  conjunction with 
intravascular injections of erythropoietin, the production of erythrocytes is enhanced. In the studies 
nine sheep fetuses were administered 100–120 units of erythropoietin intravascularly  daily in the 
late gestation period in combination with intramuscular injections of 10 mg of iron for 7 days 
(erythropoietin low-dose group). Four more fetuses received daily 1000 units of erythropoietin and 
10 mg of iron for the same period of time (erythropoietin high-dose group). The answers were 
compared with the indices of 9 control fetuses not receiving drugs. The results showed that 
immediately after the administration of erythropoietin, its  concentration increased 25 or 250 times 
in the low and high dose group, respectively. The erythropoietin concentration returned to the 
baseline level 24 hours after the injection. The plasma iron concentration increased in the 
erythropoietin low-dose group, but not in the control or in the erythropoietin high-dose group. The 
reticulocyte index increased in both groups receiving erythropoietin, but not in the control. The 
hematocrit level increased in comparison with the control by day 5 in the erythropoietin low-dose 
group and by day 2 in the erythropoietin high-dose group.  The gas content in the fetal blood did 
not change in any of the 3 groups throughout the experiment. From the above data, it can be 
concluded that, although the daily combined administration of erythropoietin and iron to non-
anemic sheep  leads to a significant dose-dependent increase in the mass of circulating red blood 
cells, this increase has only a slight similarity with the rapid increase in red cell mass following 
the administration of iron to fetuses with anemia caused by bleeding [18]. 
Iron is a natural component of the human body, which makes it one of the vital substances. It is a 
component of hemoglobin, myoglobin and a number of enzymes. Iron of hemoglobin is used to 
transfer oxygen. It is required for the metabolism of catecholamines and the adequate activity of 
neutrophils.  The body contains about 4 g of iron, most of which is contained in hemoglobin. A 
third part of the total iron in the body is stored in the form of ferritin and hemosiderin.  


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The use of iron preparations makes it possible to correct the disturbances of erythropoietic 
disorders associated with iron deficiency. Iron can be in tri- or divalent form. Unlike Fe (II), Fe 
(III) ions form a high-molecular-weight polynuclear iron hydroxide in a weakly acidic medium 
(pH about 2). The iron (III) hydroxide complex with polymaltose is an organic complex with 
trivalent Fe (III), which is an anti-anemic nutritional supplement. 
Experiments showed that there is no difference between the therapeutic activity of iron (II) and 
iron (III), as well as there is no  difference in the bioavailability of iron from salts or complex.  
2.2.2.2 Secondary pharmacodynamics 
In vivo studies 
Effect on the metabolism of Ca, P, and Mg 
Rats 
A group of Spanish authors studied the effect of iron deficiency on the utilization of Fe, Ca, P and 
Mg in rats. In addition to the well-known depletion of iron in the liver, femurs and sternum at low 
hemoglobin concentrations, iron deficiency in varying degrees disrupted the metabolism of Ca, P, 
and Mg. The change in status was not completely restored after the administration of iron, since 
minor signs of anemia in animals persisted by the end of the study. The second purpose of the tests 
was to evaluate the ability of the three iron  compounds (citrate, ferrous sulfate and ascorbate) to 
correct various adverse effects of iron deficiency. After 10 days of treatment with these additives, 
magnesium absorption in iron-deficient rats was still reduced, especially in animals treated with 
iron citrate. Concentrations of hemoglobin reached normal values in all groups; however, the 
serum iron concentration remained low, indicating that iron stores in the body were still depleted. 
Concentrations of iron in the liver and femurs were also low in all groups, regardless of the type 
of additive obtained, compared with the corresponding controls; while iron concentrations in the 
sternum were  significantly increased in all three groups, which indicated the activation of 
erythropoiesis. Concentrations of Ca, P and Mg in the liver reached normal values and normalized 
in the femurs. Only the content of Ca and P remained low when using citrate iron. In the sternum, 
known for high requirements in minerals, the concentration of Ca, P and Mg also increased. The 
obtained data showed that iron is involved in the processes of bone mineralization and, from the 
physiological point of view, has a  beneficial effect on the metabolism of Ca, P and Mg, since its 
deficiency alters the status of these metals. These data also suggest that ferrous ascorbate and 
ferrous sulphate are absorbed more efficiently in the body than iron citrate [19]. 
This study demonstrates that iron deficiency in the body in varying degrees disrupts the 
metabolism of Ca, P and Mg. Iron insufficiency led to a disruption of magnesium absorption, a 
decrease in the calcium concentration in the liver, femurs and sternum, an increase in the content 
of P and Mg in the liver and a decrease in the P concentration in the femurs. 
2.2.2.3 Safety pharmacology 
Despite the fact that the IPC has a wide range of safety, since its acute toxicity is extremely low, 
and the side effects are few, some safety aspects of the drug should be noted. It should also be 
emphasized that, as described below in toxicity studies, the toxic properties of the drug depend on 
its dose, and the occurrence of adverse effects usually also depends on the administered dose of 
elemental iron.  
Irritation of the gastrointestinal tract and abdominal pain, accompanied by nausea and  vomiting, 
after oral intake are associated with astringent action of iron. Other gastrointestinal complications 
include diarrhea and constipation. 
In case of iron overdose, in addition to gastrointestinal complications, such signs of  toxicity as 
cardiovascular disorders including hypotension and tachycardia, metabolic changes associated 
with acidosis and  hyperglycemia, central nervous system (CNS) suppression, which may vary 


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from lethargy to coma, hepatic insufficiency, blood clotting disorders, renal failure, pulmonary 
edema and death may occur [20]. 
Based on the observations made, it can be concluded that outside the overdose and  subject to the 
administration of the proposed therapeutic doses of the drug, the development of adverse 
pharmacological effects or  interaction with traditionally prescribed medications seems unlikely. 
2.2.2.4 Pharmacodynamic drug interactions 
Since iron preparations have been used in medicine for a long time in various dosage forms, such 
as tablets, syrups, drops or solutions for intravenous administration, now there are a lot of clinical 
and nonclinical data on its interactions with other drugs. Most of these interactions are insignificant 
and are mainly of scientific interest. But some interactions lead or can lead to serious 
consequences. Further an overview of the most significant interactions is provided. 
Levodopa 
In the last decade of the last century, more and more scientists have become adherent to the theory 
that iron accumulation and increasing levels of lipid peroxides in black substance are the main 
factors in the  pathogenesis of Parkinson's disease. Even L-DOPA, which is widely used for the 
treatment of parkinsonism, undergoes autoxidation (like dopamine), resulting in the generation of 
reactive oxygen molecules. In one study of the Lee group from the clinic in Mount Siani in New 
York, the processes of lipid peroxidation in brain homogenates of mice were investigated. At the 
same time, the effect of iron (5 μmol ADP-iron), L-Dopa, dopamine, and  ascorbic acid was 
investigated both in mono-administration and in the administration of mixtures. Activation of lipid 
peroxidation in brain homogenates took place under the influence of ascorbic acid or iron or both, 
which corresponded to other reports. The effect of L-DOPA was complex: L-DOPA powerfully 
suppressed lipid peroxidation, both in the presence and in the absence of ADP-iron. However, 
when L-DOPA was added in combination with ascorbic acid, no peroxidation suppression was 
observed, but an obvious peroxidation stimulation was observed after the addition of L-DOPA and 
ascorbic acid and iron. Deferoxamine, a potent iron chelator, largely suppressed lipid peroxidation 
under any conditions [21]. 
Ciprofloxacin and ofloxacin 
The purpose of the recent study by Rodriguez et al. was to evaluate the effect of  aluminum and 
iron on the dissolution kinetics of ciprofloxacin and ofloxacin in vitro and the importance of such 
in vitro data to predict  changes in in vivo absorption processes under the influence of factors such 
as those often recorded in vivo interactions between quinolones and cations. The results revealed 
significant changes in the dissolution profiles of these quinolones in the presence of cations, in 
particular Fe ++, which reduced  the maximum amount of dissolved ciprofloxacin and ofloxacin by 
34.7% and 29.1%, respectively. Al3+ also caused a decrease in the total amount of dissolved 
quinolone, but it was less evident than Fe2+ [22]. 
Tetracyclines 
A colorimetric test with siderophores found that three drugs of the tetracycline series (tetracycline, 
doxycycline and minocycline) are  iron chelators. Determination of the minimum inhibitory 
concentration (MIC) showed that doxycycline activity against the periodontal pathogen 
Actinobacillus actinomycetemcomitans only slightly changed in the presence of excess iron, which 
apparently indicated the saturation of the antibiotic. On the other hand, the MIC of doxycycline 
and minocycline against A.  actinomycetemcomitans was significantly reduced when 
microorganisms were cultured under conditions of iron deficiency compared to high-content 
conditions [23].  
Penicillamine 
The literature data indicate that the trifunctional amino acid D-penicillamine (D-P) causes various 
muscle disorders, the mechanism of which is unknown. The hypothesis of a group of British 
researchers was that such disturbances can also be a consequence of the influence of D-P on the 


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activity of protein synthesis, possibly by changing the metal content in the muscle. Male Wistar 
rats were injected DP intraperitoneally  at doses of 50 and 500 mg/kg body weight. The rats of the 
control group received 0.15 mol/L of NaCl. Twenty-four hours after the administration a decrease 
in protein content in muscle and protein synthesis capacity was noted in skeletal muscles of rats 
treated with D-P (ratio of RNA: protein) fractional protein synthesis levels, synthesis rate per RNA 
unit and synthesis rate per DNA unit. Changes in the metal content included a decrease in the 
concentration of copper, iron  and manganese with unchanged concentrations of zinc and 
magnesium. In the liver, D-P reduced the content of copper and iron, whereas the concentration of 
zinc, magnesium and manganese did not change. These effects of D-P could be direct, as the 
plasma indices of the damage degree of liver (activity of alkaline phosphatase and alanine 
aminotransferase) and kidneys (urea, creatinine and electrolytes content) did not change 
significantly under the influence of D-P [24]. 
The described studies indicate that iron can stimulate lipid peroxidation in the brain, reduce the 
quinolones content and increase the tetracycline MIC. Penicillamine reduces the iron 
concentration in muscles and liver.  
2.2.3 Pharmacokinetics 
2.2.3.1 Analitycal methods 
Not applicable. 
2.2.3.2 Absorption 
On the basis of available literature data, it can be concluded that until now no differences in the 
mechanism of iron absorption in humans and other mammals have been identified. In all studied 
species of animals, the pharmacokinetic features of saturation of the  transport system of water-
soluble iron (II) and (III) preparations were significantly similar. Thus, it can be concluded that 
both rats and people without anemia can be used to assess  the mechanisms of iron utilization or 
absorption [8] 
In vitro studies 
The process of iron absorption consists of two stages. The first step is the transport of iron through 
the villous membranes of the upper sections of the small intestine using specific transporters with 
biologically regulated activity. The second step is the interaction of iron with binding sites on the 
inner side of the  membrane. The activity of their constituents is regulated by the concentration of 
iron itself. When more iron is ingested, absorption can also occur by diffusion, that is, by 
"penetration through the mucous membrane" [25]. 
Rats were shown to have an anatomical gradient of iron transfer. It varies from 27.40 ± 3.29% in 
the duodenum to 0.47 ± 0.19% in the ileum. The corresponding figures in animals whose iron 
content was insufficient or excessive were 45.30 ± 13.19% and 13.20 ± 0.89%, respectively, in the 
upper parts of the small intestine. In addition, with the use of bound small intestine loops in vitro, 
it was demonstrated that the processes of iron absorption in the mucosa, absorption and 
accumulation of intracellular binding proteins are regulated by cytoskeletal inhibitors [14] 
The effect of iron (III) maltol on lipid peroxidation was compared with that  characteristic of iron 
(II) sulphate, lecithin lipisomes, intestinal villi and mitochondrial preparations of the small 
intestine of rats. At a concentration of 100 μmol and higher, iron (III) maltols activated lipid 
peroxidation to a lesser extent than iron (II) sulphate. Maltol by itself can slow the transition of 
Fe3+ to Fe2+. Thus, maltol can be a less toxic alternative to iron (II) salt for oral treatment of iron 
deficiency [26]. 
The level of radioactive iron [59Fe] accumulation in isolated fragments of the small intestine of 
rats in the presence of two hydroxypyrones, maltol and ethylmaltol was compared with that in the 
presence of another iron (III) chelator, nitrilotriacetic acid (NTA). Absorption rates were similar 


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for all three ligands. Saturable absorption kinetics was observed between the iron concentrations 
of 10(-6) M and 10(-4) M. The capture of iron was almost inhibited by metabolic inhibitors. In the 
presence of pyrones at an iron concentration of 10(-4) M and higher, the  absorption kinetics did 
not change by metabolic inhibitors and remained unsaturable. At low iron concentrations (10(-6) 
M), 35–40% of the absorbed metal was in a bound state with proteins, the molecular weight of 
which was similar to ferritin and transferrin. At high concentrations (10(-3) M), most [59Fe] were 
in the fraction with a low molecular weight. The transition of iron (III) to iron (II) can occur on 
the surface of the mucous membrane cells before absorption by the saturable system. Maltol, 
ethylmaltol and NTK can retain iron (III) in solution and transfer it to the endogenous capture 
system. However, hydroxypyrones may be more suitable ligands for orally administered iron  
compounds, since in combination with the latter they do not exert a toxic effect associated with 
the combination of iron (III) and NTA and iron (II) preparations. The study results confirm that 
the iron polymaltose complex is well absorbed and utilized in rats following oral administration. 
The level of absorption increases in anemic animals and is identical with that of ferrous 
preparations. Bioavailability of the drug in the experiments was the same as that of other drugs. 
Containing bivalent and trivalent iron [27]. 
In vivo studies 
Rats and human 
Both experimental animals and human had equal ferrum absorption rate in the wide dose range for 
ferrous salts and iron polymaltose complex (III) under normal conditions. In 5 µg dose, absorption 
level of ferrous sulphate (II) and iron polymaltose complex (III) was: 1.8 ± 0,17 µg and 1.9 ± 0.11 
µg (37.6% and 39.8%), and in 25 µg dose it was: 9.9 ± 1.66 µg and 9.6 ± 1.25 µg (39.7% and 
38.4%), respectively. With the dose increased to 50 µg, absolute values of the absorbed ferrous 
salts  and complex grew to 20.2 ± 3.29 µg and 12.0 ± 1.79 µg (40.4% and 24.0%) (0.001 > р 
>0.005), and with the dose increased to 250 µg, the average level of absorption was  96 ± 9.15 µg 
and 47 ± 5.30 µg (38.4 and 18.8) (0.005 >р>0.001). In animals after venesection following oral 
administration of 50 µg dose the values were as follows: 34.5 ± 1.67 µg and 25.1 ± 1.47 µg (for 
the sulphate and iron complex) (69.1 and 50.1%); and in case of 250 µg dose administration – 103 
±14.09 µg and 89 ± 11.65 µg (41.2 and 35.6%) (0.7<р<0.06). The level of hemoglobin contents 
were comparable. Increase of ferrum absorption activity after venesection can be only associated 
with the decrease of its content in spleen [14]. 
In animal investigations, relative bioavailability of 5 and 25 µg doses was comparable, but with 
the dose increase till 50 or 250 µg of ferrum, statistically significant prevalence of the salt 
compared with the complex was observed, which may have reflected absorption routes of these 
two drugs. The difference disappeared in iron-deficient rats after phlebotomy: in 250 µg dose, iron 
from polymaltose complex was as available for hemoglobin synthesis as from sulphate [14,28]. 
Rats 
Evaluation of pharmakokinetics of ferrous sulphate and iron (III) hydroxide polymaltosate 
complex in rats with and without anemia found discrepancies in serum iron content after 
absorption, invasion and  excretion constants, and volume of distribution of the two drugs. 
Nevertheless, the level of iron absorption and utilization in both drugs was similar. It is obvious 
that ferrous sulphate (II) and iron (III) complex use different absorption and/or distribution 
mechanisms [29].  
Absorption takes place mostly in duodenum and in upper jejunum and progressively weakens in 
distal segments of intestine, [14]but its precise mechanism is not known. Ferritin and 
transferrin can contribute to iron absorption, but there are data on existence of specific iron 
receptors on the surface of villous membrane of gastrointestinal tract, which control iron 
absorption. These receptors and other unknow iron absorption mechanisms may possibly differ 
between the genders before pubescence [30]. 


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In animals with iron deficiency anemia, a trend for absorption of higher amount of  iron is 
observed. This figure is approximately proportional to the level of iron deficiency. In animals 
without iron deficiency, lower percent of this metal is absorbed. Equally significant discrepancies 
were detected in respect of supplements containing FeSO4. 
A group of scientists from University of California, Berkeley studied in detail the patterns of 
stimulating doses recommended  by World Health Organization, supplements containing FeSO4in 
Sprague Dawley male rats with iron deficiency and normal iron content. During 12 days after 
weaning, animals were treated less than 20 (iron-deficient group) or 400 microgram (normal iron 
content group) of Fe twice a day before feeding, followed by feeding with Fe-free feed AIN-76 
during 1 hour. After that, each group (both iron-deficient and normal) was divided into three more 
groups, one of them continued initial diet, two other groups received 4000 microgram of Fe each 
before meals on a daily basis or every 3 days, i.e. according to frequency of regeneration of gut 
lining. During the experiment, evaluation of food consumption, hemoglobin concentration and the 
level of absorption and losses of   59Fe was carried out. Anemia, low appetite and growth 
impairment were observed in rats with iron deficiency. The level of iron absorption was sustainable 
in the normal group (34.2%), the group of deficiency (89.7%) and the normal group regularly 
receiving a supplement (9.5%). Absorption activity reduced logarithmically in rats receiving iron 
on a daily basis, whereas in animals with iron deficiency receiving iron alternatively, absorption 
level decreased slowly and linearly. The degree of iron loss was high in rats receiving the metal 
on a daily basis. Total level of iron content during 13 days in normal and deficient rats receiving 
a supplement alternatively was 62% and 86%, respectively, of the level identified in animals 
receiving iron on a daily basis. Iron administration correlated with the time of gut lining 
regeneration was more effective [31].  
Heme iron is absorbed actively. Non-heme iron is less available, and its reduced level of absorption 
decreases even more affected by intake of other meals. 
Ascorbic acid in the form of a supplement or taken with food promotes recovery of iron iron to 
iron compounds (II), which activates absorption of non-heme iron [25].  
Wistar male rats weighing 200–220 pounds were used in experiments. Iron was administered in 
two doses: 1.4 mg Fe/kg and 5 mg Fe/kg. Doses of non-organic iron (II) and (III) were 
administered in 1 ml of natural saline solution using a gastric tube. A lower dose of 1.4 mg/ kg can 
be compared with the standard iron dose (for an adult person weighing 70 kg this dose is 
approximately 100 mg or iron). A higher dose of 5 mg/kg corresponded to saturation area of dose-
dependent absorption of glands after single dosing of the drug to rats. The level of iron 
accumulation in animals with the metal deficiency was predictably higher than in healthy ones. 
After administering a lower dose (1.4 mg/kg) to rats with iron deficiency, absorption of the drug 
was 5–14 times more than in normal animals. After administering a higher dose  (5 mg/kg) 
absorption in rats with iron deficiency was 8–10 more than in normal animals [8]. 
Indication and distribution of [59Fe]-ferro-3N-maltol after intravenous administration was studied 
in anesthesized rats. Even after administration of high ferrum maltol doses (containing up to 1 mg 
of elemental iron), immediate dissociation of iron iron from maltol was observed in the blood flow. 
Excretion level of 59Fe and tritium from plasma and their further destiny was different. The half 
life of 59Fе from plasma was about 70 minutes, and its accumulation was mostly in the marrow 
and the liver. Tritium excretion from plasma was initially quick with the half life of 12 minutes. 
Entrance of 59Fе and tritium to blood plasma after the administration of [59Fe]-ferro-3N-maltol to 
duodenum also differed. With low doses of ferrum maltol (100 µg of elemental iron), tritium 
appeared in plasma in maximum concentrations during several seconds, later on its content 
decreased against slow increase of concentration [59Fe]. With higher doses of ferrum maltol (7 mg 
of elemental iron), levels of [59Fe] content in the plasma reached maximum values during 5 
minutes, then reduced against even increase of tritium concentration. [59Fe] processing at the level 
of mucous membrane prevented high iron doses from entering to the circulatory bed [32]. 


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Absorption of 59Fe from ferrum maltol was studied in rats, which were orally pre-administered 
non-radioactive ferrum maltol containing 7 mg of elemental iron during two weeks. The level of 
59Fe accumulation in tissues during 2 hours after administration of radioactive ferrum maltol to the 
stomach was significantly reduced in animals receiving iron beforehand, compared with control 
group receiving natural saline solution. Activity of 59Fe absorption from ferrum maltol in isolated 
ileum fragments and in duodenum was far lower compared with the absorption in small intestine. 
Profiles of plasma tests using gel chromatography in 5 and 60 minutes after intraduodenal 
administration of [59Fe]-ferro-3N-maltol demonstrated that the metal and ligand do not come into 
the circulatory bed in the form of complex even in case of increased permeability of intestinal wall 
[33]. 
Compounds that are natural and synthetic chelators of iron affect the absorption of the latter, and 
some of them can be used in treatment of diseases related to disorder of intestinal iron absorption 
[34]. 
Absorption takes place mostly in duodenum and in the proximal jejunum and progressively 
weakens in distal segments of intestine. However, its precise mechanisms are not known. Animals 
with iron deficiency tend to absorb higher amount of iron, approximately proportional to the 
degree of its deficiency in the body.  
2.2.3.3 Distribution 
Ferrum is distributed in the body bound with transferrin (glycoprotein beta-globuline) and is 
carried in the form of complexes with transferrin to the marrow, where it is included into 
hemoglobin during generation of red blood cells. Iron can circulate in blood only in trivalent form. 
Iron contained in iron (III) hydroxide polymaltosate complex does not bind to albumin or other 
plasma proteins. Small iron excess combines with apoferrin, as a result ferritin is generated, which 
is deposited in mucous cells. About 70% of iron is represented in the form of hemoglobin, 25% is 
contained in the form of ferritin and hemosiderin in iron deposit areas, 0.5% is contained in heme-
containing enzymes and 0.1% is contained in transferrin [1].  
Iron is a natural element playing vital role in many cell processes. The challenge is that iron in 
environment is permanently represented by non-solvable Fе3+-form, which reduces its 
bioavailability for the body, as even small iron concentrations catalyze generation of damaging 
reactive oxygen molecules. As a result, in the course of evolution, live bodies developed the system 
of effective iron absorption and transfer designed to extract iron from the environment, as well as 
ferritins promoting iron accumulation and storage in a non-toxic form. In higher organisms, the 
first membrane barrier is apical surface of duodenum enterocytes, specialized absorbing intestinal 
epithelial cells providing vectorial transport of iron. Initially, iron is transferred into a soluble form 
by means of recovery, and Fe2+ ions are carried through cell membranes assisted by special 
mediators. Afterwards, iron is delivered inside the cell to  basolateral membrane of enterocytes, 
comes through it and binds to blood transferrin in the portal vein system. The second sector of iron 
transport is placentary-fetal barrier transfer through which is performed using the same mechanism 
[35]. 
Three stages of iron absorption are known: 1) entrance to intestinal lumen and transport through 
apical membranes; 2) intracellular processing and transport to basolateral membranes; 3) exit of 
part of iron to the circulatory bed. Some newly identified molecules play vital role in this process. 
DcytB is a de-heme protein belonging to cytochromes b561family, which recovers trivalent ferrum 
ions in intestinal lumen prior to absorption. DMTI is an apical proton transporter of bivalent metals 
cations, providing iron transfer inside the cell. IREGI is a basolateral transporter with multiple 
binding sites, providing further iron transport. One more additional protein, hephaestin, is required 
for basolateral transport and iron binding to tranferrin in the portal vein system. Staying inside the 
cell, iron binds to ferritins, iron deposit protein [35] 


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Iron transport through placenta includes binding of transferrin-saturated iron to transferrin 
receptors on the mother side of placenta, followed by iron release to acid vesicles. Further iron 
transfer to fetus apparently involves DMTI, IREGI proteins and cuprum oxidase (hephaestin), as 
all of them are expressed in placenta [35]. 
In vivo studies 
Mice 
Iron concentration in mouse milk is about three times more than its content in blood serum. Despite 
obvious evidence of the presence of transferrin receptors in mammary gland of the rodent, precise 
mechanisms of iron entry to breast milk are not known. During lactation period, iron content in 
the milk of mice with iron concentration in serum varying from 8 to 66 µmol was linearly 
dependent on the relationship of iron and transferrin concentration in serum. Increase of iron 
content in milk by 340 µmol by means of transgenic lactoferrin administration to mammal glands 
of animals did not affect the nature of dependence between iron content in the milk and relationship 
of iron and transferrin concentration in serum. The ratio of equilibrium distribution of  125I- 
between blood plasma and milk corresponded to 0.2, which demonstrated that transferrin entering 
the milk through transcytosis provided no more than 6% of iron containing in the milk. 
Fluorescent-labeled transferrin after incubation with the mammal gland in situ was located mostly 
near the basal surface of gland alveolar cells. These experiments proved that the initial and speed-
limiting stage of iron transfer to milk is binding to basal transferrin receptor. Theoretical model of 
iron concentrations correlation in serum and milk suggests that affinity of apotransferrin to basal 
recirculation system can exceed the one observed in cells of many other species [36]. 
Rats 
A group of researches from Greece developed an experiment involving assessment of iron content 
in liver, spleen and brain of control rats and rats receiving excessive amount of iron in order to 
analyze iron and transferrin (TF) distribution. Wistar rats received 3% carbonyl iron as a 
supplement during 3 months or during 4 months intraperitoneally or intravenously in the form of 
iron polymaltose complex (total dose was 300 or 350 mg/rat, respectively). Iron concentration was 
evaluated using atomic absorption spectrophotometry, and iron and TF distribution was evaluated 
using histochemical and immunohistochemical methods, respectively. The highest iron content 
was registered in the spleen, followed by liver and brain of control rats.  In case of excessive iron 
intake, iron concentration increased more actively in liver rather than in spleen, its content in brain 
did not change significantly. In liver, iron distributed across Kupffer cell inside the lobes, and 
accumulated in hepatocytes peripherally. No difference between the number of stained cells or 
staining intensity in order to detect TF was identified in liver or central nervous system (CNS) of 
control rats and animals receiving excessive amount of iron; no TF was detected in spleen. 
Centrilobular location of TF in hepatocytes  was reported. In brain, response to TF was positive in 
oligodendrocytes, in vessel walls, in epithelial cells of choroid plexus and in some neurons. Thus, 
experimental iron overdose in rats resulted in activation of iron uptake mostly by 
reticuloendothelial (RE) cells and hepatocytes, which demonstrates exceptional significance of 
hepatocytes in iron metabolism. Activity of iron uptake by brain cells did not change significantly, 
most likely due to brain protection against iron overdose. Excessive iron uptake did not affect the 
distribution and TF content in the liver and CNS, while iron and TF visualization sites did not 
coincide. This fact indicates that TF is not only iron transporter, but also can perform other 
functions. 
Iron is distributed in the body along with transferrin and supplied to the marrow, where it is 
incorporated into hemoglobin. About 70% of iron is contained in the body in the form of 
hemoglobin, 25% is stored up in the form of ferritin and hemosiderin, 4% in the form of myoglobin, 
0.5% in the form of heme-containing enzymes, and 0.1% in transferrin. Normally, maximum iron 
concentration is observed in spleen, followed by liver and brain. In case of overdose, the degree 


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of iron concentration increase becomes higher in liver than in spleen. Iron content in brain does 
not change significantly. 
2.2.3.4 Metabolism 
After absorption and distribution in the body, iron is not exposed to metabolism. 
2.2.3.5 Excretion 
In vivo studies 
Rats 
There is no physiological iron excretion system in the body, it can be accumulated in toxic 
amounts. Most part of iron released during hemoglobin destruction comes to repository or is re-
used in the body. Excretion is carried out mostly during peeling, i.e. during the regeneration of 
skin, gastrointestinal tract mucous membrane, nails or hair. Only trace iron amounts are excreted 
with bile and sweat, excrements and urine. Iron losses increase sharply in case of hemorrhage.  
After absorption in the body, iron is excreted only in minor amounts. Normally, excretion through 
kidney with urine is not significant. Daily loss of 2% of administered dose was reported in rats. In 
relation to total radioactivity of the whole animal losses were about 9%. Three days after the 
excretion of iron dose, the level of excretion of non-absorbed fraction of radioactive 59Fe on the 6 
day was considered as iron absorption activity parameter. No information was available regarding 
gastrointestinal tract, where absorption of radioactive 59Fe was going on.  
Utilization of the same labelled 59Fe compounds 23 days after oral administration was analyzed 
by identification of blood radioactivity. The content of 59Fe in liver reflects the distribution of this 
fraction in the repository of iron administered orally previously [8]. 
 
2.2.3.6 Pharmacokinetic drug interactions 
Pharmacokinetic interactions of iron are mostly associated with the absorption, but can also take 
place at the level of distribution and excretion.  
Heme iron is absorbed actively. Non-heme iron is less available, and low activity of its absorption 
decreases even more affected by food consumed.  
Conditions of A and C vitamins deficiency can affect iron transport, its metabolism and storage in 
the body [38]. Ascorbic acid when taken in the form of supplements or with food, recovers salts 
of trivalent iron to bivalent form, which contributes to the absorption of non-heme iron [25].  
Hypervitaminosis A reduces iron concentration in liver [39].  
Interaction between absorption processes of different metals are known; cadmium inhibits the 
absorption of iron supplied with food in low and normal concentrations [40]; additional iron intake 
significantly blocks cobalt absorption [41]; zinc does not affect iron absorption, but iron reduces 
the activity of zinc absorption, if the total ion content of these metals in food (iron and zinc) reaches 
1.36 mg [42].  
Together with vitamins, iron affects bioavailability of fluorine [43]. 
Natural and synthetic iron chelators affect its absorption, and some of them can be helpful in 
treating diseases related to gastrointestinal iron absorption [34]. Simultaneous prescription of 
deferiprone, the first active oral iron chelator, reduces morbidity and mortality rate in case of acute 
iron overdose [44]. In one investigation [45], simultaneous administration of deferiprone and 
diazepam allowed to reach zero mortality level after acute iron intoxication in rats, while mono-
administration of diazepam only reduced mortality rate from 60% to 16%.  
Vitamin E and selenium being antioxidants also reduced iron concentration in mice hearts after its 
overdose [46]. Selenium also increased the activity of iron excretion with urine [47]. 
Simultaneous oral administration of iron caused significant changes in Pk/Pd of ciprofloxacin 
intravenous dose [48]. 


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Tetracyclines are known for their high affinity to generation of chelate complexes with multivalent 
metal cations such as Fe+++, Fe++, i.e. tetracyclines absorption can reduce by 50–90% and more 
[49]. 
2.2.3.7 Other pharmacokinetics studies 
Not applicable. 
2.2.4 Toxicology 
2.2.4.1 Single dose toxicity 
Mice, IV administration 
After IV administration, toxic effects in mice were studied  by means of histological test of liver, 
kidney, adrenal, lungs and spleen tissues. It was found that toxic effects can be anticipated based 
on chemical properties. The authors divided trivalent iron compounds into two groups: iron 
hydroxide complexes and iron salts. Complexes (sucrose, dextran BP/USP and dextrin) 
demonstrated low toxicity level, as they have shape and structure similar to physiologic ferritin. 
Salts, on the other hand, actively interact with some substances of human and animal bodies, which 
is the reason for multiple adverse effects, with generation of free radicals being the most serious 
of them [50]. 
Rats, oral administration 
Free iron in the circulatory channel is extremely toxic. Comparative studies of oral administration 
of bivalent iron salts and iron polymaltose complex in rats showed that LD100 for salt was 350 
mg/kg, while neither diseases, no deaths of animals were reported after administering the complex 
at doses exceeding 1000 mg/kg [28]. 
During iron LD50 dosing to Wistar rats with food, its pharmacokinetics, concentration at baseline 
and maximum content in serum, as well as mortality rate between genders were compared. 
Prepubescent animals were represented by three-week rats, pubertal rats were represented by 6–8-
week animals, adult rats were represented by 6–8-month animals. Prepubescent female rats died 
far more often than male (р < 0,01), pubertal female rats died significantly earlier than male rates 
(р < 0,04), which was also reported in adult animals (р = 0,02). Iron content in serum at baseline 
did not differ significantly in prepubescent female and male rats, but iron concentration at baseline 
in pubertal female rats significantly exceeded the one in male rats (р = 0,06). After iron dosing, 
concentration peak in serum of female rats was much higher (р < 0,03). Iron absorption mechanism 
is not known completely thus far, and it obviously differs between genders, which can be the 
reason for different metal content in blood serum of male and female rats and different mortality 
rates.  
Rats of different age received 750 mg of elemental iron per kg of body weight, which corresponded 
to LD50 of elemental iron for these animals. 
Statistically significant differences in mortality rate between genders were reported among rats. 
Among prepubescent animals (3-week-old), 16/20 (80%) female rats and 8/20 (40%) male rats (р 
< 0,01) died during 24 hours. Among pubertal rats (6–8 weeks old), 24/40 (60%) female rats and 
14/30 (46,6%) male rats (р = 0,03) died within 24 hours after iron dosing, whereas female rats 
died significantly earlier that male rats. 19 female and 17 male rats died within 10 hours after iron 
dosing (р = 0,04).  
Mortality rate in adult rats (6–8 months old) were the same as in pubertal rats. 19/20 female rats 
and 19/20 male rats died within 24 hours. However, female rats died earlier than male. 16 female 
rats died withing first 2 hours after iron dosing, while only 10 male rats died during the same 
period (р = 0,02). In all groups studied, death occurred during the first 24 hours. Death of animals 
of neither gender was reported in the control group.  


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No statistically significant differences were identified between genders in the iron concentrations 
at baseline. Mean values of ± СО iron content at baseline in female rats were 36±14 (19.4–63.2) 
µmol and in male rats 27.7 ±8.2 (19.4–44.2) µmol/l, respectively.  
6–8-week-old rats initial ± СО iron content in female rats significantly exceeded the one in male 
rats: 47.8±10.8 (in the range of 40–55.6) µmol/l and 34.8±6.6 (in the range of 27.9–39.9) µmol/l 
(р = 0,006), respectively. Comparison of iron content at baseline between genders revealed 
statistically significant differences between female rats of different age groups. For adult female 
rats, iron concentrations at baseline were much higher than those in prepubescent animals (р = 
0,049). This difference was borderly significant in adult and prepubescent male rats (р = 0,06). 
Iron pharmacokinetics after the prescription of 750 mg of elemental iron per kg of body weight 
also differed depending on the gender. Female rats had far more higher peak content of ± СО iron 
(427 ± 468,in the range of 106.1–1582 µmol/kg) than male rats (141.5 ± 188, in the range of 38.6–
805.8 µmol/l; р = 0.003). Iron peak concentration in serum established 60 minutes after the dosing 
to the most of female rats, and as a rule 30 minutes after the dosing to male rats [51]. 
A group of clinicians from Canada carried out Deferiprone test [(1,2-dimethyl-3-hydroxypyrid-4-
on) (L1)], the first active oral iron chelator, in order to use it in clinical trials for patients with 
chronic iron overdose. Its efficacy in the prevention of morbidity and mortality rate in case of acute 
iron intoxication was not studied. The investigation was aimed at the identification of deferiprone 
ability to reduce mortality rate in rats after oral administration of toxic iron doses. Rats received 
612 mg/kg of elemental iron with food, which corresponded to LD58. Concurrently, a group of 
animals received the same oral iron dose, followed by intraperitoneal administration of 400 mg/kg 
of deferiprone (initial dose), then by additional deferiprone dosing of 200 mg/kg, 100 mg/kg and 
100 mg/kg with 1 hour interval. The results showed that simultaneous administration of iron and 
deferiprone reduced the mortality level from 58% (11/19) to 15% (3/20) (р = 0,013). Deferiprone 
prescription was associated with iron excretion with urine (which was not reported in iron mono-
administration) and with the production of red iron complexes with deferiprone. During histologic 
test, less amount of iron was detected in liver and gastrointestinal tract. Consequently, 
simultaneous administration of deferiprone reduced morbidity and mortality rate associated with 
acute iron overdose [44].  
Rats, IV administration 
During intravenous administration of ferrous sulphate and iron polymaltose complex, LD 100 for 
the sulphate was 25 mg/kg of body weight, and no morbidity of mortality rate was identified for 
polymaltose iron in doses exceeding 500 mg/kg [28]. 
2.2.4.2 Toxicity after multiple doses 
Mice, intraperitoneal administration, 4 weeks 
Investigation of chronic toxicity in mice was carried out in order to evaluate iron concentration in 
tissues and the level of free radicals production under chronic iron overdose. Compared with 
placebo-treated control group, mice dosed with iron had rough and discolored wool, and lethargy 
developed with the increase of total dose of chronic load. In placebo control group and among 
mice with the total chronic dose of 100 mg of iron dextran, mortality rate was not reported. 
Mortality rate was 20% and 60% in mice dosed chronically with 200 mg and 400 mg of iron, 
respectively. 
Thus, this investigation showed that chronic iron administration resulted in highly significant, 
dose-dependant increase of iron concentration in tissues and systemic production of free radicals 
(р < 0,001) [52]. 
Rats, oral administration, 3 and 6 months 
In another investigation, iron overdose in liver was used for the induction of its damage during 
long period in order to identify iron ability to induce oval cells. Rats received a diet with 2% of 
carbonyl iron during 3 of 6 months. Repositories of excessive iron appeared periportally in 


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hepatocytes and some Kupffer cells. Pericentrally, iron deposits were less pronounced. Also, small 
oval-like cells, morphologically and immunocytochemically similar to CDE-derived oval cells 
were detected and identified. Initially they appeared periportally, and later on in small ducts and 
lobes close to the central region. They showed positive staining for alpha-fetoprotein, pi-class 
glutathione S-transferase and embroyonic form of pyruvate kinase. These cells contained very 
small amount of iron, and they were classified as iron-free. The main difference of oval cells 
derived from CDE and from cells overloaded with iron was that the latter gave negative response  
during staining for transferrin. This investigation showed that cell changes taking place in iron-
overloaded liver of rats, are similar to those observed in these animals under conditions of hepato-
cancerogenic diet and in rats with chronic exposure to alcohol [53]. 
Gerbilles, subcutaneous administration, 7 weeks 
Cardiotoxicity and hepatotoxicity coupled with hemochromatosis have never been reproduced in 
other species. A group of British researchers managed to obtain severe haemosiderosis strongly 
pronounced in liver and heart by means of subcutaneous administration of iron dextran to gerbilles 
on a weekly basis during 7 weeks. By studying gerbilles 1, 2 and 3 months following the last iron 
injection, they observed consistent development of hemochromatosis in heart and liver of animals 
treated with iron Hemochromatosis development in the form of cicatrix-shaped fibrosis became 
clear in all animals 1–3 months after iron dosing to gerbilles.  Iron content in cardiomyocytes of 
gerbilles gradually increased from 1 to 3 month and led to the development of heart 
hemochromatosis 2–3 months after the last iron dextran injection. Repeated parenteral 
administration of iron dextran to gerbilles led to the development of heart and liver 
hemochromatosis, aspect of which is similar to the one specific for the terminal stage of disease 
in human. This pattern enabled detailed study of the mechanism of iron-induced damage of tissues 
by free radicals, which are considered to be the main reason for the development of such 
impairment. Also it can be useful during evaluation of iron chelators efficiency from the point of 
view of long-term prevention of unhealthy effect of excessive iron on heart and liver [54]. 
2.2.4.3 Genotoxicity 
In vitro studies 
Mutagenic activity of elemental and salt form of iron (Fe) including compounds used nowadays 
as supplements and for food fortification was estimated in mutagenicity tests in Salmonella 
typhimurium strains and mouse lymphoma cells L5178Y. Except for poor response obtained with 
ferrous iron fumarate, neither of compounds caused mutagenic response in experiments with 
salmonella. In test with mouse lymphoma, responses were associated with iron compounds and/or 
with the process of recovery of trivalent iron (Fe3+) to bivalent (Fe2+) iron. Responses of elemental 
iron forms were equivocal. Electrolytic iron with relatively large particles and irregular shape 
provided negative response. Smaller carbonyl iron forms which after 4 hours of incubation bound 
to cells and were absorbed by them, induced mutagenic response with and without S9.  Mutation 
incidence increase was reported with iron iron chloride and phosphate (FeCl3 и FePO4) only in the 
presence of S9. For the compounds of bivalent iron, iron sulphate (FeSO4) and fumarate 
(FeC4H2O4), positive responses were reported in the absence of S9. Iron chelate, sodium 
Fe(III)EDTA gave positive response both with and without S9. For this compounds, minimum 
effective doses (MED) of mutagenicity induction were determined and relation of MED obtained 
was calculated. MED relation varied from 1 for FeSO4 to 30 for carbonyl iron, which corresponded 
to LD50 under oral administration, established in animal experiments [55]. 
Blue asbestos is known to cause cell damage leading to the development of asbestosis, 
bronchogenic carcinoma and mesothelioma in human. The mechanism of asbestos carcinogenic 
activity is not known. In association with asbestos, iron is presumed to act as a catalyst in 
generation of reactive types of oxygen, which can damage DNA causing mutations and cancer. In 
this experiment, asbestos ability to induce mutations in hgprt+ V79 cells of Chinese hamster or 


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transgenic hgprt-, gpt+ V79 cells (G12) was studied. Treatment of µg/cm2 of blue asbestos during 
24 hours caused double increase of mutation incidence in gpt locus of G12 cells, but not in hgprt 
locus of V79 cells. Mutation incidence of gpt locus in G12 cells grew with the increase of blue 
asbestos dose. Mutations induced by blue asbestos were considered to be the result of reactive 
oxygen production catalyzed by iron associated with fibers. This statement was based on the fact 
that during the treatment of G12-cells in iron-free medium containing fibers with active from 
oxidation-recovery point of view iron eliminated using desferrioxamine B, mutation incidence in 
gpt-locus did not exceed the level reported in non-treated control. Besides, cell treatment with 
soluble iron in the form of 1.5 M iron iron ammonium citrate caused the increase of the incidence 
of gpt-locus mutation approximately 1.5 times more against the level of untreated G12 cells. 
Whereas, mutation incidence affected by iron iron ammonium citrate did not grow in hgprt locus 
of V79 cells. The authors also studied the effect of nitrogen oxide on the mutagenicity of blue 
asbestos in G12 cells.  When treating G12 cells with blue asbestos at a dose of 3 µg/cm2 in the 
presence of compound being the source of nitrogen oxide, i.e. 200 µmol of diethyl triamine/NO, 
mutation incidence grew till the level exceeding additivity threshold in relation to data obtained 
during mono-treatment with blue asbestos or diethyl triamine/NO. The results obtained suggest 
that the presence of iron and nitrogen oxide can lead to either formation of other reactive mutagenic 
compounds, like peroxynitrite, or, as is the case with nitrogen oxide, to inhibiting of DNA repair 
enzymes promoting increase of mutations amount [56]. 
Ceruleoplasmin (Cp) was found to promote oxidative damage to DNA in vitro, as evidenced by 
the formation of 8-hydroxy-2’-deoxyguanosine and strand breaks when incubated with a cysteine 
metal-catalyzed oxidation system (Cys-MCO) comprised of Fe(3+), O(2), and cysteine as an 
electron donor.  The ability of Cp to induce oxidative DNA damage was blocked by hydroxyl-
radicals arresters, such as sodium azide and mannitol, by metal chelators, like 
diethylenetriaminepentaacetic acid, spin trapping agent 5,5-dimethyl-1-pyrroline-N-oxide 
(DMPO) and by catalase. Caeruloplasmin also caused double increase of mutations in pUC18 lacZ 
gene in the presence of Cys-MCO, which was measured as the loss of ability for alpha-
complementation. Cp incubation in the presence of Cys-MCO led to the increase of carbonyl group 
content and to significant change in ferroxidase activity, as well as proteolytic susceptibility of 
matter. Tests with deoxyribose and salicylate hydroxylation showed that generation of free 
hydroxyl-radicals took place in reaction of Cp with Cys-MCO. Herewith, the release of Cu atoms 
from Cp molecule was observed, and conformational changes of molecule were registered 
according to the change of fluorescence spectrum. Based on the results obtained, activating effect 
of Cp on the induction of DNA damage and Cys-MCO mutagenicity was interpreted as the result 
of active oxygen formation.  This may be referred to free hydroxyl-radicals, which are produced 
in the reaction of free copper Cu2+ released from Cp molecules damaged during oxidizing, and 
from hydrogen peroxide molecules Н2О2 produced by Cys-MCO. Release of cuprum atoms from 
Cp affected by oxidative stress may not only activate the processes of reactive oxygen production, 
but immediately cause cell damage [57]. 
In vivo studies 
We didn't identify descriptions of mutagenic effects in vivo of iron or iron supplements as is. 
However, one investigation by American team of authors describes mutagenic effects of nickel 
and iron combination. 
In this investigation, authors were primarily focused on nickel known as toxic, mutagenic and 
cancerogenic metal posing major threat to the body and environment. Despite the fact that some 
cell targets of nickel were identified, solid amount of data indicate that it can indirectly affect 
DNA, inducing formation of oxidized purines or pyrimidines contributing to the formation of 
promutagenic regions. In the reported investigation, kidney sarcoma induced by nickel sulphide 
(Ni3S2) or Ni3S2/Fe in F344 rats was studied for the presence of transforming mutations in К-ras-
oncogene. In the course of selective oligonucleotide hybridization assay of К-ras oncogene 


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sequences amplificated using polymerase chain reaction, it was found that 1 of 12 basic tumors 
induced by Ni3S2, 7 of 9 basic tumors induced by Ni3S2/Fe contained exclusively GGT→GTT 
activating mutations in the 12 codon. Such mutations correlate with known ability of nickel, in the 
presence of oxidizing agent presented by iron in this case, to catalyze formation of 8-hydroxy-
deoxyguanosine, which in its turn causes dATP misincorporation opposite oxidated guanine 
residue.  Presence of GGT to GTT transversion was confirmed by direct sequencing of Polymerase 
chain reaction products. Absence of transforming mutations as per 13 or 59-61 codons was also 
discovered in the course of sequencing. Additionally, direct correlation between the reduction of 
latent period of tumor and presence of activating ras-mutations was reported. These results showed 
that Ni3S2 can cause transforming mutations in rat  kidney, which is coherent with oxidizing 
properties of nickel. Whereas, iron aggravating the degree of oxidative damage to cells may 
increase the incidence of such transforming mutations [58]. 
2.2.4.4 Carcinogenicity 
Long-term studies 
Carcinogenicity study was carried out in mice species susceptible to carcinogenic substances.  Iron 
polymaltose complex was administered i.m. at a total dose of 180 mg Fe+++/kg compared with 
other organic iron complexes. Only female mice were included into test animal group, with their 
condition being monitored till death, with burnt out tumors, their occurrence rate and latent period 
in comparison with control being registered. Conclusion made on the basis of test results, when 
iron polymaltose complex route of administration provided its complete absorption, was that the 
drug under consideration did not have stimulating effect on the formation of spontaneous tumors.  
Investigation of 400 rats, in the course of which iron (III) polymaltose complex was also 
administered i.m. at a dose of 180 mg/kg, showed no carcinogenic properties in it [59]. 
2.2.4.5 Reproductive and developmental toxicity 
Fertility and early embryogenesis  
It is well known that the deficiency of micronutrients during early embryonic development can 
lead to structural problems and/or embryo death. Recently, the interest in the issue concerning the 
negative influence of slight excess of natural metals on the development of embryo has increased. 
A group of scientists from University of California, Davis suggested a hypothesis that, from the 
point of view of toxic effect, metals with similar physical and chemical properties use similar 
mechanisms for the impact on embryo prior to implantation. In this investigation, they carried out 
analysis of impact of four natural micronutrients (Cu, Mn, Fe, Zn) and 8 non-natural micronutrients 
(Cr, Hg, Pb, V, Al, Ag, Cd, As) on mice embryo development before implantation. Mice embryos 
at bicellular stage were cultivated during 72 hours in the medium containing different 
concentrations of metals (0.05–200  µmol). Differentiation and proliferation of embryo cells was 
evaluated based on the analysis of blastocyte formation and final amount of embryo cells. Both 
natural and non-natural metals were toxic for embryo cells in relatively low concentrations. 
However, contrary to all expectations, similar molar concentrations of redox active natural metals 
were less toxic than of inactive ones in redox reactions of non-natural metals.  This data indicates 
that direct binding of metals to critical sites of membrane and/or with intracellular ligands, 
including proteins and nucleic acids can cause impairment of development or death before 
oxidative damage associated with metals [60].  
Impact of exogenic iron and folate to reproductive function of pigs can be interpreted in two ways. 
Although impact of exogenic iron and folate on the secretion of relevant transport matricular 
proteins has not been previously reported. Twenty breeding pigs (5 animals per group) were 
infused with 1) saline, 2) alpha tocopherol, 3) alpha tocopherol and iron citrate, or 4) alpha 
tocopherol and tetrahydrofolate on the 11 and 14 days of pregnancy. Intravenous administration 
of iron citrate and tetrahydrofolate (р < 0.05) correspondingly increased the content of iron and 


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folate in plasma 6–8 hours after treatment. These manipulations didn't have impact on the content 
of uteroferrin or secreted folate-binding protein in uterus lavage on the 15 day of pregnancy. These 
data allows concluding that production of uteroferrin and folate-binding protein in uterus doesn't 
depend on iron and folate content in plasma, hence it may explain two-way impact of iron and 
folate on the reproduction activity of pigs [61]. 
Embryofetal development 
To study the impact of iron deficiency and anemia on placenta of female parent, analysis of the 
composition and vascularization of placentary labyrinth in rats with limited iron intake was carried 
out. Rats from experimental group were placed under the conditions of limited iron intake with 
food 1 or 2 weeks prior to mating and received such diet during all gestation period. Placenta was 
studied on the 21 day of gestation. Tissue segments were stained with lectin for identification of 
foetal capillars and analyzed using stereological methods. Area density of capillars and total area 
of capillar surface significantly decreased in both experimental groups receiving limited amount 
of iron compared with the control. Total length of capillars was significantly reduced in the group 
of limited iron intake 1 week prior to mating, but not in the limitation group 2 weeks prior to 
mating in comparison with the control. The volume of endothelial cells was increased in both 
experimental groups. There were no significant deviations from the control in terms of foetal 
capillars, volume of mother blood regions or surface area of female parent contact with the embryo. 
The volume of labyrinth, labyrinth tissues and surface area of female parent contact with the 
embryo were increased in 2-week group compared with 1-week. Such changes in the degree of 
placenta vascularization can contribute to growth impairment of the embryo observed under iron 
deficiency [62]. 
Preliminary study was conducted in order to analyze significance of calcium or iron deficiency in 
the diet for the reinforcement of embryotoxic and teratogenic effect of lead administered orally to 
hamsters. Female animals in the experimental group received water containing 0.05% or 0.1% of 
lead acetate and food with insufficient iron or calcium content during several weeks prior to and/or 
during pregnancy. Frequency of embryofetal death and development of abnormal changes in 
embryo significantly increased in offspring of these animals who were born prematurely (on the 
15th day of gestation), compared with offsping of control animals also receiving water with lead, 
but against adequate nutrition [63]. 
Pre and postnatal development (including mother's condition) 
During the perinatal period the brain requires for precisely regulated iron transport system. 
Regulating iron transport proteins 1 and 2 (RITP) are cytosolic proteins that control stability of 
mRNA of two major cell iron transporters – transferrin receptor (TFR) and bivalent metal 
transporter-1 (DMT-1). In the experiment the RITP localization, changes in their perinatal 
expression, and their relationship with TFR and DMT-1 levels in rat brain between postnatal days 
(PND) 5 to 15 were studied. Fixed frozen cerebral tissue 12 micron samples were obtained from 
offspring of Sprague Dawley rats on PND 5, 10, and 15. The samples were visualized under a 20–
1000-power optical microscope to detect diaminobenzidine reaction after incubation with specific 
primary antibodies to RITP-1, RITP-2, DMT-1, and TFR; and universal secondary biotinylated 
antibodies, and tertiary antibodies. The RITP expression was increased parallel with the transport 
protein expression over time. RITP-1, RITP-2, and DMT-1 were expressed partially in choroid 
plexus epithelial cells on PND 5 and 10, and fully on PND 15. RITP-1, RITP-2, and DMT-1 have 
been widely expressed by cerebral vessels and ependymal cells by the PND 5. Glial and neuronal 
expression of RITP-1, RITP-2, TFR, and DMT-1 in cerebral cortex, hippocampus, and striatum 
was increased over time, and these changes included the number of cells and expression intensity 
depending on brain region, cell type, and age. Such changes reported in the course of the RITP 
and iron transporters expression are indicative that various periods of susceptibility to iron 
deficiency or supplementation are attributable to various brain structures [64].  


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Studies in which the offspring (newborn animals) received doses and/or was further 
investigated. 
2.2.4.6 Local tolerance 
Not applicable. 
2.2.4.7 Other toxicity studies 
Not applicable. 
2.2.5 Summary and Conclusions  
Currently iron deficiency is one of the most significant  nutrition concerns in the world.  
Iron has numerous biological functions, and that establishes the significance of the problem related 
to its deficiency. This metal is well-known due to its role in oxygen transportation by the blood. 
Found in hemoglobin that is essential for effective erythropoiesis, iron provides oxygen capture 
by the lungs, its transport, and release in the body.  
Use of oral iron supplements is indicate for prophylaxis and treatment of patients with iron 
deficiency anemia (hypochromic and microcytic) or blood loss. 
Iron also serves as a cofactor of a number of metabolic enzymes (including cytochromes, 
mitochondrial and other oxidative enzymes). Taken orally with food or as a food additive, iron 
penetrates into mucosal cells and is bound to the protein transferrin. Iron protein binding results in 
hemosiderin or ferritin production. Reticuloendothelial system and hepatocytes are the major iron 
storages. Iron flows from transferrin to intracellular sites by means of specific transferrin receptors. 
Transferrin-iron complexes bind to receptors, and the emerging tertiary complex is absorbed by 
receptor-associated endocytosis. With the sufficient iron content is achieved, transferrin receptors 
synthesis is delayed, and ferritin protein production is increased. Absorption is believed to be 
regulated by hematopoietic transcription factor (NF-E2) which determines correlation between 
intestinal transport and erythropoiesis under common control of chromosome gene [6]. 
It is possible to make general conclusions on main processes involved in the iron absorption and 
distribution based on close interrelation between physiology and biochemistry of iron metabolism, 
especially under iron deficiency conditions, in warm-blooded animals, particularly in mammals. 
In both experimental animals and humans, absorption of bivalent iron from ferrous salts and iron 
(III) from polymaltose complex was equivalent quantitatively but took place using different 
absorption and distribution mechanisms. From this point of view, the iron consumption in GI tract 
may be increased through the adherence to common recommendations on composition of meals. 
Pharmacokinetic characteristics of iron were highly similar in all species. From 20 to 30 % of iron 
coming from diet was absorbed in species with iron deficiency, and 3–10 % in the absence of such 
a deficiency.  
Ferrous(III) hydroxide polymaltose complex had a very low acute toxicity. In mice and rats the 
LD50 value was approximately 7,000 μg Fe+++/kg when administered intraperitoneally which 
represents about 2,500 times maximum daily human dose.  
Maximum oral dose was 1.665 mg Fe+++/kg (500 times the recommended human dose). 
Administered at this dose, the drug product did not result in death, gastrointestinal pathologies, or 
have any systemic exposure. Studies showed that the iron polymaltose complex has a wide safety 
profile. In the experimental conditions it was not teratogenic and had no adverse effect on fertility. 
Also it did not initiate any spontaneous tumors. The iron polymaltose complex did not show 
mutagenic effects. 
IPC (tablets, syrup, drops, ampoules for IM and IV administration) is an antianemic drug 
containing the element necessary for the formation of hemoglobin. It has favorable 


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pharmacological and toxicological profiles when used to prevent and treat conditions caused by 
iron deficiency. 
 
2.3 Summary of Clinical Study Results 
Introduction 
This clinical overview is made with reference to  Ferrum Lek chewable tablets and Ferrum Lek 
syrup within the framework of submitting documents to update the internal marketing licence for 
the drug products by the applicant. 
The objective of this report is to provide the accurate and relevant information of iron preparations 
presented in the form of tablets, chewable tablets, and syrup. In particular, a review of recently 
published literature will be performed to provide detailed presentation of new safety and efficacy 
information associated with the above mentioned drug products. Sections in italics will include the 
critical evaluation of the presented data. Various databases were searched for published literature 
to reveal complete and up-to-date information (preferentially, in Medline system). The Summary 
of Product Characteristics (SPC) included in this application was drawn up by the applicant. The 
document does not contain any new significant information to be included in the approved version 
of the SPC. All publications cited are listed in Section 15 – References. 
2.3.1 Product Development Rationale 
Each Ferrum Lek ® chewable tablet contains 100 mg of iron(III) hydroxide polymaltose complex 
(IPC). Each 1 mL of syrup contains 10 mg of iron(III) hydroxide polymaltose complex (IPC). Each 
5 mL of syrup (1 measuring spoon) contain 50 mg of iron(III) hydroxide polymaltose complex 
(IPC).  
Iron can be used in various forms of administration. Oral administration is the safest and cheapest 
one, and results in lower number of complications [65]. Oral ferrous fumarate, sulfate, gluconate, 
and polysaccharide iron complexes are commercially available, and prescribed for prevention or 
treatment of iron deficiency. 
Ferrum Lek ® chewable tablets and syrup are clinically tested medical products aimed for the 
prevention and treatment of iron deficiency unless there is iron malabsorption in the 
gastrointestinal tract. The listed drug products contain the non-ionized iron that is well-tolerated 
and typically does not cause adverse events. 
Chemically a polynuclear iron(III) hydroxide core is surrounded by non-covalently bound 
polymaltose molecules. The total molecular weight of a complex is approximately 50 kDa. 
Therefore, the diffusion of the complex through the mucous membrane occurs 40-times slower 
compared to iron(II) chloride hexahydrate complex. The complex is stable and does not release 
ionized iron under physiological conditions. Structures similar to the physiological protein ferritin 
are formed inside the polynuclear core. Due to this similarity only trivalent iron from the complex 
is extensively absorbed. Iron(III) hydroxide polymaltose complex does not have pro-oxidative 
properties typical for ferrous salts [66,67]. 
The polysaccharide iron complex is brown amorphous powder, very soluble in water and insoluble 
in alcohol.  
The iron(III) hydroxide polymaltose complex is a water-soluble non-ionised macromolecular 
compound of polynuclear iron(III) hydroxide and partly hydrolysed dextrin (polymaltose) 
chemically described as: [Fe(OH)3 (H2O)]n * [C6H10O5]a. Structural formula of the molecule is 
currently unknown [68]. 
Iron deficiency anemia is the most common nutritional problem and clinical condition in the world 
and represents the most progressing iron deficiency. It is characterized by reduced number or 
complete lack of iron storage sites, low serum iron, decreased transferrin saturation levels, and low 


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hemoglobin concentration or hematocrit values. Iron deficiency occurs when the volume of iron 
absorbed from the gastrointestinal system is not enough to meet the body demand due to the low 
amount of the iron that comes from diet, increased need for this metal or chronic blood loss. 
Amount of iron ingested and available for the synthesis of hemoglobin largely depends on patient's 
tolerance to the drug and their adherence to the recommended dosage regimen. The adequate 
therapeutic margin of the IPC used for iron deficiency anemia has been proved during clinical 
practice. 
The iron(III) hydroxide polymaltose complex is used to treat the iron deficiency both for during 
its latency and upon manifestation, as well as to prevent iron deficiency during pregnancy. 
Efficacy in treating iron deficiency and its prevention during pregnancy was proved by controlled 
studies in adults and children. The volume of iron inclusion into body processes associated with 
trivalent iron has been demonstrated to be equal to that of ferrous sulphate, i.e. there was no 
evidence that iron (III) is less effective (slightly less prominent daily increase of hemoglobin 
concentration during first three weeks of therapy with iron(III) hydroxide polymaltose complex 
provided efficiency equal to that of the ferrous sulphate patients in 9 weeks of treatment) [69,70]. 
IPC has a favourable pharmacokinetic profile. The polymaltose complex does not release  ionized 
iron during its pass through the stomach, i.e. on most cases it does not induce gastrointestinal 
conditions. Radioactive iron studies have shown that after taking iron(III) hydroxide polymaltose 
complex the serum iron concentration did not increase as prominently it does after ferrous sulphate 
exposure. Additionally IPC is safe in simultaneous administration of other drug products as it does 
not decrease the iron absorption activity and does not call for interruption of iron therapy [71]. 
The iron deficiency therapy with iron preparations should be continued for several weeks after 
normal values of hemoglobin concentration are achieved in order to replenish the iron stores. 
Ferrum Lek ® Iron(III) hydroxide polymaltose complex is registered as a drug product in the form 
of chewable tablets and syrup in Slovenia since 1994 and 1995, respectively. Iron(III) hydroxide 
polymaltose complex was first synthesized by Vifor (International) Inc. Lek, Ljubljana 
manufactures Freem Lek medicinal products using its own manufacturing process.  
Multiple post-marketing data of observational studies proves that iron(III) hydroxide polymaltose 
complex has a good risk/benefit ratio and is one of the most efficient iron preparations. 
The data suggest that IPC is generally well tolerated. The most frequent adverse events were such 
gastrointestinal tract irritations as abdominal fullness, pressure in epigastric region, nausea, 
constipation, and diarrhea. These reactions are extremely rare, easily tolerated, and transient in 
nature.  
Efficacy and favorable risk-benefit ratio of  iron(III) hydroxide polymaltose complex treatment 
have been shown for 20 years of the preparation (chewable tables and syrup) use in clinical 
therapy. In this report the summary of the results obtained is presented. 
2.3.2 Overview of Biopharmaceutics 
Not applicable. 
2.3.3 Overview of Clinical Pharmacology 
2.3.3.1 Pharmacokinetics 
2.3.3.1.1 Absorption 
Iron is absorbed unevenly and not completely from GI tract; it is mostly absorbed through duodenal 
epithelial cells and partially from the upper small intestine (jejunum) [91].  
Regular absorption of iron from the GI tract maintains functional amounts of the metal, and 
supports a trend of its storing. Drugs with enteric coating and some slow-release medications may 
transport iron outside the duodenum and the jejunum which slows down iron absorption [72]. 


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Iron absorption is a complex process influenced by many factors including route of iron 
administration, dose, presence of iron storage, erythropoiesis activity, and diet. Bioavailability of 
oral iron varies from less than 1% to over 50%, and amount of the metal pool is the major factor 
that regulated iron absorption in GI tract [71,72]. 
About 5–13% of iron coming from diet is absorbed in healthy people, and about 10–30% in 
patients with iron deficiency. In adults, the extent of alimentary iron absorption is about 6% in 
males, and approximately 13% in non-pregnant women of childbearing potential. During 
pregnancy the activity of iron absorption in GI tract increases to compensate tissues growth and 
blood loss during labor. However, the precise extent of such intensification of the absorption is 
not known. The absorption rate in GI tract also increases in patients with iron deficiency. Up to 
60% of therapeutic ferrous iron dose may be absorbed in subjects with iron deficiency; however, 
absorption of inorganic iron is reduced when prescribed together with various food and some drug 
substances. Inorganic iron is known to be absorbed almost twice more actively than the alimentary 
one. Although it is not known exactly what iron form is absorbed, ferrous sulphate absorption is 
considered more effective [72,73]. 
Bioavailability of iron in oral preparations is affected by composition of meals, and amount of the 
metal stored in the body depot. The less the metal stores are, the more active its absorption is.  
The absorption of bivalent iron compounds is more effective compared to trivalent iron 
preparations [65]. Difference in the absorption rates is primarily that in fact the trivalent iron 
compounds are slightly soluble at pH > 3, whilst iron (II) preparations are highly soluble even at 
рН = 7 [66, 67]. Iron (III) and (III) ions form insoluble complexes with some food components 
and drugs that are poorly absorbed. Decreased gastric acid secretion makes iron (II) absorption 
less effective. 
The precise iron absorption mechanism is unknown. However, it is considered to involve two 
mechanisms at the same time. Active transport by enzymes or transporters takes place mainly upon 
intake of normal iron concentrations coming from food. Passive transport starts mainly upon intake 
of iron doses exceeding those of normal diet [74].  
The iron(III) hydroxide polymaltose complex does not release ionized iron during its pass through 
the stomach, i.e. in most cases it does not induce gastrointestinal conditions. Absorption of the 
iron(III) hydroxide polymaltose complex does not require acid environment, making it effective 
in the treatment of iron deficiency anemia in the patients who underwent gastrectomy. 
The radioactive iron studies have shown that the iron serum concentrations increased rapidly 
(within 2–6 hours) after intake of ferrous sulfate.  There was no significant increase in the iron 
content in serum after an iron(III) hydroxide polymaltose complex dose, but iron inclusion in the 
liver was also reported in 28 hours after its administration. However, the volume of iron inclusion 
into body processes was similar for both medicinal products [74,75]. High iron (II) serum 
concentrations after ferrous sulphate administration results in iron-albumin interaction. Thus, the 
ferrous sulphate accumulates in blood, and volume of its inclusion into body processes does not 
increase significantly. To achieve the required absorption activity the ferrous sulphate it should be 
used 2 hours before meals, whereas the iron(III) hydroxide polymaltose complex can be taken 
during or immediately after meals with equal efficacy [75]. 
Absorption of iron complexes with moderate stability, irrespective of metal valency, differs from 
that of stable ferrous salts. Such stable complex as IPC releases iron into the transport system 
actively and directly on mucous surface immediately after passing through the stomach. This 
process is not accompanied by oxidation – recovery reactions with aggressive radicals release, as 
transport proteins can accept only trivalent iron, in the form that is contained in IPC. There are no 
free iron (III) ions as iron of IPC flows directly to an absorption site where iron-binding proteins 
are arranged. Once iron need is met, transport into mucosal cells stops, and IPC is naturally 
excreted from the body. 


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IPC remains soluble at pH 1 to 14 as it has optimised complex stability. It will decompose to trace 
amounts of iron (II) ions during stomach transit, and in the duodenum become available for 
transport. 
A need for replenishment of iron stores provides a number of benefits to IPC as it has better 
tolerability that those known for ferrous sulphate. Such iron may be captured by enterocytes using 
the same mechanism which is used for alimentary iron capture. A similar explanation could justify 
relatively low toxicity of the drug and absence of concerns for its overdose in patients who have a 
pathologic iron accumulation gene expressed. 
2.3.3.1.2 Distribution 
Bivalent iron crosses the cells of the GI tract mucous membrane immediately into the blood and 
binds to transferrin. It supplies iron to the marrow where it is included into hemoglobin.  
If the iron stock sufficient to meet all body needs, most part of iron (70%) is functional. More than 
80% of the functional iron is represented in the form of hemoglobin in erythrocytes, and the rest 
part of it is contained in myoglobin and intracellular respiratory enzymes (the enzymes contain 
less than 1% of all iron stores present in the body). 
Ferritin that is a soluble protein complex is the primary storage of iron (about 70% in males, and 
80% in females) in the body. A lower amount of this metal is deposited as hemosiderin that is an 
insoluble protein complex. Ferritin and hemosiderin are produced primarily by the liver, 
reticuloendothelial system (RES), bone marrow, spleen, and skeletal muscle. Small amounts of 
ferritin also circulate in plasma [72]. 
Iron can circulate in blood only in trivalent form. Iron contained in iron (III) hydroxide 
polymaltosate complex does not bind to albumin or other plasma proteins. 
It binds to blood transferrin the same as iron released during erythrocyte destruction. The excessive 
iron is stocked up in the form of ferritin and hemosiderin in the RES and reused when necessary. 
The transferrin-bound iron can be extracted from the blood using standard laboratory methods. Its 
normal concentrations are highly variable. Morning values exceed evening concentrations. On 
average, about 35% of transferrin is normally saturated with iron. The remaining protein is 
presented in free form and may bind to additional amounts of iron [74]. 
2.3.3.1.3 Metabolism 
Iron metabolism occurs in a basically closed system. Most part of iron released during hemoglobin 
destruction is converted and reused in the body. 
2.3.3.1.4 Excretion 
The human body excretes 0.5–2 mg of iron daily. Sexually mature females and women of 
childbearing potential lose 0.9–1.0 mg and 1.5–2.0 mg of iron per day, respectively. Iron is 
excreted primarily in feces and shedding cells of skin, gastrointestinal mucosa, nails, and hair; and 
only trace iron amounts are excreted with bile and sweat. 
Iron losses increase sharply in case of hemorrhage. 
Radioactive iron studies showed that in sexually mature males and females 8% of the absorbed 
iron is excreted within 1 year, while women of childbearing potential lose up to 20% of iron per 
year. 
2.3.3.1.5 Pharmacokinetic interactions 
As iron contained in iron(III) hydroxide polymaltose complex is completely bound, reducing the 
absorption level insoluble chelates resulting from reactions with food ingredients (such as phytin, 
oxalates, and tannin) and related medicinal substances (tetracyclines, antacids) are not formed 
which happens when ferrous salt preparations are administered. 


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2.3.3.2 Pharmacodynamics 
Iron is contained in molecules of hemoglobin, myoglobin, and a number of such enzymes as 
cytochrome, oxidase. A third part of the total iron in the body is stored in the form of ferritin and 
hemosiderin. In adults, up to 2.5 g of iron can be contained in hemoglobin, 1.5 g in the pool, less 
than 0.4 g in myoglobin, and about 4 mg in transferrin, respectively [72]. 
The recommended daily dose of iron in diet for adults and children older than 12 years should be 
12 mg, for women of non-childbearing potential 10 mg, for pregnant women 30 mg, for women 
of childbearing potential and breast-feeding women 15 mg, and 10 mg for children from 1 to 2 
years old. However, it should be considered that the average level of iron absorption is 10%. 
Standard iron loss is approximately 0.9 mg in adult males and 0.8 mg in adult females, and this 
value is regulated by level of iron absorption from food. Normally the volume of iron absorbed 
and excreted daily should be similar [73]. 
2.3.3.2.1 Mechanism of action 
Iron is present in every cell and has several essential functions. Ionized iron is a component of 
several enzymes that are necessary for energy transfer (cytochrome oxidase, xanthine oxidase, 
succinate dehydrogenase), as well as some compounds that transport and utilize oxygen 
(hemoglobin and myoglobin). Cytochromes transfer electrons inside the cells. Hemoglobin carries 
oxygen from lungs to tissues, myoglobin helps to use and store oxygen in muscles. Iron deficiency 
can affect the aforementioned functions, which results in diseases and death [72]. 
The range of iron deficiency manifestations varies from iron depletion, which doesn't cause any 
physiological changes, to anemia, which leads to dysfunction of some organ systems. Iron pool 
depletion is characterized by the decrease of iron stock in the body, but the share of functional iron 
(for example, within hemoglobin) may stay the same. If patients with iron deficiency have an 
increased need for iron, there is no pool in their body, which could provide iron. Iron deficiency 
is characterized by the depletion of iron stock due to erythropoeisis, which further slows iron 
transport. Absorption in GI tract is not enough to substitute depleted stock or to provide the body 
with necessary iron for growth and functioning. Decrease of iron supply causes production of 
imperfect functional compounds containing iron, including hemoglobin; red blood cells become 
microcytic and hypochromic [73]. 
Pharmacodynamic action means iron deficiency effect (effect on red blood cells, reticulocyte 
response, hemoglobin recovery, effect on iron pool). 
Iron preparations are used for the prevention and treatment of iron deficiency, but iron doesn't 
correct hemoglobin structure distortion, caused by reasons other than iron deficiency. When such 
preparations are used to treat anemia, which is not related to iron deficiency, it can lead to the 
development of iron-storage disease. 
Iron preparations compensate erythropoietic disorders caused by iron deficiency. Iron cannot 
stimulate erythropoeisis [72]. 
Iron preparations can also help relieve other symptoms of iron deficiency, such as tongue 
tenderness, dysphagia, skin and nails dystrophia, and cracking mouth corners [72]. 
Other effects 
Iron is necessary for vital activity of such microorganisms as bacteria, because minerals are 
important both for the bacterial pathogenicity and their ability to support protective mechanisms 
of the host [72]. 
Due to several reasons, potential consequences of prescribing iron supplements to patients with 
iron deficiency have so far raised doubts. Some patients can be in a risk group for potential 
bacterial infection due to the use of such supplements (iron is also necessary for vital activity of 
microorganisms and can create favourable conditions for bacterial growth). Despite the fact that 
there is no evidence suggesting that small additional amounts of iron can make a healthy person 
more susceptible to infections, there are data demonstrating that in populations with high 


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prevalence of such endemic infections as malaria iron therapy can cause an increase in teh 
incidence of infection complications [76]. However, several studies failed to demonstrate this 
harmful influence [77].  
Iron can be associated with the development of ischemic heart disease due to the modification of 
low-density lipoproteins, which leads to an increase in their atherogenic potential. There is 
preliminary data allowing to suggest that introduction of ferrous sulfate to the diet can increase 
susceptibility of plasma lipoproteins to oxidation; however, no such effect was found when using 
non-ionized iron contained in the polymaltose complex [78,79].  
2.3.3.2.2 Pharmacodynamic interaction 
So far no such interaction has been observed. As iron is bound into complexes, its interaction with 
food components (phytin, oxalates, tannin, etc.) and related medicinal substances (tetracyclines, 
antacids) is unlikely.  
Iron(III)-hydroxide polymaltose complex is practically inert from the point of view of interaction 
with multiple potential food and drug products ligands. This is justified at least in relation to time 
interval necessary for the passage through GI tract; one way or another, substances should preserve 
their ability to react with carrier iron-binding proteins. 
Iron(III)-hydroxide polymaltose complex is safe in coadministration with other drug products and 
it does not lead to lowered the iron absorption activity and interruption of iron therapy [71]. 
Iron(III)-hydroxide polymaltose complex neither exerts oxidative stress, nor interacts with food 
components. Moreover, it was shown that administering this complex with a meal helps to increase 
the volume of absorbed iron.  
Laboratory Changes 
Although it was demonstrated in vitro that ferrous sulfate provokes false-positive reaction in fecal 
occult blood test, such effects are not revealed in vivo in patients receiving oral iron therapy (it 
might be due to in vivo iron being excreted with stool in the form of non-reactive insoluble 
precipitates).  
Results of fecal occult blood test (hemoglobin test) are not altered, which makes it possible to 
continue treatment without interruption at the time of the test. 
IPC is effective in the treatment of iron deficiency anemia (IDA). It can be taken with meals, which 
promotes patient compliance. IPC is known to have a pathway into red blood cells closely 
resembling that of alimentary iron, i.e. it is expected that when the pool is overfilled, absorption 
will slow down due to the switching of physiological mechanisms. Therefore, an assumption can 
be made that this drug product may play a potentially significant role in long-term supplementary 
therapy. 
Low incidence of several adverse effects is favourable for prescribing IPC to patients susceptible 
to these effects and not eligible for fast iron recovery. 
It was demonstrated that IPC is a highly bioavailable drug, which is well tolerated for long periods 
of time and is associated with minimum adverse events. Such observations are tremendously 
important for the iron therapy in general and in patients in particular, especially in the pregnant.  
Based on the compatibility evaluation, we may conclude that oral iron(III)-hydroxide polymaltose 
complex can be coadministered with various medications, which will not alter the absoption of 
iron or other substances.  
Pharmacokinetic and pharmacodynamic data are properly described in the Summary of Product 
Characteristics (SPC) submitted by the applicant.  
2.3.4 Review of efficacy 
2.3.4.1 Treatment of anemia (associated with iron deficiency) 
Dose Ranging Studies 


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Iron(III)-hydroxide polymaltose complex was tested in a group of 113 children aged 6 to 48 
months with iron deficiency anemia. It was prescribed for the period of 90 days at a daily dose of 
2.5 mg/kg body weight with a meal or in the fasting state. A significant increase in hemoglobin 
concentration, HTC, and RBC count was noted in both groups [70]. 
Replacement therapy of iron deficiency anemia was based on iron preparation at a daily dose 2.5 
to 4 mg/kg body weight [73]. 
Controlled studies 
Several clinical studies showed that iron(III)-hydroxide polymaltose complex is highly effective 
in treatment of patients with iron deficiency anemia. The aim of these studies was to demonstrate 
the efficacy and tolerance of iron(III)-hydroxide polymaltose complex or to compare it with other 
iron preparations. 
Several most significant studies are described in Table 1. 
Table 1 Comparative studies of iron(III)-hydroxide polymaltose complex 
Reference 
Design 
Criteria for 
evaluation 
Number 
of 
patients, 
sex, age 
Dose, 
mg/day 
Observation 
period 
Results 
Yakobs P. 
et al., 17 
P, c, r, 
 
Comparison 
to FeSul 
Hb recovery, 
pool recovery 
(ferritin level),  
AE 
159 blood 
donors: 
137F, 22M 
 
32  
(17-64) 
FeSul:  
60 mg/BID 
 
IPC: 
100 
mg/QD 
 
IPC: 
100 
mg/BID 
 
12 weeks 
Recovery of Hb: 
FeSul = IPC (both 
doses) IS 
In 12 weeks, FeSul 
> IPC with 
recovered pool  
AE: FeSul > IPC  
Withdrawal: 
20% FeSul (nausea 
and vomiting) 
0% IPC  
Langstaff 
RJ et al., 5 
D, b, m, 
 
Comparison 
to FeSul 
Recovery of Hb,  
AE 
104:  
90F, 14M 
 
 
 
IPC: 
2 х 100 
mg/QD 
 
FeSul:  
3 х 200 
mg/QD 
9 weeks 
Recovery of Hb: 
FeSul > IPC in 3 
weeks (р = 0.03) 
and in 6 weeks (р = 
0.005) 
FeSul = IPC in 9 
weeks 
AE: FeSul > IPC  
(р = 0.03) 
Bogdanova 
OM et al., 
19 
R, c 
 
Comparison 
to ferrous 
salt 
Recovery of Hb, 
serum ferritin 
level,  
AE 
69 elderly 
patients 
FeSul:  
60 mg/BID 
 
IPC: 
100 
mg/QD 
 
IPC equally 
effective, good 
tolerance 
AE: minimum 
Yakobs P. 
et al., 17 
O, r 
 
Comparison 
to FeSul 
Recovery of Hb, 
serum ferritin 
level, transferrin 
saturation % 
AE 
Blood 
donors 
IPC 100 
mg 
IPC 100 
mg + 0.9 
mol/l GPH 
IPC 100 
mg + 1.8 
mol/l GPH 
FeSul 100 
mg 
12 weeks 
Recovery of Hb:  
IPC = IPC + GPH = 
FeSul; 
 
Serum ferritin: 
FeSul > IPC  
 
AE: 
FeSul > IPC  
Notes. P = prospective; r = randomized; c = controlled; o = open-label; IPC = iron(III)-hydroxide polymaltose 
complex; FeSul = ferrous sulfate; AE = adverse events; IS = insignificant; Hb = hemoglobin; BID = bis in die; QD = 
quaque die; p = likelihood; d = double; b = blind; m = multicenter; GPH = glycerophosphate. 


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Table 2Non-comparative studies of iron(III)-hydroxide polymaltose complex 
Reference 
Design 
Criteria for 
evaluation 
Number 
of 
patients, 
sex, age 
Dose, 
mg/day 
Observation 
period 
Results 
Andrade J. 
et al., 6 
D, b, m, 
 
 
Recovery of Hb, 
serum ferritin 
level 
113 
children 
IPC: 
Syrup, 50 
mg 
 
6 months to 4 
years 
IPC = IPC taken 
with/without a meal;  
AE: IS in both 
regimens 
 
Notes. d = double; b = blind; m = multicenter; IPC = iron(III)-hydroxide polymaltose complex; IS = insignificant. 
 
Placebo-controlled studies 
All placebo-controlled studies (from Cochrane database) of ferrous sulfate used during pregnancy 
explicitly showed that pregnant women who took iron had substantial iron store in the body, 
increased hemoglobin level, and decreased incidence of iron deficiency anemia compared to 
women who received placebo both during pregnancy and after that. Furthermore, children born of 
mothers who received iron therapy demonstrated increased serum ferritin compared to children 
from the placebo control group.  Women took high doses of iron-containing supplements, 100 to 
200 mg a day [80]. 
In a placebo-controlled efficacy study, 48 men with decreased iron pool volume were prescribed 
iron-containing supplements in the form of ferrous sulfate (180 mg iron a day), iron(III)-hydroxide 
polymaltose complex (200 mg iron a day), or placebo, which helped to demonstrate more 
beneficial action of non-ionized iron(III)-hydroxide polymaltose complex compared to ferrous 
sulfate [79]. 
Studies with active control 
A prospective controlled randomized study of 159 healthy blood donors who developed absolute 
iron deficiency anemia compared action of 120 mg of ferrous sulfate and 100, 200 mg of iron(III)-
hydroxide polymaltose complex. Both iron forms were equally available for hemoglobin recovery 
processes, but after 12 weeks of study it was shown that ferrous sulfate was more effective in iron 
store recovery, which was evident from the results of serum ferritin test. Toxic effects were more 
prominent in ferrous sulfate group, 20% of participants refused to continue therapy because of 
nausea and vomiting. Iron(III)-hydroxide polymaltose complex was associated with fewer 
complications as well as the absence of withdrawals [81]. 
The efficacy of iron(III)-hydroxide polymaltose complex in 126 healthy patients was compared to 
that of ferrous sulfate. It was shown that in ferrous sulfate group the hemoglobin concentration 
increased in 3 and 6 weeks, and in 9 weeks of therapy both groups demonstrated an equal 
hemoglobin concentration [69]. 
In a double blind multicenter study of children aged 6 months to 4 years with iron deficiency 
anemia, iron(III)-hydroxide polymaltose complex was equally effective regardless of 
simultaneous food intake. As far as therapy tolerance is concerned, both groups again 
demonstrated the same results [70]. 
In a comparative randomized study of 69 elderly patients with GI disorders and iron deficiency 
anemia, the efficacy of iron(III)-hydroxide polymaltose complex was compared to the one of 
ferrous salt. The drugs were highly effective in improving the disease course and recovery 
processes in both groups; tolerance of iron(III)-hydroxide polymaltose complex was good, and 
adverse events were minimal [82].  
The only open-label randomized study of blood donors with anemia demonstrated that in 12 weeks 
of observation, iron(III)-hydroxide polymaltose complex and ferrous sulfate provided equal 
amounts of iron to launch the processes of hemoglobin recovery. There was an additional 


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evaluation of glycerophosphate, which was added to iron(III)-hydroxide polymaltose complex to 
activate iron inclusion processes. Increased iron inclusion due to the addition of glycerophosphate 
to the compound was not proven. However, iron(III)-hydroxide polymaltose complex was 
associated with fewer adverse events [86]. 
A more profound assessment revealed the following advantages of iron(III)-hydroxide 
polymaltose complex compared to ferrous sulfate in anemia treatment: a significant increase in 
hemoglobin concentration was noted after three days of IPC use and continued afterwards; it is 
supposed that long-term IPC use, recommended by WHO, will not be associated with toxic effect 
of iron; IPC can be taken with a meal, which does not influence absorption and helps to minimize 
adverse effects of the therapy; as a rule, IPC is well-tolerated, cases of therapy discontinuation or 
refusal are rare [84]. 
2.3.4.2 Prevention of (latent) iron deficiency 
During growth, pregnancy, and breast feeding body needs significantly more iron. As a result, iron 
deficiency values should be carefully monitored within these periods. More than a half of women 
of childbearing age demonstrate a decrease of body iron store. Iron deficiency, which can reach 
1000 mg, can develop during the first pregnancy trimester as a result of foetus development, 
placenta growth, and blood volume increase. During two following pregnancy trimesters iron need 
can increase up to 6.3 mg a day. As a result, most women develop iron deficiency. To prevent iron 
deficiency, in 80-90% of cases it is recommended to take additionally 50-100 mg of iron a day 
[80, 85]. Iron-containing supplements used during pregnancy should be suitable for the prevention 
of iron deficiency development in women.  
A double-blind placebo-controlled study of 81 teenage girls with non-anemic iron deficiency 
demonstrated the improvement of learning abilities and memory due to additional iron intake [86]. 
A long-term observational study was conducted with participation of children who had been 
examined and took iron due to its deficiency since infancy. It was shown that children with severe 
chronic iron deficiency in infancy preserved psychological and behavioral abnormalities compared 
to patients with more than 10 years of treatment [87]. 
Data of controlled studies of iron-containing drugs used for iron deficiency prevention are shown 
in Table 3. 
Table3 Controlled studies of preventive iron use 
Reference 
Design 
Criteria for 
evaluation 
Number 
of 
patients, 
sex, age 
Dose, 
mg/day 
Observation 
period 
Results 
Milman N 
et al., 16 
P, C, c, db 
 
 
Hb recovery, 
IPC advantages 
1277 
40-200 mg 
 
9 weeks – 3 
months 
Recovery of Hb: IPC 
> placebo,  
Serum ferritin level: 
IPC > placebo 
 
Notes. C = Cochrane, db = database; p = placebo; IDA = iron deficiency anemia; Hb = hemoglobin. 
 
2.3.4.3 Other unregistered indications 
A prospective randomized study of blood donors who did not pass the copper sulfate test as the 
criterion for the donation, showed that iron(III)-hydroxide polymaltose complex treatment was 
beneficial for positive balance preservation, which helped to decrease the quantity of ineligible 
donors due to the iron deficiency anemia development after phlebotomy [81]. 
In a randomized double-blind placebo-controlled study, 250 blood donors submitted 2 units of red 
blood cells. Additional use of ferrous sulfate (100 mg) helped to prevent iron store depletion in 
most donors [88]. 


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2.3.5 Dosing 
Dose and treatment duration depend on the level of iron deficiency. 
In iron deficiency manifestation, the treatment takes 3 to 5 months until the recovery of normal 
hemoglobin concentration. After that the therapy should be continued for several more weeks to 
replenish body iron pool [72]. 
In latent iron deficiency, the treatment takes 1 to 2 months. 
Daily dose can be divided into several parts or taken as a single dose.  
IPC chewable tablets should be chewed or swallowed whole and taken with food or immediately 
after food intake. 
IPC syrup can be mixed with fruit of vegetable juices or added to bottles with infant nutrition. It 
should be taken with a meal or immediately after it. A measuring spoon for precise dosing is 
provided. Slightly colored solution does not influence taste or efficacy of the syrup. 
Daily IPC doses recommended for prevention or treatment of iron deficiency are described in 
Table 4. 
Table 4Daily IPC doses for prevention or treatment of iron deficiency 
 
Dosage form 
Iron deficiency 
manifestations 
Latent iron 
deficiency 
Preventive therapy 
Infants  
(under 1 year) 
Syrup 
2.5-5 ml 
(25-50 mg of iron) 
-- 
-- 
Children  
(1-12 years) 
Syrup 
5-10 ml 
(50-100 mg of 
iron) 
2.5-5 ml 
(25-50 mg of iron) 
-- 
Children  
(>12 years) 
Adults and 
breastfeeding 
mothers 
Tablet 
 
Syrup 
1-3 tablets 
 
10-30 ml 
(100-300 mg of 
iron) 
1 tablet 
 
5-10 ml 
(50-100 mg of iron) 
-- 
Pregnant women 
Tablet 
 
Syrup 
2-3 tablets 
 
20-30 ml 
(200-300 mg of 
iron) 
1 tablet 
 
10 ml 
(100 mg of iron) 
1 tablet 
 
5-10 ml 
(50-100 mg of iron) 
Notes. (–) Due to the low dose of iron recommended for these indications tablets and syrup are not traditionally used 
dosage forms. 
 
Children under 12 years 
In case of iron deficiency manifestation in infants under 1 year, treatment starts with 25 mg of iron 
(2.5 ml, ½ of measuring spoon) in the form of IPC syrup with gradual dose increase up to 50 mg 
of iron daily (5 ml, 1 measuring spoon) in the form of syrup. Due to the fact that only very low 
iron doses are indicated for treatment of latent iron deficiency, tablets and syrup are not used for 
such indications. In case of breastfed preterm or underweight infants (less than 2.5 kg), preventive 
daily dose 2-4 mg/kg of iron (but not more than 15 mg) is prescribed at 2 months of age, better at 
1 month. Full-term infants who are not breastfed of partially breastfed should receive preventive 
daily dose 1 mg/kg of iron during the first year of life. 
In the case of iron deficiency manifestation in children aged 1 to 12 years, daily dose should be 
50-100 mg of iron (5-10 ml, 1-2 measuring spoons) in form of IPC syrup. In the case of latent iron 
deficiency, daily dose is 2.5-5 ml (25-50 mg of iron) of syrup. Due to the fact that only very low 
iron doses are indicated for preventive therapy, tablets and syrup are not used for such indications. 
In the case of a sudden early pubescence, the need for additional daily iron intake can increase up 
to 2-5 mg in boys and girls, respectively. 
Children older than 12 years, adults and breastfeeding mothers 


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In the case of iron deficiency manifestation, standard daily dose varies from 100 to 300 mg a day 
(1-3 chewable IPC tablets or 10-30 ml of IPC syrup, 2-6 measuring spoons). In the case of latent 
iron deficiency, daily dose varies from 50 to 100 mg of iron (1 tablet or 5-10 ml of IPC syrup, 1-
2 measuring spoons). Due to the fact that only very low iron doses are indicated for preventive 
therapy, tablets and syrup are not used for such indications. Standard preventive dose for adults is 
60-120 mg of iron a day.  
Pregnant women 
To prevent iron deficiency development during pregnancy additional iron-containing supplements 
should be recommended and prescribed on general or selective basis. As far as nutrition is 
concerned, selective prevention is preferable; women at risk of iron deficiency development are 
detected by means of ferritin in blood test. This approach helps women with adequate iron store 
to avoid excessive therapy, which could be potentially dangerous for 12-13% of heterozygotes and 
0.3-0.5% of homozygotes for HFL gene, which codes hereditary hemochromatosis [92]. 
Preventive use of iron-containing supplements should stat with a dose of 30 mg a day.  
In the case of iron deficiency manifestation, daily dose from 200 to 300 mg a day is prescribed (2-
3 chewable IPC tablets or 20-30 ml of IPC syrup, 4-6 measuring spoons) until the recovery of 
hemoglobin concentration. After that the therapy should continue at 100 mg of iron a day (1 
chewable IPC tablet or 10 ml of IPC syrup, 2 measuring spoons) until the end of pregnancy to 
recover iron pool. 
In the case of latent iron deficiency and its prevention, daily dose from 50 to 100 mg of iron is 
prescribed (1 chewable tablet or 5-10 ml of syrup, 1-2 measuring spoons). 
As far as the increase of hemoglobin concentration is concerned, IPC is almost equally effective 
as ferrous sulfate. Treatment efficacy is also the same regardless of food intake. Moreover, 
simultaneous food intake decreases the amount of adverse effects, which provides adequate 
adherence to recommendations.  
IPC is the most suitable form of therapy for patients who do not need a fast iron store recovery, as 
well as for patients susceptible to adverse GI reactions, such as pregnant women and children. 
Indications included by the applicant into the SPC were proven in clinical studies and comply with 
the current level of knowledge and understanding of the problem.  
2.3.6 Safety review 
Replacement iron therapy based on IPC is usually well-tolerated, much better than other iron drugs 
used for the comparison. Apart from minimal adverse effects profile (minor and temporary) it was 
shown that refusal, interruption, and discontinuation of therapy with IPC are rarely noted 
compared to other iron drugs. There is also no interaction with other medications. There is almost 
no ground for concern about malabsorbtion due to food intake or other drug products. IPC has an 
extended safety profile with minimal risk of accidental overdose. Additional important advantage 
of proposed drug is the absence of teeth coloring when using liquid IPC forms due to their non-
ionic nature [74, 90]. 
2.3.6.1 Adverse effects 
Adverse effects of using oral iron drugs include nausea, vomiting, abdominal pain, diarrhea, and 
constipation. Severity and incidence of such adverse effects depend on the amount of available 
ionized iron. GI toxicity is considered to be the consequence of direct mucous cells involvement 
[91].  
Adverse effects associated with IPC use are, as a rule, minor and temporary. When using chewable 
IPC tablets or syrup, such GI symptoms as abdominal fullness, discomfort in upper abdominal 
cavity, dizziness, constipation, and diarrhea are rare [84]. 


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A double-blind comparative study of 104 patients demonstrated that in the IPC group there were 
less adverse events, and there was a significant difference between patients receiving IPC or 
ferrous sulfate, as far as incidence of indigestion, nausea, and vomiting was concerned. Other 
adverse effects with 10% incidence noted in both therapeutic groups included abdominal pain, 
constipation, headache, and change of stool color [69].  
In a multicenter comparative study of 113 patients (children) aged 6 to 48 months with iron 
deficiency anemia who received 2.5mg/kg of IPC for 90 days with or without food, only 3 patients 
of 113 had an adverse effect associated with iron therapy [70].  
Monitoring of toxic adverse events showed that ferrous sulfate can cause gastric mucosa erosion 
or ulceration. This occurrence was not detected when using iron(III)-hydroxide polymaltose 
complex [68]. 
A randomized controlled study comparing toxicity and adverse effects range related to oxidizing 
action of ferrous sulfate and IPC in children with iron deficiency anemia showed only insignificant 
difference, however, SOD and LDL values were significantly higher in the IPC group [92].  
Data of a comparative study with participation of 25 children with IDA who received IPC or 
ferrous sulfate showed that group there is a suppression of copper and ceruloplasmin metabolism 
in the ferrous sulfate group, whereas the IPC use did not influence the normal activity range of 
these processes [93].  
A randomized study comparing bioavailability of iron(III)-hydroxide polymaltose and ferrous 
sulfate in blood donors with iron deficiency  revealed such adverse effects as nausea and vomiting, 
which were less common in the IPC group. The difference was even more significant due to the 
fact that no donors in the IPC group interrupted the treatment on the grounds of adverse effects 
development [81].  
As far as IPC tolerance is concerned, the drug is tolerated for long periods of time and is associated 
with insignificant minor adverse effects. This observation is especially important for iron therapy 
in the case of certain patients, such as pregnant women, children, and blood donors. 
Effects causing treatment refusal 
None.  
Shifting from oral iron drugs 
If a patient cannot take drugs orally, iron should be administrated intramuscularly or intravenously. 
2.3.6.2 Overdose 
So far there have been no documented intoxication or excessive iron stock events in case of 
overdose, as iron of active substance iron(III)-hydroxide polymaltose complex is not present in the 
body in a free form and does not enter cells through passive diffusion [68]. 
Literature reflects specific issues of iron overdose in children. Most cases of death occur in 
childhood, especially in the age from 12 to 24 months. As little as 1-2 mg of iron can cause death, 
however, lethal cases are usually related to the intake of 2-10 mg. The incidence of iron 
intoxication is defined by its domestic availability, particularly if there are certain supplements left 
after pregnancy. Colorful sugar-containing coating of most commercially available tablets makes 
them look like candy. Therefore, all iron-containing drugs should be kept in child-proof bottles 
[94]. 
2.3.6.3 Local tolerance 
Not applicable. 
2.3.6.4 Contraindications/Precautions 
Ferrum Lek chewable tablets or syrup are contraindicated to patients with hypersensitivity to any 
of the drug components. 


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The drug is contraindicated to patients with excessive iron content or with disorders of iron 
utilization processes (hemosiderosis, hemochromatosis, lead anemia, sideroachrestic anemia, 
thalassemia), as well as with anemia not associated with iron deficiency. 
The drug should not be prescribed to patients receiving repeated blood transfusion.  
IPC should not be prescribed simultaneously with parenteral iron. 
Precautions should be taken in patients with phenylketonuria (Ferrum Lek tablets contain 
aspartame, a source of phenylalanine in an amount equivalent to 1.5 mg/tablet). 
Caution should be exercised in patients with diabetes mellitus. Insignificant increase in iron store 
concentration is associated with a significant increase in glucose homeostasis parameters [95].  
Iron preparations are not used in patients with anemia caused by chronic inflammation or 
malignant neoplastic diseases, as iron is pooled in reticuloendothelial cells. Use of such iron to 
synthesize hemoglobin starts only after the elimination of pathology [96]. 
Oral iron drugs can color feces dark, but this effect is clinically insignificant.  
There is data indicating that additional iron received by children without iron deficiency causes 
growth impairment [97]. 
If oral use of iron drugs was not successful, a possible reason could include incorrect diagnosis, a 
lack of compliance, constant bleeding, underlying infection, malignant neoplasms, liver disorders, 
and iron malabsorption. 
2.3.6.5 Usage during pregnancy and lactation 
Animal studies of efeects on reproduction identified no risk for offsprings. Controlled studies of 
pregnant women after the first pregnancy trimester showed no adverse reactions in mothers or the 
newborns. There is also no data on risk associated with this therapy during the first pregnancy 
trimester, negative influence on foetus is improbable [80]. 
Breast milk contains iron bound to lactoferrin. Only a small amount of iron from IPC complex is 
contained in breast milk; the likelihood of adverse effects in infants is very low. Toxic, 
cancerogenic, and mutagenic action of iron was not proven neither by means of clinical, nor 
epidemiological methods [80]. 
IPC tablets or syrup can be taken during pregnancy only after consultation with a physician.  
2.3.6.6 Paediatric use 
Chewable tablets are not recommended for use in children under 3 years, as there's a risk of 
aspiration. Consequently, young children should receive IPC syrup.  
In the case of children under 12 years, syrup is also a more preferable dosage form than chewable 
tablets, as it simplifies dose selection. 
2.3.6.7 Geriatric use 
In the case of elderly patients with IDA, iron(III)-hydroxide polymaltose complex demonstrated 
high efficiency and good tolerance with minor adverse effects [83]. 
2.3.6.8 Use in patients receiving dialysis 
Multiple studies showed that oral iron therapy is inadequate when treating iron deficiency in 
patients on dialysis. In the case of such patients, intravenous iron administration is preferable [98]. 
2.3.6.9 Influence on the ability to drive and use machines 
No influence. 
2.3.7 Post-marketing data 
Apart from the well-known benefits of iron(III)-hydroxide polymaltose complex, there have lately 
been revealed other therapeutic advantages of such preparations.  


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Iron(III)-hydroxide polymaltose complex is a drug with slow release which enables only small 
amounts of iron to contact duodenal mucosa at a given period of time, increasing absorption and 
GI tolerance of the drug. Therefore, smaller amounts of iron provide the same therapeutic effect 
(compared to other iron drugs), and at the same time patient is ready to adhere to therapy 
recommendations thanks to the decreased amount of adverse effects. The drug demonstrates 
desired safety profile compared to other iron drugs and is suitable for treatment of patients with 
increased sensitivity to GI effects, namely pregnant women and children. It also more convenient 
to store at home, as far as children's safety is concerned, and can be for long periods of time and 
is associated with insignificant adverse effects. Such observations are also important for blood 
transfusion services, where administration of insignificant supplements helps to preserve adequate 
iron pool in the body, maintaining physical and psychological well-being of donors. 
Iron in the form of various drug products is registered in many countries. Ferrum Lek is a iron(III)-
hydroxide polymaltose complex and has a long history of clinical use. Multiple post-marketing 
data of observational studies proves that iron(III)-hydroxide polymaltose complex has a favorable 
risk/benefit ratio and is one of the most efficient iron drugs [69, 70, 81, 82]. 
Despite the fact that the absorption of ferrous sulfate is more effective compared to other iron 
preparations, and daily increase of hemoglobin concentration is more prominent during first three 
weeks of therapy, iron(III)-hydroxide polymaltose complex provides equal efficiency in 9 weeks 
of treatment, whereas the volume of iron involvement into body processes is equal to that of ferrous 
sulfate. 
Ferrum Lek is safe in coadministration with other drug products, which is not associated with the 
decrease of iron absorption. The drug is suitable for treatment of children, pregnant women, and 
elderly patients. 
So far there have been no toxic reactions and overdose cases associated with iron(III)-hydroxide 
polymaltose complex. 
Adverse events described in the SPC represent the range of possible adverse effects properly. Other 
issues related to the drug safety are described just as properly. 
2.3.8 Conclusion of risks and benefits 
All dosage forms of Ferrum Lek drug are indicated for treatment of iron deficiency manifestations 
in infants, children, adults, breastfeeding mothers, and pregnant women. Due to the fact that a low 
iron dose is recommended for treatment of latent iron deficiency in infants under 1 year, as well 
as iron deficiency prevention in infants under 1 year, children, adults, and breastfeeding mothers, 
tablets and syrup are not dosage forms traditionally used for such indications.  
Iron(III)-hydroxide polymaltose complex is characterized by the same therapeutic action and 
safety profile as ferrous sulfate drugs. Conducted clinical studies were comprehensive and 
complied with the requirements of current clinical pharmacology. Not every study described in 
this review complied with the requirements of GCP.  However, it does not affect the results of the 
review. Therapeutic efficacy of IPC seems to be appropriate to recommend this preparation as one 
of the most efficient preparation for additional iron therapy. Furthermore, IPC is a preparation of 
choice in case of high-risk categories of patients, such as preterm or newborn infants, children 
under eight years, and pregnant women, patients with ferrous sulfate intolerance. Cases of 
treatment refusal, interruption, and discontinuation are significantly less common in the case of 
IPC compared to other iron drugs. 
Considering specific features and benefits, IPC drugs can be called a new generation of iron 
therapy.  
Efficacy 


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Based on clinical use and well-controlled clinical studies, it was shown that IPC is a highly 
effective therapeutic drug for treatment of latent and manifesting iron deficiency forms, as well as 
the prevention of iron deficiency during pregnancy.  
Described dosage forms have significant benefits, whereas the safety profile was improved, as iron 
of active substance in iron(III)-hydroxide polymaltose complex is not present in GI tract in a free 
form and does not get absorbed through passive diffusion. 
It was proven that IPC has equal efficacy in iron-replacement therapy compared to ferrous sulfate, 
but it is much better tolerated.  
Safety 
Clinical studies demonstrated IPC safety in treatment of latent and manifesting iron deficiency 
forms, as well as the prevention of iron deficiency during pregnancy. Based on clinical use, there 
is a well-known range of adverse effects associated with the drug; these effects are predominantly 
minor and temporary. In general, chewable tablets and IPC syrup are well-tolerated.  
Symptoms of GI tract irritation, such as abdominal fullness, pressure in epigastric region, nausea, 
constipation, and diarrhea, are very uncommon and present the most prevalent events. Dark stool 
color has no clinical significance. There were no registered toxic adverse effects or acute 
intoxication cases associated with the product.  
Results of fecal occult blood test (hemoglobin selective) do not change when taking the drug, 
which makes it possible to continue treatment without interruption at the time of the test.  
Ferrum Lek chewable tablets are contraindicated to patients with hypersensitivity to any of the 
drug components. The drug is contraindicated to patients with excessive iron content or with 
disorders of iron utilization processes (hemosiderosis, hemochromatosis, lead anemia, 
sideroachrestic anemia, thalassemia), as well as with anemia not associated with iron deficiency 
(hemolytic anemia). 
Due to the low recommended iron dose chewable tablets are not used with children under 12 years. 
Chewable tables should not also be prescribed to children under 3 years, as there is a risk of 
aspiration, which means that these children should take syrup instead. 
Precautions should be taken when prescribing Ferrum Lek to patients with diabetes mellitus or 
phenylketonuria. 
Oral forms of iron therapy should not be prescribed to patients receiving EPO or dialysis for the 
correction of iron deficiency. 
In the case of pregnancy or lactation, IPC tablets or syrup can be taken only after consultation with 
physician. 
Toxic, cancerogenic, and mutagenic action of this drug was not proven neither by means of 
clinical, nor epidemiological tests.  
Oral iron drugs should not be prescribed simultaneously with parenteral forms.  
If oral use of iron drugs was not successful, a possible reason could include incorrect diagnosis, a 
lack of compliance, constant bleeding, underlying infection, malignant neoplasms, liver disorders, 
and iron malabsorption. 
So far there has been no evidence of interaction with other drug products, so interaction with food 
components and accompanying drug products is unlikely.  
Iron therapy should not be prescribed to patients receiving repeated blood transfusion. 
The SPC submitted by the applicant adequately reflects indications for use, dose descriptions, and 
possible risks associated with the use of the product. Adverse effects are described together with 
observations made during clinical studies. 
Latest data support the IPC use for treatment and prevention of iron deficiency in infants, children, 
and pregnant women. 


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2.4 Potential risk and benefit of the investigational drug products 
for the study participants 
List of known adverse events associated with Ferrum Lek® (iron(III)-hydroxide polymaltosate) 
chewable tablets, 100 mg, manufactured by Lek d.d. (Slovenia) as compared with reference 
product Maltofer® (iron(III)-hydroxide polymaltosate), 100 mg chewable tablets (Vifor S.A., 
Switzerland) is present in Sections 2.1.1 and2.1.2, respectively. 
Clinical study will be conducted according to the protocol of theclinical study and the rules of 
Good Clinical Practice (decree of the Ministry of Health of the Russian Federation No. 200n dated 
01.04.2016 "On Approval of Good Clinical Practice Rules", National standard of the Russian 
Federation GOST R 52379-2005 "Good Clinical Practice"), treatment of patients will be conducted 
by qualified healthcare personnel based on current clinical recommendations on treatment of 
patients with IDA. Treatment and examination during the study will be free of charge for the 
patients. Therefore, potential benefit of participating in the study exceeds potential risk of using 
the study and reference products. 
2.5 Description and rationale for the route of administration, 
dosing regimens, and duration of treatment 
The study drugs will be prescribed according to relevant Product Information: 
Ferrum Lek® drug will be used according to the following scheme: 200 mg (2 tablets) with or 
immediately after meal to be taken as a single dose for 84 days. 
Reference product Maltofer® will be used according to the following scheme: 200 mg (2 tablets) 
with or immediately after meal to be taken as a single dose for 84 days. 
2.6 Description of the study population 
Adult patients of both sexes (18 years and older) with IDA and indication of iron therapy. 
2.7 Legal framework for the conduction of clinical study 
This is a protocol of the clinical study planned to be conducted in accordance with principles of 
the Declaration of Helsinki, World Medical Association (adopted at the 18th Assembly of the 
World Medical Association in Helsinki in June 1964, the latest revision adopted by the 64th 
Assembly in Fortaleza in October 2013), the triangular agreement on Good Clinical Practice (GCP, 
ICH E6(R2) dated 09.11.2016), and applicable laws of the Eurasian Economic Union and the 
Russian Federation: 
• Rules for Registration and Expertise of Medicinal Products for Medical Use (adopted by 
Decision No. 78 of the Council of Eurasian Economic Commission dated November 3, 2016); 
• Guideline for Good Clinical Practice of the Eurasian Economic Union (adopted by Decision 
No. 79 of the Council of Eurasian Economic Commission dated November 3, 2016); 
• Federal Law No. 61-FZ "On Circulation of Medicines" dated 12.04.2010 (revision valid from 
January 1, 2017 with latest changes according to Federal Law No. 350-FZ dated July 3, 2016); 
• Federal Law No. 152-FZ "On Personal Data" dated 27.07.2006 (revision valid from July 2017 
with latest changes according to Federal Law No. 148-FZ dated 01.07.2017); 
• Decree of the Ministry of Health of the Russian Federation No. 200n dated April 1, 2016 "On 
Approval of Rules for Good Clinical Practice"; 
• The national standard of the RF GOST R 52379-2005 "Good Clinical Practice". 


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• Government Decree of the Russian Federation No. 714 of September 13, 2010 (with latest 
changes and updates in revision dated October 15, 2014) "Rules for Compulsory Insurance of 
the Life and Health of a Patient Involved in Clinical Trials of a Drug"; 
• Order of the Ministry of Health of the Russian Federation On Approval of the Provision on the 
Ethics Council No. 986n dated November 29, 2012. 
 
3 Study goals and objectives 
3.1 Study purpose 
The purpose of this study is to test the hypothesis of non-inferior efficacy and safety of Ferrum 
Lek® (iron (III) hydroxide polymaltosate), 100 mg chewable tablets (Lek d.d., Slovenia), as 
compared with MALTOFER® (Vifor S.A., Switzerland), in subjects with mild and moderate iron 
deficiency anemia.  
3.2. Study objectives 
Main objective: 
• To assess the non-inferiority of the therapeutic efficacy of Ferrum Lek® 2 tablets daily (200 
mg), via assessing the effect on hemoglobin level in the blood (g/l) after 12 weeks of 
treatment for patients with iron-deficiency anemia of mild and moderate severity compared 
with MALTOFER® 2 tablets daily (200 mg) during the same period. 
Secondary objectives: 
• Assessment of safety of Ferrum Lek® 2 tablets daily (200 mg), compared with 
MALTOFER® 2 tablets daily (200 mg), via the frequency, characteristics, intensity and 
relationship to treatment received of AEs. 
 
4 Study design 
4.1 Primary and secondary evaluated parameters 
Primary efficacy endpoint:  
• Changes in blood haemoglobin level (g/L) after 12-weeks of iron-deficiency anaemia 
treatment, a non-inferiority comparison, as compared with the baseline value (screening visit) 
between Ferrum Lek® and MALTOFER® groups.  
Secondary efficacy endpoints: 
• Absolute values and changes of blood hemoglobin level (g/L) after 4, 8 and 12-weeks of 
treatment in the study groups. 
• Changes in average values of iron metabolism parameters (ferritin, transferrin, percent 
transferrin saturation, serum iron) after 4, 8 and 12 weeks of iron-deficiency anaemia 
treatment, as compared with the baseline value in the study groups. 
• The frequency of response to therapy, determined as an increase in haemoglobin level by 20 
g/L and more after 12-weeks of iron-deficiency anemia treatment in the study groups.  
• Frequency and severity of all adverse events observed during the study therapy in the study 
groups. 


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Safety Measurements 
Safety evaluation will include: 
1) Determination of the total number, frequency and severity of: 
I. 
adverse events (AEs) irrespective of their relation to treatment;  
II. 
AEs related or possibly related to the treatment received;  
III. 
AEs requiring termination of the therapy.  
2) Complaints on digestive system disorders (defined through MedDRA SMQ for the 
corresponding symptoms), considered as related to the study therapy by the investigator, will be 
analyzed separately.  
Descriptive statistics will be used for presentation of the result. Comparison of all AE incidence 
between the study groups will be performed using the Fisher’s exact test or chi-square test 
depending on the number of expected observations per cell (<5 or ≥5), and comparison of intensity  
(and possible causal relationship between the treatment received and the AE) will be performed 
using Cochrane-Armitage trend test for the ordered categorical data. 
3) Changes in laboratory test results (assessed in central laboratory) over time and frequency of 
abnormal test results (according to the normal ranges of central laboratory) will be summarized by 
group and also compared by group using corresponding tests for quantitative data and qualitative 
data (see below). 
4) Changes in vital signs over time and frequency of abnormal physical examination findings will 
be summarized by group and also compared by group using corresponding tests for quantitative 
data and qualitative data (see below). 
Quantitative data will be compared using the t-test or Mann-Whitney test depending on the 
normality of the distribution (which will be tested using Shapiro-Wilk test). 
Qualitative data will be compared using the Fisher’s exact test or chi-square test depending on the 
number of expected observations per cell (<5 or ≥5). 
 
4.2 Study design description and flowchart 
4.2.1 Number of centers and patients 
20 study sites in the Russian Federation will participate in the study; they will treat and monitor 
336 patients. 
4.2.2 Study population 
Study population – 336 adult outpatients of both sexes with diagnosed mild and moderate iron-
deficiency anemia (hemoglobin level below 110 g/L (in men and women), but above 80 g/L), who 
are iron-naive patients. 
4.2.3 Design and treatment description 
Phase III multicenter randomized open-label prospective comparative parallel active-control study 
(in the Russian Federation). Upon signing of the informed consent for participation in the study, 
the subjects will undergo screening for up to 7 days (Visit 0). The eligible and ineligible subjects 
will be randomized into two treatment groups at the ratio 1:1:  
The subjects in the first group (168 subjects) will receive Ferrum Lek® chewable tablets – 2 tablets 
daily (200 mg), during or right after meals; the daily dose should be administered once daily (as a 
single dose). The subjects in the second group (168 subjects) will receive MALTOFER® chewable 
tablets – 2 tablets daily (200 mg), during or right after meals; the daily dose should be administered 


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once daily. Subjects will take the products daily during 12 weeks and fill out a diary (see Appendix 
16.1), where they will register administration of the study drugs and concomitant therapy. 
All subjects will undergo a complete blood count and blood biochemistry. Therapy under 
investigation also includes an interim Visit 2 (Day 29 ± 2), Visit 3 (Day 57 ± 2), and final Visit 4 
(84 ± 2). After the final visit a subject's participation in the study shall be terminated, and further 
treatment shall be performed by an attending physician.  
Study design is depicted in Figure 1. 
4.2.4 Duration of the study 
Total duration of the study will be no more than 12 months and will include subjects recruitment 
(9 months), treatment (3 months) and a Follow-up visit (by phone) 14 days after the end of the 
active therapy period. 
4.2.5 Study type 
Phase III multicenter randomized open-label prospective comparative parallel active-control study 
(in the Russian Federation). Randomization is a measure aimed at minimizing subjectivity due to 
random allocation of subjects. Randomization excludes subjective, as well as unperceived 
allocation of population, which differs significantly from the population of the second group, into 
one group by the Investigator. 
A study of non-inferior efficacy and safety of Ferrum Lek® (iron-III-hydroxide polymaltosate), 
100 mg chewable tablets (Lek d.d., Slovenia), compared to MALTOFER® (Vifor S.A., 
Switzerland), for treatment of mild and moderate iron deficiency anemia in adults, will be 
conducted. 
4.2.6 Study design flowchart 
 
Figure 1 Study design flowchart 
4.2.7 Visit schedule 
After the randomization during Visit 1 subjects will be asked to take the drug daily on their own 
(Ferrum Lek® or MALTOFER®) and make a Visit 2 (day 29 ± 2), Visit 3 (day 57 ± 2), and Visit 
Visit 0 
Ferrum Lek® 
(n = 168) 
Randomization 
n = 336 
MALTOFER®  
(n = 168) 
Visit 1 
Treatment for 12 weeks 
Day 29 ± 2 
Days 
 -7…-1 
Day 1 
Signing of ICF, 
screening 
Day 57 ± 2 
Visit 2 
Visit 3 
Visit 4 
Day 84 ± 2 
Day  98± 2 
Follow-Up Visit 
№2 


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4 (day 84 ± 2). After the last planned visit to the study site, a Follow-up visit (by phone) is to be 
made 14 days after the end of the active therapy period for the registration of delayed adverse 
events (Day 98 ± 2). 
Patients can make unplanned visits at the center, if they need medical intervention, at the discretion 
of an investigating physician. 
Table 5 contains visit and procedure schedule. 
 


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Table 5 Schedule of study procedures   
Study periods 
Screening 
Randomization 
and start of the 
treatment 
Treatment  
 
Visit No. / days  
Visit 0 
Days 
-7…0 
Visit 1 
Day 
1 
Visit 2 
Day 
29±2 
Visit 3 
Day 
57±2 
Visit 4 
Day 
84±2 
Study procedures 
Signing of the informed consent 
Х 
 
 
 
 
Inclusion/non-inclusion criteria 
Х 
Х 
 
 
 
Demographic and baseline data 2  
Х 
 
 
 
 
Vitamin B12 (cyanocobalamin) level 
Х 
 
 
 
 
Vitamin B9 (folic acid) level 
Х 
 
 
 
 
TSH level 
Х 
 
 
 
 
T4 level 
Х 
 
 
 
 
The history of iron-deficiency anemia and 
significant concomitant diseases 
Х 
 
 
 
 
Physical examination, BP and heart rate 
measurement 
Х 
 
Х 
Х 
Х 
Urinalysis 3CL 
Х 
 
 
 
X 
Urine pregnancy test  
Х 
 
 
 
Х 
HIV antibody testing 4CL 
Х 
 
 
 
 
Blood chemistry 5CL 
Х 
 
 
 
X 
Complete blood count 6CL 
Х 
 
Х 
Х 
Х 
Iron metabolism parameters 7CL 
Х 
 
Х 
Х  
Х 
Creatinine index8 
 
 
 
 
 
Randomization 
 
Х 
 
 
 
Start of therapy with the study drugs 
 
Х 
 
 
 
                                                 
 
1 Follow-up visit will be conducted by contacting patient by phone to find out possible AEs. 
2 Date of birth, sex, body weight.  
3 General properties (color, pH, specific gravity, protein) and sediment microscopy. 
4 Except for the subjects with HIV test results obtained within the last 6 months. 
5 Total protein, total and conjugated bilirubin, AST, ALT, alkaline phosphatase, blood creatinine, glucose, CRP.  
6 At screening – hemoglobin, hematocrit, RBC, PLT, WBC, WBC differentiation, ESR. During the Visit 2, 3 and 
final visit – hemoglobin, hematocrit, RBC. 
7 Serum ferritin, serum iron, transferrin, percent transferrin saturation.  
CL – Central laboratory 
8 For males (reference range 90–150 mL/min): 
𝐺𝐺𝐺𝐺𝐺𝐺= 1.23 ∗ ൫140 −𝑎𝑎𝑎𝑎𝑎𝑎 (𝑦𝑦𝑦𝑦𝑦𝑦𝑦𝑦𝑦𝑦)൯∗𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤ℎ𝑡𝑡 (𝑘𝑘𝑘𝑘)
𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 (𝑢𝑢𝑢𝑢𝑢𝑢𝑢𝑢
𝐿𝐿
)
 
 
 
 
For females (reference range 90–130 mL/min): 
𝐺𝐺𝐺𝐺𝐺𝐺= 1.05 ∗ ൫140 −𝑎𝑎𝑎𝑎𝑎𝑎 (𝑦𝑦𝑦𝑦𝑦𝑦𝑦𝑦𝑦𝑦)൯∗𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤ℎ𝑡𝑡 (𝑘𝑘𝑘𝑘)
𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 (𝑢𝑢𝑢𝑢𝑢𝑢𝑢𝑢
𝐿𝐿
)
 
 
 


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Handing out of a subject's diary and fill-in 
instructions 
 
Х 
Х 
Х 
 
Check of a subject's diary completion and 
collection of diaries 
 
 
Х 
Х 
Х 
Keeping a subject's diary  
 
daily 
Accounting and distribution of the study 
drugs 
 
Х 
Х 
Х 
Х 
Compliance analysis 
 
 
Х 
Х 
Х 
Concomitant therapy  
Х 
Х 
Х 
Х 
Х 
Exclusion criteria 
 
Х 
Х 
Х 
Х 
Recording of adverse events 
Х 
Х 
Х 
Х 
Х 
 
 
 


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4.2.8 Study procedures 
4.2.8.1 Collection of complaints, medical history, demographic and anthropometric data 
When collecting history, particular attention is paid to the history of iron deficiency anemia (IDA): 
• Investigator will register primary diagnosis which led to the development of IDA (ICD-
10), if present, as well as the cause and duration of IDA (from the moment of diagnosis). 
Registration of previous IDA treatment with iron drugs or blood transfusion (if applicable); 
• IDA causes, is applicable, should be classified to:  
o Vast blood loss (polymenorrhea, uterine myoma, intrauterine contraceptive, 
abortion, endometrial polyps, menorrhagia of different genesis, hemorrhoidal 
bleeding, nasal bleeding, GI bleeding); 
o Donation; 
o Alimentary iron deficiency; 
o Other (if applicable). 
Patient is asked about previous diseases, concomitant chronic diseases, hereditary issues, social 
habits (smoking, alcohol consumption, drug consumption). History of allergies, previous surgeries 
or traumas, professional history, permanent or periodic drug therapy. A contraception method used 
by the patient is specified; by signing the informed consent, the patient agrees to use one of the 
recommended contraception methods (by the protocol) during the study and 1 month after the 
study completion. 
Primary documents must contain data on the sex, age, race, and ethnicity of the patient. A height 
meter is used to measure the patient's height in centimeters, the weighing scales—body weight. 
The anthropometric examinations will be conducted in accordance with the Health Risk 
Monitoring (EHRM) Recommendation for indicators, international collaboration, protocol and 
manual of operations for chronic disease risk factor surveys, 2002 (European Health Risk 
Monitoring (EHRM), 2002). 
Height should be measured in all the patients (the causes which make the height measurement 
impossible include hair-style peculiarities (e.g., mohawk), patient's refusal to take off a headwear 
(e.g., turban), patient's incapacity to stand, exceedance of the height meter's scale). The height 
meter is a vertically positioned panel with a centimeter division with a sliding horizontal ruler. A 
standard error must not exceed 2 mm. The patient will be asked to take off his/her shoes, thick 
clothes, hairpins, or other hair accessories. The patient must touch a vertical panel with his/her 
hindhead, back, buttocks, calves, and heels (the toes are stuck together). Upper boundary of the 
external ear canal must be at the same level with lower boundary of the orbital cavity (the jugal 
bone). The patient is asked to look forward. If the patient's height exceeds that of the Investigator, 
the latter should use a platform. A height meter's ruler is put on the patient's head, the scale's 
divisions are counted. The height must be recorded while the patient is still standing under the 
ruler. An error must not exceed 0.5 cm. 
The patient's weight must be measured in the morning in the fasting condition, after urination and 
defecation, in the underwear (with further subtraction of an average underwear weight). The 
weighing scales must be horizontally positioned on a solid ground. An error must not exceed 0.2 
kg. If the weight measurement is impossible, the Investigator should not record any values based 
on the patient's claims.  
BMI will be calculated according to the formula: 
BMI = body weight in kg / height in m2 
Rounding to decimals will be done according to the standards of mathematical rounding. 


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4.2.8.2 Assessment of the vital signs 
During the examination before study (screening) and during each visit, systolic and diastolic blood 
pressure, pulse rate must be measured on the non-dominant arm after a 5-minute rest in the sitting 
position. Respiratory rate shall also be measured. 
Body temperature must be measured using the same method (axillary temperature) throughout the 
study. 
4.2.8.3 Physical examination  
Physical examination will be conducted according to the general rules of the propedeutics of 
internal diseases: general visual examination, inspection of the mucous membranes, lymph nodes 
palpation, evaluation of bones and muscles, palpation, percussion, and auscultation of the main 
organ systems (cardiovascular, respiratory, gastrointestinal, urinary systems) will be conducted 
sequentially. 
4.2.8.4 Laboratory tests 
The blood samples for analysis will be collected in the morning, in the fasting state (8–10 hours 
after the last meal) from the cubital vein by a disposable sterile syringe under aseptic conditions. 
Approx. 12 ml of blood are necessary for the test. For the urinalysis patient collects morning 
midstream urine after proper hygiene of perineum. Blood samples for hematology test, blood 
chemistry, as well as urine samples for urinalysis are taken during Visit 0 (screening) and 3. 
Hematology test (hemoglobin level, hematocrit, RBC, PLT, WBC, leucogram, ESR), blood 
biochemistry (total protein, total and conjugated bilirubin, AST, ALT, alkaline phosphatase, blood 
creatinine, glucose); iron metabolism evaluation (ferritin, transferrin, iron transferrin saturation 
percentage, serum iron), and urinalysis (general properties (color, pH, specific gravity, protein) 
and sediment microscopy) will be conducted in Invitro central laboratory. 
Results of hemoglobin measurement must be interpreted according to the classification of WHO 
and A.A. Miterev:  
• Hemoglobin 110-90 g/L – mild anemia; 
• Hemoglobin 89-70 g/L – moderate anemia; 
• Hemoglobin <70 g/L – severe anemia. 
After obtaining blood creatinine results, blood creatine will be calculated using the Cockroft-Gault 
Formula [97]: 
For males (reference range 90– 150 mL/min): 
𝐺𝐺𝐺𝐺𝐺𝐺= 1.23 ∗ ൫140 −𝑎𝑎𝑎𝑎𝑎𝑎 (𝑦𝑦𝑦𝑦𝑦𝑦𝑦𝑦𝑦𝑦)൯∗𝑤𝑤𝑒𝑒𝑖𝑖𝑖𝑖ℎ𝑡𝑡 (𝑘𝑘𝑘𝑘)
𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 (𝑢𝑢𝑢𝑢𝑢𝑢𝑢𝑢
𝐿𝐿
)
 
 
 
 
For females (reference range 90– 130 mL/min): 
𝐺𝐺𝐺𝐺𝐺𝐺= 1.05 ∗ ൫140 −𝑎𝑎𝑎𝑎𝑎𝑎 (𝑦𝑦𝑦𝑦𝑦𝑦𝑦𝑦𝑦𝑦)൯∗𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤ℎ𝑡𝑡 (𝑘𝑘𝑘𝑘)
𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 (𝑢𝑢𝑢𝑢𝑢𝑢𝑢𝑢
𝐿𝐿
)
 
Vitamin B9 (folic acid) and vitamin B12 (cyanocobalamin) blood tests will be done at the screening 
visit to exclude vitamin B12 and folic acid deficiency. 
TSH and T4 blood test will be conducted at the screening visit to exclude thyroid dysfunction. 
HIV antibodies tests will be conducted during screening of patients without the results of HIV test, 
made within last 6 months; samples will be sent to Invitro central laboratory. 
Urine pregnancy test with a dipstick must be performed for all women with the preserved 
childbearing potential at the screening visit (pregnancy test is not necessary for women with 


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documented hysterectomy and/or bilateral ovariectomy and/or tubal ligation, as well as for women 
in postmenopause [with menostasia for more than 1 year, with the corresponding clinical profile]).  
4.2.8.5 Randomization 
Upon signing of the informed consent for participation in the study, the subjects undergo screening 
for up to 7 days. The eligible and ineligible subjects will be randomized into two treatment groups 
at the ratio 1:1, distribution method is described in Section 4.4. 
4.2.9 Visit objectives 
4.2.9.1 Visit 0 (screening, days -7...-1) 
Visit objective: 
• Signing of the informed consent; 
• Assessment of inclusion/exclusion criteria;  
• Collection of demographic and anthropometric data; 
• Collectopn of history of iron deficiency anemia and significant concomitant diseases; 
• Physical examination, blood pressure and heart rate measurement; 
• Laboratory tests:  
o Urinalysis (general properties (color, pH, specific gravity, protein) and sediment 
microscopy);  
o Urine pregnancy test; 
o HIV antibodies test, except for subjects who had an HIV test within last 6 months; 
o Blood chemistry (total protein, total and conjugated bilirubin, AST, ALT, alkaline 
phosphatase, blood creatinine, glucose, CRP); 
o Complete blood count (hemoglobin level, hematocrit, RBC, PLT, WBC, 
leucogram, ESR); 
o Metabolic parameters of iron (serum ferritin and iron level, transferrin, iron 
transferrin saturation percentage); 
o Vitamin B9 (folic acid) and vitamin B12 (cyanocobalamin) blood levels; 
o TSH and T4 blood levels; 
o Calculation of creatinine clearance using the Cockroft-Gault Formula; 
• Evaluation of the concomitant therapy; 
• Adverse events registration. 
4.2.9.2 Visit 1 (randomization / start of the treatment, day 1)  
Visit objective: 
• Assessment of inclusion/exclusion criteria; 
• Randomization; 
• Start of the treatment with the study product; 
• Hand-out of the patient diary (Appendix16.1) and instructions on its completion; 
• Accounting and dispensing of the study product; 
• Evaluation of the concomitant therapy; 
• Adverse events registration. 
4.2.9.3 Visit 2 (continuation of the treatment, day 29±2) 
Visit objective: 
• Physical examination, blood pressure and heart rate measurement; 
• Metabolic parameters of iron (serum ferritin and iron level, transferrin, iron transferrin 
saturation percentage); 


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• Complete blood count (hemoglobin level, hematocrit, RBC); 
• Hand-out of the patient diary (Appendix16.1) and instructions on its completion; 
• Check of a patient diary completion and collection of diaries; 
• Accounting and dispensing of the study product; 
• Evaluation of compliance; 
• Evaluation of the concomitant therapy; 
• Adverse events registration. 
4.2.9.4 Visit 3 (continuation of the treatment, day 57±2) 
Visit objective: 
• Physical examination, blood pressure and heart rate measurement; 
• Metabolic parameters of iron (serum ferritin and iron level, transferrin, iron transferrin 
saturation percentage); 
• Complete blood count (hemoglobin level, hematocrit, RBC); 
• Hand-out of the patient diary (Appendix16.1) and instructions on its completion; 
• Check of a patient diary completion and collection of diaries; 
• Accounting and dispensing of the study product; 
• Evaluation of compliance; 
• Evaluation of the concomitant therapy; 
• Adverse events registration. 
4.2.9.5 Visit 4 (efficacy and safety evaluation, day 84±2) 
Visit objective: 
• Physical examination, blood pressure and heart rate measurement; 
• Laboratory tests:  
o Urinalysis (general properties (color, pH, specific gravity, protein) and sediment 
microscopy);  
o Urine pregnancy test; 
o Blood chemistry (total protein, total and conjugated bilirubin, AST, ALT, alkaline 
phosphatase, blood creatinine, glucose, CRP); 
o Complete blood count (hemoglobin level, hematocrit, RBC); 
o Metabolic parameters of iron (serum ferritin and iron level, transferrin, iron 
transferrin saturation percentage); 
• Check of a patient diary completion and collection of diaries; 
• Accounting and dispensing of the study product; 
• Evaluation of compliance; 
• Evaluation of the concomitant therapy; 
• Adverse events registration. 
 
4.2.9.6 Follow-up visit (Visit 5, day 98 ± 2) 
The follow-up visit is conducted in the form of contact with the patient by phone to determine 
the state of health and the presence of adverse events. This visit is performed 14 days after 
the EOT visit. 
Follow-up visit procedures (by phone): 
• Adverse events assessment. 


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If there are any adverse events, the patient may be invited to the site for an unplanned visit. 
4.2.10 Early study termination 
Sponsor has the right to terminate the study, and the Investigator has the right to stop subjects 
recruitment at any time. In the case of premature closing of the center/study, all completed, as well 
as unused CRFs (including unused pages of partially completed CRFs) and other documents 
(excluding documents, which must be kept in the centre) must be returned to the Sponsor. Study 
materials can be destroyed only with the consent of the Sponsor. 
4.3 Handling of the investigational drugs 
4.3.1 Delivery of drugs to the center 
The Sponsor provides Ferrum Lek® and MALTOFER® to the study site. The Sponsor is 
responsible for manufacture, packaging, labelling, and delivery of drugs, specification of storage 
conditions and drug's shelf-life. Primary and secondary packaging of drugs will contain the label 
"For Clinical Study Only".  
The Investigator or an authorized person will receive the delivery of the investigational products 
at each study site. drugs must be stored in a restricted area, where the temperature corresponds to 
that of storage conditions. Each delivery of drugs must be confirmed by means of acceptance note.  
The Investigator is responsible for the proper drug storage, its administration to the study 
participants and accounting. In the case of violation of drug storage conditions, as well as the 
observation of flaws or damage of investigational drugs or their packaging upon delivery to the 
research center, the Investigator must immediately notify the Monitor of the study. 
4.3.2 Quality complaints 
4.3.2.1 Definitions 
Claims for the investigational drug product (study product and reference product) or medical 
device may include:  
1) 
Claims related to the quality of the product/medical device such as 
• any fault of quality and/or efficacy e.g. change of visual appearance, change of amount, 
damaged tablets/capsules, presence of particulate matter. 
• any fault of the containers and outer packages e.g. surface defect, container leakage, broken 
syringe/plunger, missing contents, device malfunction. 
• any fault of the labeling e.g. missing or illegible label. 
• any falsification of the medicinal product or medical device e.g. suspected product mix-up, 
tampering or counterfeiting. 
2) 
Complaints related to the transportation of the product, such as damaged packaging 
for transport and/or damaged secondary packaging after receipt of the goods, a lack of quantity of 
medicinal product in the packaging for transport, inadequate transport conditions. 
4.3.2.2 Procedure 
In case any of the complaints listed above are detected or information about these complaints has 
been received, the completed Non-conformance Report must be sent to the Sponsor (study 
manager/Clinical Research Manager) within 24 hours. Simultaneously local monitor or CRA of 
the respective study must be informed about the complaint. If possible, a photo of the affected 
material should be attached to the report. Affected material should be retained and stored according 
to the storage conditions label and/or returned to sponsor if requested by the Sponsor. 


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4.3.3 Dispensing and return of drugs 
Investigational products are intended only for the study subjects and must be used according to the 
protocol. 
Investigational products will be dispensed to patients during each visit in the quantities calculated 
until the next visit. Patients will be asked to return all used and unused drug packages to the center 
upon each visit. 
4.3.4 Drug records 
The Investigator or a designated person must keep records of all the drugs in the center during the 
study by means of completing record forms for the drugs provided by the Sponsor. Records of 
investigational drugs will be controlled by the Monitor regularly. 
The Investigator or any designated person will count the number of packages of used or unused 
drugs returned by the patient and enter this data into the record forms for the drugs in CRFs. 
Moreover, CRFs will contain the number of missing visits, investigational product dose changes 
(if any, according to the patient diary). 
4.3.5 Return and destruction of drugs 
Upon completion of the study or in case of early study termination on the part of the study site, all 
unused investigational products and packages of used preparations must be returned to the 
Sponsor. The Sponsor is responsible for the destruction of investigational products. After the 
counting of all the packages of used and unused drugs and control of the packaging labels, the 
Monitor organizes drug shipping to the Sponsor for the following destruction. 
 
4.4 Subjectivity minimization measures 
4.4.1 Randomization 
A randomized open prospective comparative phase III trial in parallel groups with active control 
is planned. 
Randomization is a measure aimed at minimizing subjectivity due to the random distribution of 
the patient. Randomization will exclude the subjective, including unconscious, selection by the 
researcher in one of the patient population groups, which will differ significantly from the 
population recruited in the second. 
Automated randomization lists will be formed, randomization will be carried out through the e-
CRF system with a randomization module. 
Each randomized patient will be assigned a unique number for issuing the drug during the study. 
The patient's number consists of the letter R and the numbers from 001 to 336. The numbering of 
patients does not depend on the research center and is “transparent”. In addition to the number, the 
system will indicate the treatment group to which the patient is distributed. Randomization will be 
stratified by two factors depends on patient’s data (gender and baseline Hb level) entered to the e-
CRF before randomization: 
- 
Gender (male vs female); 
- 
Hb level (80–94 g/L vs 95–110 g/L). 
In order to randomize patients in the e-CRF system, each center will be provided with secure 
access and appropriate training in the use of the system will be provided. 


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The randomization number and name of the treatment group issued by the system. The researcher 
records in the primary documentation and enters information on the randomized patient in the list 
of included patients. The randomization number cannot be changed during the study. 
The drug is given to the patient according to the information on the group of therapy received from 
e-CRF system. Research therapies also cannot be changed during the research process. 
4.4.2 Blinding 
The study treatment is prescribed openly. Blinding within this study is not planned. 
4.5 Dosing schedule for investigational products 
Study product Ferrum Lek® (iron-III-hydroxide polymaltosate), 100 mg chewable tablets (Lek 
d.d., Slovenia), 2 tablets daily (200 mg), during or right after meals; the daily dose should be 
administered once daily. 
Reference product MALTOFER® (Vifor S.A., Switzerland) (iron-III-hydroxide polymaltosate), 
chewable tablets, 2 tablets daily (200 mg), during or right after meals; the daily dose should be 
administered once daily.  
4.6 Dosage form, package and labeling of the investigational 
products 
4.6.1 Dosage form 
Investigational products: Ferrum Lek®, 100 mg chewable tablets (Lek d.d., Slovenia). Dark 
brown round flat tablets with light brown impregnations and a bevel. 
Reference product: MALTOFER® (Vifor S.A., Switzerland) 100 mg chewable tablets. Dark 
brown, round, flat scored tablets with white impregnations. 
4.6.2 Container 
Investigational products: 100 mg chewable tablets. 10 tablets per strip or blister. 3, 5 or 9 strips 
or blisters in a carton pack along with the Patient Information Leaflet. 
Reference product: 100 mg chewable tablets. 10 tablets in polyethylene laminated aluminum foil 
blisters. 1 or 3 blisters per carton pack along with the Patient Information Leaflet. 
4.6.3 Labeling of the study drugs 
This study is open-label, the study site will be provided with the packed drug products 
from the series commercially available.  
 
Each package, in addition to the commercial label with the name, composition, shelf life and drug 
product manufacturer, will be labeled with a sticker containing following information: note "For 
Clinical Trials Only", clinical study protocol number, name and contacts of the study Sponsor and 
Investigational Site, and place for writing patient’ randomization number. 
 
The label should not cover the drug name, active substances, and their strength, shelf life, 
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4.7 Duration of patients participation in the study 
Duration of each patient participation in the study will be not longer than 98 days (including 
screening, 7 days; randomization and treatment, 84 ± 2 days). 
Minimal duration of patients participation in the study: 83 days (on condition of minimally 
acceptable treatment duration and screening duration, 1 day). 
4.8 Rules of termination of clinical study parts or the study on the 
whole 
The study may be terminated on the following grounds: 
1. Upon the Sponsor's initiative:  
a. availability of new toxicological or pharmacological data, or data on SAE which require 
re-consideration of the previous evaluation of the benefit/risk ratio. 
b. AEs incidence or severity require the study termination; 
c. other reasons including administrative ones. 
2. Upon the Investigator's initiative: AEs incidence or severity unacceptably increases risk of 
patients participation in the study. 
3. Upon the decision of the regulatory authorities. 
In the case of early termination of the study, the Sponsor must inform the study site personnel as 
well as regulatory authorities with indication of the reason thereof. 
4.9 Record keeping procedures for investigational drug products 
The study sites will be provided with the investigational product (the study product and reference 
product) in the amounts sufficient for the study completion, taking into account the planned 
number of patients to be screened. 
An authorized study site specialist shall keep a logbook for the drugs where the drugs delivery to 
the study site, dispensing to the subjects, and return of the unused drugs are noted. Storage 
conditions must be also noted. The study drugs may be used for the purposes of this clinical study 
only. 
Authorized representatives of the Sponsor or regulatory authorities may check the drugs log or 
availability of the drugs at stock during the study site audit/monitoring. The drugs must be stored 
under the required conditions in a room with an access for the authorized personnel responsible 
for the drugs dispensing only. 
4.10 Storing and unblinding of randomization codes 
The table with treatment randomization codes will be stored in Sponsor's company, the access to 
this information will be restricted to designated persons. Procedures of unblinding of 
randomization codes are not applicable within this study, as the blinding of treatment groups for 
this study is not planned. 
Randomization plan will be known to the investigating physician, the Principal Investigator, the 
Sponsor, the regulatory authorities (in observation of serious adverse events). 
4.11 List of data registered in Case Report Form (without 
preliminary written or electronic record) and recognized as 
primary data 
All study data will be entered into primary documentation and CRFs. 


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5 Selection and exclusion of patients 
5.1 Inclusion criteria 
Patients will be included into the study, if they comply with the following criteria: 
 
1) 
The signed and dated written informed consent prior to participation in the study. 
2) 
Men and women aged 18 and older (by the time of screening). 
3) 
Outpatients. 
4) 
Diagnosed iron-deficiency anemia, based on two criteria: 
a) 
hemoglobin level below 110 g/L (in men and women), but above 80 g/L, 
b) 
serum ferritin levels below 30 µg/L. 
5) 
Women are eligible for enrollment if they are: 
a) 
 not fertile (i.e., women in postmenopause or after surgical sterilization). 
Surgically sterile women are considered as female subjects with documented hysterectomy 
and/or bilateral ovariectomy and/or tubal ligation. Women in postmenopause are 
considered as women with menostasia for more than 1 year, with the corresponding clinical 
profile, e.g. older than 45 years, in absence of hormonal replacement therapy. However, in 
case of doubt, a blood sample shall be taken, where FSH content shall be above 40 IU/ml, 
and estradiol content – below 40 pg/ml (below 140 pmol/L), in order to confirm 
postmenopause. 
OR 
b) 
fertile, but the result of pregnancy test at screening is negative, and the 
subject agrees to use one of the following contraception methods constantly and properly 
(i.e. in accordance with the approved prescribing information and the doctor's orders) 
during the whole period of participation in the study: 
i) 
Total sexual abstinence  
ii) 
Oral contraceptives (combination drugs containing progestogen, or 
progestogen alone) 
iii) 
Injectable progestogen 
iv) 
Levonorgestrel implants 
v) 
Estrogen-containing vaginal ring 
vi) 
Transdermal contraceptive patches 
vii) 
Intrauterine device or intrauterine system 
viii) 
A male partner has been sterile (vasectomy with documented azoospermia) 
prior to enrollment of a woman, provided that he is the only partner of the female subject. 
For the purpose of this definition, "documented" is related to the result of a subject's 
medical examination by an investigator/responsible person or a subject's past medical 
history review for assessment of eligibility for enrollment, obtained during the interview 
with a subject or from his/her medical records.  
ix) 
Double barrier method: a condom or an occlusive cap (diaphragm or 
cervical/vault caps) with a spermicide (foam/gel/film/cream/suppository). 
5.2 Non-inclusion criteria 
Patients cannot take part in the study if they comply with any of the following criteria: 
1) Administration of any iron-containing drugs during the last 3 months. 
2) History of erythropoietin drugs administration. 
3) Hypersensitivity to iron therapy (both Oral and/or IV administration) and other components 
of the study drugs.  


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4) Hormone therapy (including the use of androgens/anabolic steroids) or administration of 
drugs that inhibit blood formation, less than 3 months before the start of the study. 
5) History of severe allergic reactions or drug intolerance. 
6) Fructose intolerance, glucose-galactose malabsorption syndrome, and sucrase-isomaltase 
deficiency. 
7) Pregnant or lactating women, or women intending to become pregnant during the study. 
8) Failure of iron therapy for iron-deficiency anaemia in a subject's past medical history.  
9) Heme metabolism disorders (e.g., sideroachrestic anaemia, lead anaemia, thalassaemia). 
10) Iron overload including haemochromatosis and hemosiderosis 
11) Other causes of anemia, apart from iron deficiency, including: 
a) Haemolysis (determined as per analyses results at screening, or as per anamnestic data),  
b) Vitamin B12 and folic acid deficiency (as per the screening data),  
c) Chronic kidney disease (creatinine clearance at screening is below 90 ml/min (based on  
Cockcroft-Gault Formula)), 
d) Systemic connective tissue diseases, chronic infectious diseases requiring regular therapy 
(as per the past medical history), and other conditions which may, in the investigator's 
opinion, be accompanied by anaemia of chronic diseases.  
12)  Dysfunction of the thyroid gland (based on the data obtained at screening). 
13) Laboratory and clinical signs of an active inflammatory process for 10 days before screening.  
14) AST, ALT, and total bilirubin levels exceeding the upper limit of normal 1.5 times and more.  
15) Clinically apparent hypothyroidism, in the investigator's opinion. 
16) Malignant diseases, including blood and lymphoid tissue disorders (leukemia, Hodgkin 
disease, myelodysplastic syndrome, myeloma, etc.) at screening or in the past medical history, 
provided that the remission was less than 5 years before screening.  
17) Signs of bone marrow aplasia at screening or history of bone marrow aplasia. 
18) The necessity of parenteral iron therapy, i.e. the following cases:  
a) impaired absorption in case of an intestinal pathology (enteritis, coeliac disease, 
malabsorption, small intestinal resection, stomach resection, including the duodenum);  
b) exacerbation of gastric or duodenal ulcer;  
c) the necessity of quick iron saturation, e.g. in patients with iron-deficiency anaemia with 
upcoming surgery; 
d) continuous vast blood loss and other causes, at the discretion of the investigator.  
19) Known presence of an active infection caused by Helicobacter pylori. In case of presence of 
Helicobacter pylori, a subject may be enrolled after eradicative therapy.  
20) Concomitant diseases and conditions, which, in the investigator's opinion, pose risk to 
a subject's safety in case of his/her participation in the study, or able to affect the safety data 
analysis in case of exacerbation of this disease/condition during the study, including: 
a) Myocardial infarction or stroke within 6 months before screening. 
b) Unstable angina; 
c) Severe arrhythmia, not controlled by drug therapy; 
d) Decompensated diabetes mellitus; 
e) Nephrological disorders; 
f) Other significant diseases, at the discretion of the investigator.  
21) HIV infection (as per the screening data or the results of analysis performed within 6 months 
before screening).  
22) Known or suspected drug or alcohol abuse for the last 2 years. 
23) Suspected poor adherence of a subject (e.g., due to mental disorders). 
24) Participation in any clinical drug studies less than 3 months before the study.  
25) Blood donation/blood transfusion within 30 days prior to screening or planned blood 
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26) History of smoking, unless leave off smoking > 6 months. 
 
) 
 
 
5.3 Exclusion criteria  
5.3.1 Terms and conditions for the subjects exclusion from the study 
The subjects may be excluded from the study on their own free will at any moment, without giving 
any reason, as well as upon decision of the Investigator or Sponsor in cases when continuation of 
the participation may inflict harm to the patient's health and/or life. In addition, the patient must 
be excluded in the cases listed below: 
1. Negative trend of the disease  
2. The Ethics Committee, regulatory authorities or Sponsor terminate the study or participation 
of the specific study site for any reason. 
3. The Investigator's decision to withdraw the patient from the study in the interests of the 
patient.  
4. Withdrawal of the informed consent (unwillingness of the patient to continue his/her 
participation in the study). 
5. Serious deviation from the study protocol; 
6. Individual intolerance of study drugs; 
7. Clinically significant adverse event or serious adverse event related to investigational drug; 
8. Patient's non-compliance; 
9. False inclusion (e.g., the patient was included in breach of the inclusion/non-inclusion 
criteria); 
10. The patient complies with the non-inclusion criteria during the study; 
11. Patient receives/needs additional treatment, which may influence the study results or patient's 
safety; 
12. Other conditions or events which, in the Investigator's opinion, require the patient's exclusion 
from the study. 
5.3.1.1 Terms and volume of data on the excluded subjects 
In the case of study discontinuation on the subject's free will, the Investigator should make effort 
to find out the reason thereof. In the case of study discontinuation due to AEs/SAEs, the subject 
should be followed-up until the AEs/SAEs are resolved. In case of early study termination by a 
patient, he/she should visit the study site for early termination procedures (as an unscheduled visit); 
if the patient refuses to visit the study site, he/she should be contacted by phone with further 
recording of all available information. 
5.3.2 Terms and conditions for suspension or discontinuation of the study 
therapy  
The patients may stop taking the study drugs according to the protocol or upon withdrawal from 
the study. 
5.3.3 Replacement of the excluded subjects 
Replacement of the excluded patients during the study is not provided for.  
 


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6 Information on drug products used in this clinical study 
6.1 Administration of study and reference products 
Study product (Ferrum Lek®): the daily dose of 200 mg (2 tablets) shall be taken once a day with 
or immediately after a meal. 
Reference product (MALTOFER®): the daily dose of 200 mg (2 tablets) shall be taken once a day 
with or immediately after a meal. 
6.2 Duration of treatment: 
Patients in both groups will take drugs daily during 12 weeks. 
6.3 Compliance control 
Compliance will be controlled by means of checking patient's diary and accounting the amount of 
left drug. 
6.4 Permitted concomitant therapy 
Patients will take medications, which they took before the enrollment, for the treatment of 
concomitant diseases during the study. Women that take oral contraceptives may continue taking 
them during the study.  
It is permitted and recommended to take vitamins (not containing iron), folic acid, and ascorbic 
acid by medical prescription, as well as adhere to a diet with products rich in iron. 
It is not recommended to take non-steroidal anti-inflammatory drugs groundlessly, including 
selective inhibitors of cyclo-oxygenase, but these drug products may be prescribed by the 
Investigator due to medical indications. 
6.5 Prohibited concomitant therapy 
During the study the enrolled patients must not administer drugs: 
• indicated for the treatment of iron deficiency anemia: 
Pharmaceutical groups  
Active ingredient (INN) 
Dietary supplements, vitamin and mineral 
complexes 
 
Dietary supplements macro and 
micronutrients 
 
Vitamins and vitamin-like products 
Vitamin C 
Pyridoxine 
Riboflavin 
Vitamins and vitamin-like products in 
combinations 
Multivitamins + Minerals 
Macro and micronutrients 
Ferrous protein succinylate 
Macro and micronutrients in combinations 
Hematogen 
Ferrous Sulfate + Serine + Folic Acid 
Multivitamins + Minerals 
Hemopoiesis stimulants 
Ferrous (III) hydroxide polymaltozate 
Ferrous (III) hydroxide sucrose complex 
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Ferrous carboxymaltose t 
Ferrous protein succinylate 
Ferrous sulfate 
Ferrous fumarate 
Ferrous chloride 
Cyanocobalamin 
Hemopoiesis stimulants in combinations 
Ferrous (III) hydroxide polymaltozate + Folic 
acid 
Ferrous sulphate + folic acid + Cyanocobalamin 
Ferrous sulfate + folic acid 
Ferrous fumarate + folic acid 
as well as any other drugs that affect blood formation (for example, cytostatics, interferons, 
chloramphenicol, streptomycin). 
• Other drugs stimulating hematopoiesis (epoetins, anabolic steroids, etc.) 
• Drugs that slow iron absorption (antacids, calcium supplements) 2 hours before 
administration of the investigational products. It is not recommended to drink strong tea, 
coffee 2 hours before medications administration.  
During the study, patients should not undergo any physiotherapeutic procedures and other 
procedures potentially affecting erythropoiesis (for example, Buteyko breathing technique). 
7 Assessment of efficacy 
7.1 Methods and periods for registration of efficacy parameters 
The efficacy of the study therapy is based on laboratory and clinical data.  
Laboratory parameters for effectiveness evaluation will be collected at screening visits (Visit 0), 
Visit 2, Visit 3 and the final visit (Visit 4): 
• Complete blood count (hemoglobin); 
• Iron metabolism indices (ferritin, transferrin, transferrin saturation percentage, serum iron). 
7.2 Efficacy endpoints 
Primary efficacy endpoint:  
• Changes in hemoglobin level (g/L) in 12 weeks of iron deficiency therapy (at the final 
visit) as compared to baseline (determined at the screening visit) in the study groups.  
 
Secondary efficacy endpoints: 
• Absolute values and changes in hemoglobin level (g/L) in 4, 8 and 12 weeks of therapy 
(determined at the final visit) between the study groups. 
• Changes in iron metabolism parameters mean values (ferritin, transferrin, transferrin saturation 
percentage, serum iron) within the therapy period (from the screening to the final visit) in the 
study groups. 
• Responder rate (%), determined as an increase in hemoglobin level by 20 g/L and more after 
12 weeks of treatment (from screening till the final visit) in the study groups.  
 


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8 Safety evaluation 
8.1 Methods and periods for registration of safety parameters 
Safety evaluation of the study therapy will be performed throughout the study and will be based 
on detection of any adverse events occurring during the study. The following will be performed: 
• Physical examination, including measurement of blood pressure and heart rate, and 
gastrointestinal disorders identification (at the screening, during the second visit and the 
final visit).  
• Complete blood count (at screening and in 4, 8 and 12 weeks of therapy), 
• Blood biochemistry (at screening and after 12 weeks of treatment), 
• Clinical urinalysis, pregnancy test (at screening and in 12 weeks). 
• Registration of concomitant therapy (during each visit).  
 
8.2 Safety parameters 
Procedure for primary safety parameters assessment (including physical examination, laboratory 
and instrumental examinations) is detailed in the section 4.2. Safety evaluation will be performed 
throughout the study (see the planned procedures for visits in the section 4.2.9). 
8.3 Requirements for reporting, registration, and reporting of 
adverse events and intercurrent diseases 
8.3.1 Adverse Events / Serious Adverse Events Definitions 
Adverse Event (AE) — any untoward medical occurrence in a patient or clinical study subject 
after administration of a medicinal product which does not necessarily have a causal relationship 
with this treatment. 
An adverse event (AE) can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
use of a medicinal product, whether or not considered related to the medicinal product. 
Serious Adverse Event (SAE) is any unfavorable medical occurrence that at any dose: 
• results in death 
• Is life threatening; 
• Requires hospitalization or its extension; 
• results in persistent or significant disability/incapacity; 
• is a congenital anomaly/birth defect; 
• is medically significant: medical and scientific judgement should be exercised in deciding 
whether expedited reporting is appropriate in other situations, such as important medical 
occurrences that may not be immediately life-threatening or result in death or hospitalization 
but may jeopardize the patient or may require intervention to prevent one of the other outcomes 
listed in the definition. These should also usually be considered serious. 
The characteristics/consequences should be considered at the time of the event. For example, the 
term "life-threatening adverse event" refers to a medical occurrence in which the subject is at risk 


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of death at the time of the adverse event; it does not refer to a medical occurrence which 
hypothetically might have caused death if it were more severe. 
(Serious) Adverse Reaction ((S)AR) is any (S)AE for which a causal relationship with a 
medicinal product is regarded by the Investigator or Sponsor as plausible (see Section 8.8.3 
below). 
(Serious) unexpected adverse reaction is defined as (serious) adverse reaction, the character or 
severity of which does not correspond to the safety information of the drug (for example, Summary 
of product characteristics [SPC], drug product certified pharmacopoeial description, Investigator’s 
Brochure) The term "severity" is used here to describe the intensity of a specific adverse event. 
This has to be distinguished from the term ‘serious’. Reports which add significant information on 
the specificity, increase of occurrence, or severity of a known, already documented serious adverse 
reaction constitute unexpected events. 
 
Information on common known side effects of the Investigational Medicinal Product (IMP) can 
be found in the Reference Safety Information (e.g. SPC, Product Monograph, Investigator 
Brochure). Otherwise, it will be communicated in the form of Investigator Notification. This 
information will be included in the Patient Information Sheet and should be discussed with 
patients. 
For further details, please refer to the Quick Reference Guide for completing the Serious Adverse 
Event Report Form. 
8.3.2 Severity of Adverse Events 
The term "severity" is used here to describe the intensity of a specific event. This has to be 
distinguished from the term ‘serious’. During the trial, the Investigator should define any emerging 
AEs and rate their severity as follows: 
 
Mild 
an AE that is usually of transient nature and, as 
a rule, does not limit daily activity. 
Moderate 
Sufficiently discomforting to interfere with 
normal activities 
Severe 
prevents routine daily activity. 
 
8.3.3 Relation to the IMP 
The Investigator should evaluate all AEs considering all accessible data, at any time new 
information becomes available. The definition of IMP includes the test product and the comparator 
drug or placebo administered during any phase of the trial. 
 
The Investigator should assess whether, in his/her expert opinion, the relationship of the AE to the 
drug is suspected based on the following considerations: 
Suspected: 
The temporal relationship of the clinical event 
and the study drug administration is possible, 
while 
other 
drug 
products, 
therapeutic 
interventions or an underlying condition do not 
provide a sufficient explanation for the 
observed event. 
Not suspected: 
The temporal relationship of the clinical event 
and the study drug administration is unlikely, 


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or 
other 
drug 
products, 
therapeutic 
interventions or an underlying condition 
provide a sufficient explanation for the 
observed event. 
 
Causal relationship assessments are critical and must be provided for each individual AE in 
relation to each IMP, non-investigational medicinal product (NIMP) or other concomitant 
medicinal product, if applicable. Missing causality assessments will be handled as suspected to 
IMP by the sponsor. 
AEs with a suspected relationship to NIMP or other concomitant medication (for both Sandoz and 
non-Sandoz products), even if non-serious, need to be reported by the investigator to the respective 
Country Organization Patient Safety Team (see section 8.3.5 for contact details). 
8.3.4 Adverse Events Documentation 
Any AE (non-serious and serious) occurring after the subject has provided study-specific informed 
consent and until the last study visit of the subject, has to be recorded on the AE pages of the Case 
Report Form (CRF). 
 
The data on AEs should be collected by nonintrusive questioning of the subject at each visit during 
the study. AEs also may be identified when they are volunteered by the subject during or between 
visits or during physical examination, laboratory test or other assessments. All AEs should be 
given appropriate medical care. Treatment may include one or more of the following actions: no 
action is taken (i. e. further observation only); IMP dosage is adjusted/temporarily interrupted; 
IMP is permanently discontinued due to this AE; concomitant medicinal product is given; non-
drug therapy is given; patient is hospitalized/patient’s hospitalization is prolonged. The treatment 
of the AE should be documented in the CRF. In addition, the actions taken concerning the IMP 
should be documented and assigned to one of the following categories: "no changes", 
"discontinuation", "dose reduction", "dose increase", "interruption", "unknown", and "not 
applicable". Concomitant medicinal product, other types of treatment, or changes in the 
administration of the IMP should be specified and documented. 
Medical conditions/diseases present before starting IMP are only considered to be AEs in the case 
of their worsening after the patient enrolment. Abnormal laboratory findings or other test results 
constitute AEs only if they induce clinical signs or symptoms, are considered to be clinically 
significant, or require therapy. 
 
Once an AE is identified, the investigator should follow-up as specified below. Each time, the 
outcome should be documented and assigned to one of the following categories: "not 
resolved/unchanged", "condition deteriorating", "recovered/resolved", "improving/recovering", 
"recovered/resolved with sequelae", "fatal", or "unknown". The assessment of the AE should be 
performed during each planned visit (or more frequently, if necessary). The Investigator should 
document in the CRF any changes in seriousness, severity, the suspected relationship with the 
IMP, the interventions required to treat the AE, as well as its outcome. 
 
Adverse events occurring between informed consent and the last visit 
The Investigator should continue observations for all AEs which occurred in the period between 
the study-specific informed consent signing and the last visit of the subject, at which the outcome 
assessment is documented in the CRF. 
 
Serious adverse events still ongoing at the time of the last visit 


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For any SAEs still ongoing at the time of the last visit, the Investigator should continue 
observations until the SAE has resolved, stabilized or is judged permanent in the case of SAEs 
considered to be related to IMP (SARs), or for up to 30 days after the last visit of the subject in 
the case of non-related SAEs. The Investigator should send SAE follow-up reports to recipients as 
per Section 8.8.5, SAE reporting, presented below. 
 
Serious adverse events occurring after the last visit 
SAEs registered after the last visit should be reported to the Sponsor only if they are evaluated by 
the study physician as related to drug administration. The Investigator should send SAR follow-
up reports to recipients as per Section 8.8.5, SAE reporting, presented below. 
 
8.3.5 SAE Reporting 
It is vital that the investigator reports any SAEs, or updates to previously reported SAEs 
immediately, i.e. not later than 24 hours after the information has been received, even if the 
investigator does not consider the AE to be drug-related. 
To report on a SAE the Investigator should send a Serious Adverse Event Report Form (a Novartis 
document) as an initial or follow-up report, via fax or e-mail to the relevant Country Organization 
Patient Safety Team with a copy to the accountable study manager (Sponsor/CRO) to the addresses 
given in the table below. 
 
The Investigator should also send all updates/new information on a new SAE Report Form as a 
follow-up data to previously reported SAE. The follow-up data should describe whether the 
adverse event resolved or is ongoing, if a diagnosis is available, if (and how) it was treated, and 
whether the subject is continuing or was withdrawn from the trial. 
Recurrent episodes, complications, or progression of the initial SAE must be reported as follow-
up information to the original episode, regardless of when the adverse event occurs. 
Any new SAE (that is considered completely independent of a previously reported SAE) should 
be reported as a new and separate initial SAE report. 
Any queries from the Country Organization Patient Safety Team, Contract Research 
Organization (CRO), or Sponsor regarding SAE reports should be answered by the Investigator 
within 24 hours. 
For further information see Brief Reference Guide for filling out of the Serious Adverse Event 
Report Form  
 
The Investigator should retain SAE reports delivery confirmations to all recipients in the 
Investigator File. 
 
Addresses for SAE reporting 
Novartis Pharma 
Full name: 
Address:
Phone: 
Mobile:
(24h) 
Fax:
E-mail:
 Sandoz (a Novartis division): 


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Full name: 
 
Address: 
 
Phone:
Fax:
E-mail:
 
 
 


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Contact persons in charge for handling questions: 
 
Sandoz: 
Full name: 
 
Address: 
 
Phone:
Mobile:
Fax: 
E-mail:
  
CRO:
Full name:
Address:
Phone: 
;  
Mobile: 
Fax:
E-mail:
 
 
Investigator Notification and 6 monthly line listings 
If a SADR is not listed in the Reference Safety Information (e.g. SmPC, Product Monograph, 
Investigator’s Brochure), the sponsor may urgently require further information from the 
investigator for Health Authority reporting. 
 
The Sponsor may, where applicable, forward Investigator Notifications and biannual tabulated 
listings of Suspected Unexpected Serious Adverse Reactions (SUSARs) to all Investigators taking 
part in any clinical trial covering the same IMP. 
 
The submission of these Investigator Notifications and biannual listings, if applicable, to the local 
Institutional Review Board/Ethics committee is the responsibility of the Investigator or the CRO 
as stipulated in the study contract. The submission of Investigator Notifications and 6-monthly 
line listings to national Ethics Committee is the responsibility of the CRO, if applicable. 
 
Health authority reporting 
The Sponsor submits all reportable cases within the required timelines to all concerned authorities. 
 
8.3.6 Pregnancy 
All cases of pregnancy among subjects during the study must be immediately (within 24 hours) 
reported by the Investigator to the Country Organization Patient Safety Team, with a copy sent to 
the study manager (Sponsor / CRO), as described in Section 8.3.5. Pregnancies are only reported 
from the date of the first IMP dose administration. 
 
The Investigator should immediately discontinue the subject from the study, and should follow-up 
each case of pregnancy, and report its outcome, including spontaneous or voluntary termination, 
and submit detailed data on birth, any birth defects, congenital abnormalities, or maternal and/or 
newborn complications. 
 
If it becomes known to the Investigator that a male subject has impregnated his/her partner between 
the first dosing and the final visit (paternal exposure), this pregnancy should also be reported. 
 
Pregnancies are reported on the Case Report of Pregnancy Exposure Form (a Novartis document). 
Information on pregnancy follow-up monitoring of is reported using the same form. It should 
include an assessment of the relatedness of any untoward pregnancy outcome to the IMP. 
Any SAE during pregnancy of a subject must be reported on the SAE Report Form and reported 
as described in Section  8.3.5 


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The Investigator must store in investigator's file information about the delivery of forms to all 
recipients of messages on the Form. 
For further information see Brief Guidance for completing the form of a report on the effects of 
the drug during pregnancy (a Novartis document). 
8.3.7 Complaints related to IMP/medical device 
In the case of claims in respect of quality of IMP/medical device, Investigator shall inform the 
Sponsor within 24 hours after receiving the information on such a claim in accordance with the 
instructions given in Appendix 4.3.2. Any AEs related to quality claims must be documented and 
reported by the Investigator in addition as described in Sections 8.3.4and 8.3.5. 
8.3.8 Special cases 
Special cases can be serious or non-serious (see table below). They should be reported as cases of 
AEs, as described in Sections 8.3.4and 8.3.5, even if no (other) AEs are associated with them. 
 
Special case 
The Investigator notifies the 
Country Organization Patient 
Safety Team within 24 hours 
Drug exposure during breastfeeding 
X 
Intentional Overdose by patient (including suicide 
attempts, suicide attempt is always serious) 
Only if associated with SAE 
Interaction with other medicinal products 
Only if associated with SAE 
Withdrawal syndrome/reaction 
Only if associated with SAE 
Drug dependence, misuse, abuse or addiction (always 
treated as serious event) 
X 
Suspected transmission of infectious agents (always 
serious) 
X 
Death (including cases in the absence of other adverse 
events, is always treated as a serious event) 
X 
 
8.3.9 Reconciliation 
Reconciliation between the safety database of the sponsor and the clinical database at the CRO 
will be done periodically / at the end of the study as described in a reconciliation plan / by 
comparing line listings from the safety database with the data in the clinical database. 
 
Data managers will study the CRF/clinical database for possible cases that have not been reported. 
For any case to be reported, the following parameters must exactly match in the clinical database 
and the safety database: number of study, number of study site, number of participant/patient 
number, randomization number, investigational product, seriousness, date of death (if applicable), 
and Investigator assessment of causality. All other parameters should be coordinated from a 
medical point of view and believably consistent with each other. For any case to be reported and 
evaluated as being presumed to be associated with treatment, or for other AEs of particular interest 
(if applicable), more detailed agreement should be made, including also the dates of treatment, 
outcomes, history, and concomitant therapy. 
 


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8.3.10 Investigator Training 
By his/her signature of the study protocol, the principal investigator certifies that he/she has been 
trained in the Sponsor AE/SAE and pregnancy reporting obligations by the CRO as defined in the 
study protocol. 
 


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9 Statistical methods description 
9.1 Analysis methods description 
Statistical analysis will be performed using R Project specialized software.  
All continuous (quantitative) indicators will be submitted in the form of the following descriptive 
statistics parameters: 
• 
Number of observations,  
• 
arithmetic mean,  
• 
95 % confidence interval (CI) for the average, 
• 
standard deviation,  
• 
median,  
• 
interquartile range,  
• 
minimum, 
• 
maximum. 
All the ordinal, categorical and qualitative indicators will be submitted in the form of the following 
descriptive statistics parameters:  
• 
absolute frequency (observations number),  
• 
relative frequency (expressed as percent), 
• 
95% CI for proportion. 
All the performed types of statistical analysis will be identical in the study product Ferrum Lek® 
group and in the comparator MALTOFER® group. 
The concomitant diseases and AEs will be coded using MedDRA terms. 
This section contains a brief description of the planned analysis. Full analysis will be presented in 
the statistical anaysis plan. 
9.1.1 Demographic and other baseline data (group comparability for the 
analysis) 
All the data obtained in the groups before the study therapy initiation (demographic, laboratory, 
instrumental, and physical examinations data, vital signs, etc.) will be compared between the 
groups to determine the groups comparability for analysis. 
The Fisher's exact test and χ2 (chi-square) will be used to compare the qualitative and serial data, 
while the t-test or the Mann–Whitney test will be used for the quantitative data (depending on the 
quantitative data distribution). 
To assess the normality of the distribution, the Shapiro-Wilk Test will be applied. 
In the event that any of the initial data reveal the incomparability of the study groups (statistically 
significant differences in demographic and other initial data between the groups), the analysis of 
the efficacy and safety parameters will be additionally performed, together with the primary 
planned analysis, using multi-factor statistics (ANOVA, ANCOVA or logistic regression analysis 
depending on the type of the studied parameter), as adjusted for the initial indicator(s) that vary 
between the groups. 
9.1.2 Analysis of the primary efficacy endpoint 
Primary efficacy endpoint: 
• Changes in blood haemoglobin level (g/L) after 12-weeks of iron-deficiency anaemia 
treatment (during the final visit), as compared with the baseline value (the screening visit) 
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Analysis of covariance (ANCOVA) will be used as the main method of assessment of the primary 
endpoint, with baseline haemoglobin value being a covariate and four fixed factors (treatment 
group, gender, weight and baseline Hb level (80–94 g/L vs 95–110 g/L). Unrestricted least 
significant differences (LSD) method will be applied to the ANCOVA results with the calculation 
of least-square (LS) means with 95% CI for LS means for the difference between the study groups. 
Non-inferiority will be confirmed if the upper limit of the two-sided 95% confidence interval for 
LS mean will not exceed the pre-defined non-inferiority margin of 5 g/L. 
 
9.1.3 Analysis of the secondary effecacy endpoints 
Secondary efficacy endpoints: 
All secondary efficacy analysis will be considered explorative, therefore, no multiplicity 
correction will be done for any tests, and no formal power calculation will be provided for the test 
results. 
• Absolute values and changes (compared to baseline) of blood hemoglobin level (g/L) after 
12 weeks of treatment (during the final visit) between the study groups. 
Values at individual time points and values of change between the individual time points will be 
compared using the t-test or Mann-Whitney test depending on the normality of the distribution 
(which will be tested using Shapiro-Wilk test). 
Additionally, it is planned to use ANCOVA for analysis of changes in the assessed parameters 
over time where group will be a fixed factor,  screening hemoglobin level will be a covariate , and 
hemoglobin level at  Week 12 will be a response variable.  
• Changes in average values of iron metabolism parameters (ferritin, transferrin, percent 
transferrin saturation, serum iron) during the treatment period (from screening till the final 
visit) in the study groups. 
 Values at individual time points (baseline and Week 12) and values of change between the 
individual time points (baseline and Week 12) will be compared using the t-test or Mann-Whitney 
test depending on the normality of the distribution (which will be tested using Shapiro-Wilk test). 
• The percentage (%) of subjects with response to the therapy, determined as an increase in 
hemoglobin level by 20 g/L and more after 12-weeks of treatment (from screening till the 
final visit) in the study groups.  
Comparison between the two groups will be performed using the Fisher’s exact test or chi-square 
test depending on the number of expected observations per cell (<5 or ≥5). Two-sided 95% 
confidence interval will be calculated using exact Clopper-Pearson method. 
These changes will be compared between the groups using the t-test or Mann-Whitney test 
depending on the normality of the distribution (which will be tested using Shapiro-Wilk test). 
 
9.1.4 Safety parameteres analysis 
Safety evaluation will include: 
1) determination of the total number, incidence and severity of the folowing: 
I. 
adverse events (AEs), regardless of their relationship to the treatment;  
II. 
AEs associated or potentially associated with the drug;  
III. 
AEs leading to discontinuation.  
2) Gastrointestinal disorders (determined by means of a standardized  MedDRA query for the 
corresponding symptoms), regarded by the Investigator as related to the study therapy, will be 
analyzed separately.  
Methods of descriptive statistics will be used to represent the results. A comparison of the 
incidence of new AE cases in the study groups will be performed using the Fisher's exact test or 


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the chi-square test, depending on the number of proposed observations in one cell (<5 or ≥5), and 
a  comparison of the severity (and the possible causality between the study drug and AE) will be 
conducted using the Cochran—Armitage test for linear trends for ordered categorical data. 
3) Changes in the results of laboratory studies (conducted in the central laboratory) over time and 
the incidence of abnormal results of studies  (based on the reference values of the central 
laboratory) will be summarized by group, and a comparison will be made between the groups using 
appropriate tests for quantitative and qualitative data (see below). 
4) Changes in the vital signs over time and the incidence of pathological abnormalities revealed 
during physical examination will be summarized by group, and a comparison will be made 
between the groups using appropriate tests for quantitative and qualitative data (see below). 
Comparison of quantitative data will be conducted using the t-test or the Mann—Whitney  test, 
depending on the distribution normality (which will be estimated using the Shapiro—Wilk test). 
Qualitative data will be compared using the exact Fisher's exact test or the  chi-square test, 
depending on the number of proposed observations in one cell (<5 or ≥5). 
 
9.2 Interim analysis 
One formal Interim analysis to assess the primary and secondary endpoints of efficacy is planned 
when the population of patients with available primary efficacy endpoint data is at least 240 
patients (120 patients in each group treatment: the main group is Ferrum Lek® (iron (III) hydroxide 
polymaltosate) and the reference group MALTOFER® (iron (III) hydroxide polymaltosate). Safety 
and Efficacy will be assessed for all patients who received at least one dose of the randomized 
treatment at the time of the interim analysis. Based on the results of the interim analysis of the 
primary and secondary  statistical endpoints of the efficacy and safety of the study Sponsor may 
decide to stop the study if study endpoints have been met as per protocol based on the results of 
interim analyses or sample size might be recalculated using results of interim analyses. 
9.3 Target number of the clinical trial subjects with the sample size 
justification 
Calculation of the sample size is based on published works focusing on iron (III) hydroxide 
polymaltosate efficacy: 
7) Maltofer 
Product 
Information 
leaflet 
(http://www.aspenpharma.com.au/product_info/pi/PI_Maltofer.pdf) 
8) Santiago P. Ferrous versus ferric oral iron formulations for the treatment of iron deficiency: 
a clinical overview. Scientific World Journal. 2012;2012:846824. 
9) Geisser P. Safety and efficacy of iron(III)-hydroxide polymaltose complex / a review of 
over 25 years' experience. Arzneimittelforschung. 2007;57(6A):439-52;  
10) Toblli JE, Brignoli R. Iron(III)-hydroxide polymaltose complex in iron deficiency anemia 
/ review and meta-analysis. Arzneimittelforschung. 2007;57(6A):431-8); 
11) Reinisch W, Staun M, Tandon RK, Altorjay I, Thillainayagam AV, Gratzer C, Nijhawan 
S, Thomsen LL. A randomized, open-label, non-inferiority study of intravenous iron 
isomaltoside 1,000 (Monofer) compared with oral iron for treatment of anemia in IBD 
(PROCEED). Am J Gastroenterol. 2013 Dec;108(12):1877-88.  


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12) Zaim M, Piselli L, Fioravanti P, Kanony-Truc C. Efficacy and tolerability of a prolonged 
release ferrous sulphate formulation in iron deficiency anaemia: a non-inferiority 
controlled trial. Eur J Nutr. 2012 Mar;51(2):221-9. 
Based on the data of these publications, during 12-weeks of oral administration of iron (III) 
hydroxide polymaltosate the hemoglobin level can increase on average by 8-15 g/L with a 
standard deviation up to 15 g/L. As similar efficacy is expected in both groups, zero difference in 
primary efficacy parameter will be used for calculation of sample size. Maximum value of 
standard deviation was used – 15 g/L to take a maximum variability of the primary endpoint 
variable into account for properly powered study. 
The value of 5 g/L was selected as the non-inferior efficacy limit (in accordance with the limit 
stated and justified in the above mentioned works. 
Thus, the following assumptions were proposed for calculations: 
10) Changes in blood hemoglobin level (g/L) after 12-weeks of iron-deficiency anemia 
treatment (during the final visit), as compared with the baseline value (the screening visit 
0) are expected to be similar for the investigational and reference drug groups (i.e. expected 
difference between the two groups is set to zero). 
11) The pooled standard deviation for the changes in hemoglobin level was 15 g/L. 
12) Non-inferiority margin is 5 g/L. 
13) The significance level (two-sided, in accordance with FDA recommendations) is 95%, 
which corresponds to the type I one-sided error 0.05. 
14) Power of the study is 80%, which corresponds to the type II error 0.20. 
15) Statistical hypotheses – evidence of a non-inferior efficacy: 
H0: μA−μB≤5.0  
H1 :μA−μB>5.0 
 
16) The ratio between the study and control group sizes is 1:1 
17) Interim analysis will be performed at 70% of the total sample size 
18) O’Brien-Fleming alpha-spending function will be used with 80% power for efficacy 
boundary that will correspond to the following critical values for t-test: 2,628 for interim 
analysis (corresponds to p=0,005) and 1,976 for final analysis (corresponds to p= 0,0245); 
Calculation was performed using the clinfun package of Microsoft R Open software (available at 
https://mran.microsoft.com – Microsoft R Application network), that uses the group sequential 
design approach for the calculation of fixed sample sizes for the interim and final analysis. 
According to the output from the clinfun package, 143 subjects per group (286 subjects in total) 
should complete the study in order to confirm non-inferiority. 200 (100 per group) subjects 
should have evaluable data to perform interim analysis. Taking 15% withdrawal rate into 
account, one need to randomize 336 subjects (168 subjects per group). Taking 30% screening 
failure rate, up to 480 subjects should be screened to achieve target randomization. 
 


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9.4 Applied significance level of the clinical trial 
All the statistical tests within this study will be performed at 95% confidence level (threshold value 
p to confirm stastistical significance is less 0.05). The two-sided statistical criteria will be used for 
all other studied parameters. 
9.5 Clinical study termination criteria 
The trial may be terminated under conditions described in Section 4.8of this protocol.  
9.6 Accounting for missed, unanalyzable, and questionable data 
During the monitoring visits to the trial sites, the clinical trial specialists (monitors) authorized by 
the Sponsor will analyze eCRFs for the data completeness. In the absence of data on CRFs and the 
availability of relevant information in the primary documentation, questions for investigators and 
regulations to address inconsistencies will be formulated. 
At the database check, the expert in statistics authorized by the Sponsor, and the data control and 
processing managers will analyze the trial results for questionable, missed, and unanalyzable data, 
which might be the basis for the questions for investigators. 
If possible, the investigators will eliminate the errors identified in eCRFs and inform the Principal 
Investigator and authorized representatives of the Sponsor hereof. In case the identified data errors 
cannot be eliminated after the completion of the patients participation in the trial, the analysis of 
the resulting parameter sensitivity to questionable data will be conducted in the statistical analysis. 
Information about the missed, questionable, and unanalyzable data will be summarized in the final 
clinical trial report. 
A method of  filling in the missing data based on maximum likelihood estimation, MLE for the 
primary end-point will be applied if needed[64]. 
Analysis of the rest of endpoint types and other parameters will be performed only on the basis of 
the actually available information without filling in the missing data in view of short duration of 
the clinical trial.  
9.7 Procedures for reporting any deviations from the original 
statistical plan 
All deviations from an initial statistical plan must be described and justified in a protocol 
amendment and/or a final trial report (in the latter case, a statistical analysis plan developed before 
the start of a final statistical analysis must contain a list of those deviations with justification for 
the reasons thereof). 
 
9.8 Procedures for clinical trial participants selection with a view 
to analysis 
The following data sets will be used for analysis: 
• 
The intention-to-treat (ITT) population: all randomized subjects who were administered at 
least one dose of the investigational product or comparator and who have hemoglobin level 
data both before and after treatment with the investigational product and the reference 
product. 
In accordance with principles of ICH E9 guidelines, the ITT population will be considered to be a 
population for statistical analysis. 


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• 
The per protocol (PP) population: all randomized subjects who have completed 
participation in the trial in accordance with the protocol (have completed the prescribed 
period of treatment and follow-up without significant deviations from the protocol). 
• 
The safety population (safety): All randomized subjects who received at least one dose of 
the study drug/comparator drug and completed at least one safety parameters evaluation 
visit. Unlike the ITT population, the safety population will be analyzed depending on 
actually received treatment rather than not only prescribed (in the case of difference 
detection between the prescribed and received therapies). 
 
 
 


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10 Description of arrangements for quality control and quality 
assurance  
10.1 Trial monitoring and quality control 
Regular visits by a clinical trial specialist (Monitor), on request of the Sponsor and according to 
SOPs, before initiation, throughout, and upon completion of the trial contribute to a successful 
trial conduct and accurate data collection, timely detection of errors, proper documenting of the 
trial process, protection of the subjects' rights, and consistence with the principles of ICH GCP, 
international and Russian laws. 
Routine trial monitoring includes: 
• Confirmation for the proper conduct and documenting of the informed consent receipt, 
screening, and inclusion of the subjects in the trial. 
• Verification of the data in CRF and primary medical documents.  
• Confirmation for documenting and timely reporting of AEs during the trial; 
• Confirmation for compliance of the study site personnel with the requirements for diagnostic 
and therapeutic procedures stipulated by the protocol; 
• Confirmation for documenting the shipments, storage, distribution, and utilization of the study 
product/comparator drug and trial materials; 
• Confirmation for competence of the study site personnel and external laboratories needed for 
the trial conduct. 
• Confirmation for compliance of the diagnostic and laboratory equipment with the safe use 
requirements during the trial. 
• Confirmation for cooperation of the Investigator with the local Ethics Committee regarding 
the trial safety and introduction of the protocol amendments agreed upon by the Sponsor. 
Quality control of the trial results by the Sponsor's authorized persons or representatives who keep 
a trial electronic database, reveal for any inconsistence, data imputed by error, or missing data 
during the cross check of all eCRFs. In the case of any questions or necessity of clarification, a 
special form (a data clarification request) should be forwarded to the Investigator and satisfied in 
writing during 7 days since the receipt thereof. 
In accordance with the requirements of the legislation, the Sponsor or authorized federal 
authorities have the right to inspect (audit) the logistical support and documentation on the trial. 
The Investigator is obliged to provide direct access to documents and all relevant information to 
the authorized persons for the audit or inspection. 
10.2 Amendments to the protocol 
The investigators' signatures on a signature list of the protocol mean a written consent to perform 
a trial in accordance with this protocol. During the trial, the trial materials may be amended and 
appended. Such changes and additions are considered to be amendments. 
A protocol amendment is a written description of changes or formal clarification of the clinical 
trial protocol wordings. The amendments may be significant and insignificant. Any protocol 
amendment, before making effective, must be approved according to the established procedure 
and SOPs of the Sponsor, than approved by regulatory authorities and signed by the Investigator. 
Order of the Ministry of Health of Russia On Approval of a Review Procedure of a Message on 
Necessity to Introduce Amendments to a Protocol of the Clinical Trial of the Drug No. 775 of 
August 31, 2010 contains a list of significant/insignificant amendments and a procedure of 
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The protocol amendments are significant if they may influence objectives, organization, methods 
of the trial, statistical methods of data processing, and patients' safety measures during the trial. 
The protocol amendments are insignificant if they may not influence the objectives, organization, 
methods of the trial, statistical methods of data processing, and measures for patients' safety during 
the trial. 
In the case of necessity to introduce changes into this protocol, the Investigator shall submit a 
message on necessity to introduce amendments to the clinical trial protocol to the Ministry of 
Health of Russian Federation. The Ministry of Health of Russia shall consider the submitted 
documents and decide on approval or refusal to the introduction of changes. The protocol 
amendments must be stored together with the initial protocol version. A title page of the protocol 
must contain a number and date of the amendments. 
10.3 Protocol deviations 
Protocol deviation is an unintentional deviation from the approved protocol. 
Serious protocol deviation is a deviation, which may, in the opinion of the Investigator or a person 
assigned by the Investigator, result in withdrawal of the subject from the study or exclusion of his 
data from bioanalytical and/or statistical parts of the study. The deviations that were no classified 
as serious shall be considered minor protocol deviations. 
Serious deviations from the Protocol should be reported as soon as possible to the Sponsor by the 
Site staff and/or CRO and Monitor (if he/she is in the Site). The Sponsor may propose to reclassify 
the protocol deviation (minor into serious and vice versa) based on the conducted evaluation. In 
such a case, the classification performed by the Sponsor shall prevail and must be communication 
to CRO together with written rationale. 
The Sponsor must be informed of minor protocol deviations within 10 business days but before 
the start of the next study period or before the start of the bioanalytical/statistical phase. 
An exception is represented with minor protocol deviations, which can be included in the draft 
report on the trial: 
• 
Logistic deviations (deviation in time from the planned blood sampling schedule; follow-up 
visit which were outside the time limits set up in the Protocol due to a participant's 
plans/schedule, etc); 
• 
Administrative deviations (e.g. change of the name). 
If less than planned number of volunteers is enrolled, the CRO should contact the Sponsor, who 
may approve using smaller than planned number of volunteers. It is not considered to be a 
deviation from the Protocol. 
Notification and reporting on deviations from the Protocol shall be submitted to the Regulatory 
authorities 
and 
relevant 
Ethical 
Committees 
in 
compliance 
with 
the 
applicable 
requirements/instructions/laws. 
Procedure for documentation of Protocol deviations 
The Investigator or a person assigned by the Investigator must document and explain any deviation 
from the approved Protocol. Notification of the Sponsor on a protocol deviation can be verbal in 
exceptional cases (if immediate action/notification is required), and must be followed with written 
report (e.g. via e-mail; during updates on the study period process). All Protocol deviations must 
be described in the final report on the study. 
 


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11 Description of ethical aspects of the clinical trial 
11.1 General provisions 
The trial will be performed in accordance with the principles and requirements set forth in the 
documents: 
• Declaration of Helsinki, World Medical Association (adopted at the 18th Assembly of the 
World Medical Association in Helsinki in June 1964, the latest revision adopted by the 64th 
Assembly in Fortaleza in October 2013),  
• ICH E6 Harmonized Tripartite Guidelines for Good Clinical Practice dated 09.11.2016  
• Guideline for Good Clinical Practice of the Eurasian Economic Union (adopted through the 
decision No. 79 of the Council of Eurasian Economic Commission dated November 3, 2016); 
• Federal law dated April 12, 2010 № 61-FZ "On Circulation of Medicines" (as amended); 
• Order No. 200n dated April 01, 2016 of the Ministry of Health of the Russian Federation "On 
Approval of Rules for Good Clinical Practice"; 
• The national standard of the RF GOST R 52379-2005 "Good Clinical Practice". 
The study will be initiated in all research centers only after obtaining a written permission to 
conduct research and approval of the Ethics Committee of  the Ministry of Health of the Russian 
Federation and Local Ethics Committees and getting the signatures of each party participating in 
the study in the Clinical Trial Protocol. 
Investigators will be familiarized with the study materials in time prior to the study initiation. 
Investigators' qualification will meet the requirements essential for conducting high-quality 
clinical trials. 
Selection of prospective study participants is carried out on a voluntary basis.  
Ethics Committee 
Clinical trial materials (including CRF, materials provided to the patient) will be approved by the 
Ethics Committee of the Ministry of Health of the RF and Local Ethics Committees prior to the 
trial start. All the amendments to the Protocol and updated versions of the Patient Information 
Leaflet will be submitted to the Ethics Committee for approval. 
The clinical trial will be performed in accordance with the Protocol approved by The Ethics 
Council. 
 
11.2 The informed consent receipt procedure 
Before the inclusion, a subject is provided with written information and verbal clarification on 
objectives, goals, and methods of the trial, as well as expected benefit and possible risks associated 
with the participation in the trial. Besides, the subjects must be informed on voluntary nature of 
the participation in the trial and their rights to refuse to participate at any moment without influence 
on quality of the provided medical care. While a subject is not obliged to report his/her reasons to 
terminate his/her participation in the trial, the Investigator should try to find out the reasons without 
violating the subject's rights. The subject's consent must be obtained before initiation of any of the 
trial procedures. 
Processing of the data gathered during the trial is performed with the maintenance of 
confidentiality of personal data. The subjects should be made aware of the goals of the planned 
computed data processing and publication terms (e.g., on medical conferences, in magazine 
articles, and other publicly open sources), when the data is presented in summary not allowing for 
the subjects identification. 


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Subjects should be made aware that the authorized representatives of healthcare authorities and of 
the Sponsor will have access to their confidential health information for the purpose of monitoring, 
inspection, and audit. The subjects must receive guarantees of the strict confidentiality and non-
disclosure of all personally identifiable information. 
Patient Information Sheet with the informed consent form should be filled in in duplicates, signed, 
and dated by the subject and Investigator in person. One copy of the signed Patient Information 
Sheet with the Informed Consent Form should be kept in the Investigator's file, the other copy 
should be given to the subject. 
11.3 Confidentiality and identification of the trial subjects 
Personally identifiable information will be kept confidential in observance of the right to privacy 
and confidentiality protection according to the applicable laws. Personally identifiable 
information will be kept confidential and may be disclosed only to the extent required by law. On 
publication of the trial results, confidentiality of the personally identifiable information will be 
maintained. 
11.4 Enrollment of subjects from the vulnerable and special 
populations 
The inclusion/non-inclusion criteria do not envisage for participation of the subjects from the 
vulnerable populations.  
Special populations in this trial include women with childbearing potential who, according to the 
inclusion/non-inclusion criteria, may participate only upon their consent to use effective 
contraception during the trial which is stated in the patient information sheet and confirmed by 
signing of the Informed Consent Form. 
12 Data processing and record keeping 
All the trial relevant records and documents of the trial site, including those contained in the 
Investigator's file (eCRFs, Informed Consent Forms, logbooks, subject accounting sheets, etc.), as 
well as primary medical documentation of the subjects must be stored for 25 years after the trial 
completion. The study Sponsor must control storage and availability of all the study site materials 
during a life cycle of the investigational drug. Archival data may be stored as photocopies, as well 
as on the optical or electronic data storage devices. The Principal Investigator must inform the 
Sponsor immediately on the unintentional damage/destruction as well as change of the storage 
place of the archival data from the clinical trial. A targeted destruction of the archival data may be 
performed only upon a written permission of the Sponsor. 
As far as the subjects perform visits to the trial sites and the Investigator fills in the eCRFs, the 
authorized monitors of the Sponsor will verify the data in eCRFs and primary documents. In the 
case of any questions arising during the eCRFs data check on part of a data control manager and/or 
a biostatistics specialist, all the clarifications and changes will be documented by creating a special 
form (a data clarification request).  
The trial must be conducted in accordance with the protocol and applicable Sponsor's SOPs. If the 
protocol needs to be changed, one should follow a procedure described in Section 10.2 of this 
protocol. 
The Investigator must fill in all the primary medical documents and eCRFs for all the included 
subjects. 


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The Investigator is responsible for the complete and accurate filling of the eCRFs. All the data 
entered in eCRFs must be also recorded in subject's medical records in printed form or in the form 
of records made by the Investigator or another authorized person of the trial site. 
The eCRFs, in accordance with the primary documents, should contain all significant information 
on the subject's participation in the trial. Besides, eCRFs should contain data on the trial 
completion by the subject. The eCRFs must be filled in not less than 5 days after the subject's visit 
to the trial site.  
confidential. The Investigator may disclose the trial information to the parties not directly involved 
in the trial only upon the Sponsor's permission. 
 
All data provided for the evaluation will be integrated into the final clinical study report which 
will describe the methodology for conducting statistical analysis, as well as clinical conclusions 
regarding efficacy and safety. 
The CS report will be prepared by the CRO in cooperation with the Sponsor. The principal 
investigator of each study site will receive a copy of the Report for review and subsequent signing. 
The structure and content of the Report will generally comply with the requirements of the ICH 
E3 guidelines, as well as applicable local regulatory requirements. 
If recalculation of the sample size using the results of the interim analysis is necessary, Report on 
the interim analysis results will be generated, it will be submitted to the regulatory authority of the 
Russian Federation with a view to obtaining permission to continue the clinical study involving an 
increased number of patients. 
 
 


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13 Direct access to primary data/documents  
Primary data represent entire information contained in original records and certified copies 
regarding clinical data, observations, and other measures within the trial scope and which is 
required for reconstruction and evaluation of the trial. The investigator must cooperate for the 
purposes of monitoring, audit(s), expert evaluation by the Ethics Committee and regulatory 
authorities and provide the access to the primary data/records. 
The primary data must be stored in a proper quality throughout the time stipulated for by the local 
and international laws, as well as written contracts with the Sponsor company. For each subject 
included, the Investigator must note in the primary records the fact of such participation as well as 
the following data: an individual identification code, personal data (full name, address), dates of 
the drug intake, vital signs, any AEs, trial completion dates, the main reasons for discontinuation 
(if applicable). 
The Investigator is obliged to provide direct access to the primary data and documents for the 
clinical trial specialists and/or authorized representatives (CRO) of the Sponsor, competent bodies' 
auditors, representatives of the insurance companies, Ethics Committees. 
 
 
14 Finance and insurance 
14.1 Funding 
The trial is financed by the Sponsor through CRO. The relevant agreements will be concluded 
between CRO and every trial site before the trial initiation. 
14.2 Insurance 
The Principle Investigator of the research center is responsible for the safety of patients during this 
study. In case the patient develop adverse event, principle investigator and its personnel will 
provide medical care and do their best for the treatment.  
When the patient agrees to participate in the trial, his participation in this study will be insured by 
 (
) in accordance with the 
Federal Law of April, 12 2010. No. 61-FZ "On circulation of medicines", Government Decree of 
the Russian Federation No.714 of September 13, 2010 "On approval of typical rules for 
compulsory insurance of the life and health of a patient involved in clinical trials of a medicinal 
product" and Government Decree of the Russian Federation No 393 of May, 18 2011 "On 
amendments to the typical rules for compulsory insurance of the life and health of a patient 
involved in clinical trials of a medicinal product".  
In accordance with the Russian Federation Government Decrees No. 714 of 13.09.2010, No. 393 
of 18.05.2011 "On approval of typical rules for compulsory insurance of the life and health of a 
patient involved in clinical trials of a medicinal product" the amount of the insurance payment 
under the contract makes: 
a) in the event of death of the Insured Person - RUR 2 million. The benefit in mentioned extent 
shall be distributed throughout beneficiaries accordingly to theirs quantity share and share alike; 
b) in the case of the Insured Person’s health impairment with the following sequelae: 
• first class disability  - 1.5 mln rubles; 
• second class disability - RUR 1 million; 
• third class disability - RUR 500 thousand; 


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c) in the case of the Insured Person’s health impairment without any disability – not more than 
RUR 300 thousand. 
Each patient will receive in person an original certificate of insurance and a reminder card with 
policy conditions and a plan of action in the case of injury. In order to preserve anonymity, personal 
data of each patient in the certificate of insurance will be replaced with an individual identification 
code of the patient which is assigned to her/him within the study according to the form established 
in the territory of the Russian Federation. In the case of harm to the health of a volunteer associated 
with the clinical study, the Insurance Company 
 shall reimburse all costs of 
required medical examination and care the need for which will arise as a result of direct exposure 
to the investigational medicinal product and reference product and/or medical procedures used 
according to the study protocol. 
For additional information patients can refer to the insurance company office: 
 
The study does not specify any additional types of voluntary insurance or other options to grant 
treatment and / or compensation in the event of a patient's death or injury to the patient within the 
study. 
The Sponsor shall not be liable for any loss, harm and/or injury caused to the patient, provided that 
such loss, harm and/or injury are induced by: 
• Administration of the excluded medication within the study; 
• Deviation on the part of the patient from the study protocol, study requirements and/or any 
instructions or guidelines that the study physician can give; 
• Action or inaction of the third party in terms of proper response to adverse event or 
investigational drug reaction. 
 
15 Publications 
The information contained in this document is the property of the Sponsor, and its transfer to third 
parties is allowed only with the written permission of the Sponsor. This information may be 
accessed only by the investigators and the trial site personnel, members of the independent Ethics 
Committee, or health authorities responsible for the clinical trial control. Information about the 
trial, to the extent necessary to make a decision about provision of consent to participation, shall 
be provided to the volunteers, whom the Investigator plans to include into the trial. 
The exclusive rights for this trial results belong to the trial Sponsor. No data from this trial may be 
presented or published without a prior written permission of the Sponsor. 
16 Bibliography 
1. Aisen P., Enns C., Wessling-Resnick M. Chemistry and biology of eukaryotic iron 
metabolism // Int. J. Biochem. Cell Biol. 2001. Vol. 33, № 10. P. 940–959. 
2. Mckay R. et al. Tissue effects of iron deficiency in the rat // Biochim. Biophys. Acta BBA 
- Gen. Subj. 1983. Vol. 757, № 3. P. 352–358. 
3. Grasso J.A., Hillis T.J., Mooney-Frank J.A. Ferritin is not a required intermediate for iron 
utilization in heme synthesis // Biochim. Biophys. Acta. 1984. Vol. 797, № 2. P. 247–255. 
4. Aisen P., Brown E.B. The iron-binding function of transferrin in iron metabolism // Semin. 
Hematol. 1977. Vol. 14, № 1. P. 31–53. 


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5. Klausner R.D. et al. Binding of apotransferrin to K562 cells: explanation of the transferrin 
cycle. // Proc. Natl. Acad. Sci. U. S. A. 1983. Vol. 80, № 8. P. 2263–2266. 
6. Klausner R.D., Rouault T.A., Harford J.B. Regulating the fate of mRNA: the control of 
cellular iron metabolism // Cell. 1993. Vol. 72, № 1. P. 19–28. 
7. Peters L.L. et al. Mouse microcytic anaemia caused by a defect in the gene encoding the 
globin enhancer-binding protein NF-E2 // Nature. 1993. Vol. 362, № 6422. P. 768–770. 
8. Schäfer S., Forth W. On the absorption of divalent and trivalent iron in living rats // 
Arzneimittelforschung. 1984. Vol. 34, № 11. P. 1570–1574. 
9. Forth W., Schäfer S.G. Absorption of di- and trivalent iron. Experimental evidence // 
Arzneimittelforschung. 1987. Vol. 37, № 1A. P. 96–100. 
10. Schmitz H., Müller A. Comparative study on the therapeutic effects of iron(II) and Iron(3)-
antianemics applied orally // Arzneimittelforschung. 1971. Vol. 21, № 4. P. 509–515. 
11. Jacobs P., Wormald L. The bioavailability of an iron polymaltose complex for treatment 
of iron deficiency // J. Med. 1979. Vol. 10, № 4. P. 279–285. 
12. Geisser P., Müller A. Iron pharmacokinetics after administration of iron-hydroxide-
polymaltose complex in rats // Arzneimittelforschung. 1984. Vol. 34, № 11. P. 1560–1569. 
13. Johnson G., Jacobs P. Bioavailability and the mechanisms of intestinal absorption of iron 
from ferrous ascorbate and iron polymaltose in experimental animals // Exp. Hematol. 
1990. Vol. 18, № 10. P. 1064–1069. 
14. Jacobs P. Equivalent bioavailability of iron from ferrous salts and a iron polymaltose 
complex. Clinical and experimental studies // Arzneimittelforschung. 1987. Vol. 37, № 1A. 
P. 113–116. 
15. Finch C.A. et al. Iron deficiency in the rat. J. Clin. Invest 1976; 58:447-453. 
16. Koziol, B. J. et al. Biochemical skeletal muscle and hematological profiles of moderate and 
severely iron deficient and anemic adult rats. J. Nutr. 1978, 108, 1306-1314. 
17. McLane J.A, Fell R.D, McKay R.H, Winder W.W, Brown E.B, Holloszy J.O. 
Physiological and biochemical effects of iron deficiency on rat skeletal muscle. Am. J. 
Physiol. 1981 Jul;241(1):C47-54. 
18. Zhang L., Alexander R.L., Widness J.A., Cheung C.Y., Brace R.A. Red cell mass 
responses to daily erythropoietin and iron injections in the ovine fetus. Am. J. Obstet 
Gynecol. 2002 Feb;186(2):315-320. 
19. Pallarés I., López-Aliaga I., Lisbona F., Moratalla A., Gómez-Ayala A.E., Barrionuevo M., 
Hartiti S., Alférez M.J., Campos M.S. Effects of iron replenishment on iron, calcium, 
phosphorus and magnesium metabolism in iron-deficient rats. Int J Vitam Nutr Res. 
1996;66(2):158-165. 
20. Banner W.Jr., Tong T.G. Iron poisoning. Pediatr Clin North Am. 1986 Apr;33(2):393-409. 


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21. Li C.L., Werner P., Cohen G. Lipid peroxidation in brain: interactions of L-
DOPA/dopamine with ascorbate and iron. Neurodegeneration. 1995 Jun;4(2):147-153. 
22. Rodríguez Cruz M.S., González Alonso I., Sánchez-Navarro A., Sayalero Marinero M.L. 
In vitro study of the interaction between quinolones and polyvalent cations. Pharm Acta 
Helv. 1999 Feb;73(5):237-245. 
23. Daniel Grenier, Marie-Pierre Huot, Denis Mayrand. Iron-Chelating Activity of 
Tetracyclines 
and 
Its 
Impact 
on 
the 
Susceptibility 
of 
Actinobacillus 
actinomycetemcomitans to These Antibiotics. Antimicrob Agents Chemother. 2000 Mar; 
44(3): 763–766. 
24. Preedy V.R., Wassif W.S., Baldwin D., Jones J., Falkous G., Marway J.S., Mantle D., Scott 
D.L. Skeletal muscle protein loss due to D-penicillamine results from reduced protein 
synthesis. Int J Biochem Cell Biol. 2001 Oct;33(10):1013-1026. 
25. Thomas 
Ems; 
Martin 
R. 
Huecker. 
Biochemistry, 
Iron 
Absorption. 
[https://www.ncbi.nlm.nih.gov/books/NBK448204/] 
26. Rajiv K. Singh Margery A. Barrand. Lipid peroxidation effects of a novel iron compound, 
iron maltol. A comparison with ferrous sulfate. 1990 Royal Pharmaceutical Society of 
Great Britain. (https://doi.org/10.1111/j.2042-7158.1990.tb05407.x) 
27. Levey J.A., Barrand M.A., Callingham B.A., Hider R.C. Characteristics of iron(III) uptake 
by isolated fragments of rat small intestine in the presence of the hydroxypyrones, maltol 
and ethyl maltol. Biochem Pharmacol. 1988 May 15;37(10):2051-7. 
28. Jacobs P., Wormald L.A., Gregory M.C. Absorption of iron polymaltose and ferrous 
sulfate in rats and humans. A comparative study. S Afr Med J. 1979 Jun 23;55(26):1065-
72. 
29. Geisser P., Müller A. Pharmacokinetics of iron salts and iron hydroxide-carbohydrate 
complexes. Arzneimittelforschung. 1987 Jan;37(1A):100-4. 
30. Paul Sharp, Surjit Kaila Srai. Molecular mechanisms involved in intestinal iron absorption. 
World J Gastroenterol. 2007 Sep 21; 13(35): 4716–4724. 
31. Viteri F.E.1, Liu X., Tolomei K., Martín A. True absorption and retention of supplemental 
iron is more efficient when iron is administered every three days rather than daily to iron-
normal and iron-deficient rats. J Nutr. 1995 Jan;125(1):82-91. 
32. Barrand M.A., Callingham B.A. Dissociation of a iron maltol complex and its subsequent 
metabolism during absorption across the small intestine of the rat // Br. J. Pharmacol. 1991. 
Vol. 102, № 2. P. 408–414. 
33. Kontoghiorghes G.J. Chelators affecting iron absorption in mice // Arzneimittelforschung. 
1990. Vol. 40, № 12. P. 1332–1335. 


Ferrum Lek® 
Page 109 of 116
Protocol No. TE_005_FER_CHT 
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34. Srai S.K.S., Bomford A., McArdle H.J. Iron transport across cell membranes: molecular 
understanding of duodenal and placental iron uptake // Best Pract. Res. Clin. Haematol. 
2002. Vol. 15, № 2. P. 243–259. 
35. Zhang P. et al. The effect of serum iron concentration on iron secretion into mouse milk // 
J. Physiol. 2000. Vol. 522, № 3. P. 479–491. 
36. Papanastasiou D.A., Vayenas D.V., Vassilopoulos A., Repanti M. Concentration of iron 
and distribution of iron and transferrin after experimental iron overload in rat tissues in 
vivo: study of the liver, the spleen, the central nervous system and other organs. Pathology 
Research and Practice. 2000;196(1):47–54. 
37. Lynch S.R. Interaction of iron with other nutrients // Nutr. Rev. 1997. Vol. 55, № 4. P. 
102–110. 
38. Alarcón O.M. et al. Effects of acute overdose of vitamin A on the hepatic content of K, Na, 
Mg, Fe, Cu and Zn, in rats // Arch. Latinoam. Nutr. 1994. Vol. 44, № 4. P. 249–251. 
39. Crowe A., Morgan E.H. Effect of Dietary Cadmium on Iron Metabolism in Growing Rats 
// Toxicol. Appl. Pharmacol. 1997. Vol. 145, № 1. P. 136–146. 
40. Reuber S., Kreuzer M., Kirchgessner M. Interactions of cobalt and iron in absorption and 
retention // J. Trace Elem. Electrolytes Health Dis. 1994. Vol. 8, № 3–4. P. 151–158. 
41. Fairweather-Tait S.J., Southon S. Studies of iron:zinc interactions in adult rats and the 
effect of iron fortification of two commercial infant weaning products on iron and zinc 
status of weanling rats // J. Nutr. 1989. Vol. 119, № 4. P. 599–606. 
42. Chan J.T. et al. Influence of vitamins and iron on plasma fluoride levels in rats // Pediatr. 
Dent. 1992. Vol. 14, № 1. P. 37–40. 
43. Fassos F.F. et al. Efficacy of deferiprone in the treatment of acute iron intoxication in rats 
// J. Toxicol. Clin. Toxicol. 1996. Vol. 34, № 3. P. 279–287. 
44. Fassos F.F. et al. The efficacy of diazepam in the treatment of acute iron overload in rats 
// Can. J. Physiol. Pharmacol. 1998. Vol. 76, № 9. P. 895–899. 
45. Bartfay W.J. et al. The synergistic effects of vitamin E and selenium in iron-overloaded 
mouse hearts // Can. J. Cardiol. 1998. Vol. 14, № 7. P. 937–941. 
46. Bogden J.D. et al. Effect of selenium and molybdenum on methylbenzylnitrosamine-
induced esophageal lesions and tissue trace metals in the rat // J. Nutr. 1986. Vol. 116, № 
12. P. 2432–2442. 
47. Wong P.Y., Zhu M., Li R.C. Pharmacokinetic and pharmacodynamic interactions between 
intravenous ciprofloxacin and oral ferrous sulfate // J. Chemother. Florence Italy. 2000. 
Vol. 12, № 4. P. 286–293. 
48. Wong P.Y., Zhu M., Li R.C. Pharmacokinetic and pharmacodynamic interactions between 
intravenous ciprofloxacin and oral ferrous sulfate. J Chemother. 2000 Aug;12(4):286-293. 


Ferrum Lek® 
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Protocol No. TE_005_FER_CHT 
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49. Neuvonen P.J. Interactions with the absorption of tetracyclines. Drugs. 1976;11(1):45-54. 
50. Moon S.N., Han J.W., Hwang H.S., Kim M.J., Lee S.J., Lee J.Y., Oh C.K., Jeong D.C. 
Establishment of secondary iron overloaded mouse model: evaluation of cardiac function 
and analysis according to iron concentration. Pediatr Cardiol. 2011 Oct;32(7):947-952. doi: 
10.1007/s00246-011-0019-4. Epub 2011 Jun 9. 
51. Berkovitch M., Livne A., Lushkov G., Barr J., Tauber T., Eshel G., Koren G., Bistritzer T. 
Acute iron intoxication: significant differences between sexes. Vet Hum Toxicol. 1997 
Oct;39(5):265-7. 
52. McCullough K.D., Bartfay W.J. The dose-dependent effects of chronic iron overload on 
the production of oxygen free radicals and vitamin E concentrations in the liver of a murine 
model. Biol Res Nurs. 2007 Apr;8(4):300-4. 
53. Park C.H., Bacon B.R., Brittenham G.M., Tavill A.S. Pathology of dietary carbonyl iron 
overload in rats. Lab Invest. 1987 Nov;57(5):555-63. 
54. Carthew P., Dorman B.M., Edwards R.E., Francis J.E., Smith A.G. A unique rodent model 
for both the cardiotoxic and hepatotoxic effects of prolonged iron overload. Lab Invest. 
1993 Aug;69(2):217-22. 
55. Dunkel V.C., San R.H., Seifried H.E., Whittaker P. Genotoxicity of iron compounds in 
Salmonella typhimurium and L5178Y mouse lymphoma cells. Environ Mol Mutagen. 
1999;33(1):28-41. 
56. Park S.H., Aust AE., Ann E. Aust. Participation of iron and nitric oxide in the mutagenicity 
of asbestos in hgprt-, gpt+ Chinese hamster V79 cells. Cancer Res. 1998 Mar 
15;58(6):1144-8. 
57. Kim R.H., Kwon O.J., Park J.W. Ceruloplasmin enhances DNA damage induced by 
cysteine/iron in vitro. Biochimie. 2001 Jun;83(6):487-95. 
58. Higinbotham K.G., Rice J.M., Diwan B.A., Kasprzak K.S., Reed C.D., Perantoni A.O. 
GGT to GTT transversions in codon 12 of the K-ras oncogene in rat renal sarcomas induced 
with nickel subsulfide or nickel subsulfide/iron are consistent with oxidative damage to 
DNA. Cancer Res. 1992 Sep 1;52(17):4747-51. 
59. F. J. C. Roe, A. Haddow, C. E. Dukes, and B. C. V. Mitchley. Iron-Dextran Carcinogenesis 
in Rats: Effect of Distributing Injected Material Between One, Two, Four, or Six Sites. Br 
J Cancer. 1964 Dec; 18(4): 801–808. 
60. Hanna L.A., Peters J.M., Wiley L.M., Clegg M.S., Keen C.L. Comparative effects of 
essential and nonessential metals on preimplantation mouse embryo development in vitro. 
Toxicology. 1997 Jan 15;116(1-3):123-131. 
61. Vallet J.L., Christenson R.K., Klemcke H.G., Pearson P.L. Intravenous infusion of iron 
and tetrahydrofolate does not influence intrauterine uteroferrin and secreted folate-binding 
protein content in swine. J Anim Sci. 2001 Jan;79(1):188-192. 


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62. Andrew G. Woodman, Alison S. Care, Yael Mansour, Stephana J. Cherak, Sareh Panahi, 
Ferrante S. Gragasin, and Stephane L. Bourque. Modest and Severe Maternal Iron 
Deficiency in Pregnancy are Associated with Fetal Anaemia and Organ-Specific Hypoxia 
in Rats. Sci Rep. 2017; 7: 46573. 
63. Fairbanks V.F., Beutler E. Iron deficiency. Williams Hematology / ed. Beutler E. et al. 
McGraw-Hill, 2001. 2047 (447) p. 
64. Forth W, Schaefer S.G. Absorption og di- and trivalent iron, Drug Res. 1987; 37: 96-100. 
65. Schneider W. The rate of iron compounds in the gastrointestinal tract. Coordination-
chemical facts // Arzneimittelforschung. 1987. Vol. 37, № 1A. P. 92–95. 
66. Schaub E. et al. Gastrointestinal tolerance of iron haematinics on rabbits // Hausmann 
laboratories. 1984. 
67. Langstaff R.J. et al. Treatment of iron deficiency anaemia: A lower incidence of adverse 
effects with Ferrum Hausmann than ferrous sulfate. 1993. Vol. 4. P. 191–198. 
68. Andrade J.V.D. et al. Tratamento da anemia ferropriva com hidróxido de ferro 
polimaltosado: estudo multicêntrico comparativo entre tratamento ministrado com e sem 
alimentaçäo concomitante // Arquivos brasileiros de medicina. 1992. № 66(3). P. 253–258. 
69. Geisser P. In vitro studies on interactions of iron salts and complexes with food-stuffs and 
medicaments // Arzneimittelforschung. 1990. Vol. 40, № 7. P. 754–760. 
70. AHFS Drug Information, 2001; 1365-1366 [Electronic resource] // AHFS Drug 
Information. 2001. URL: http://www.ahfsdruginformation.com/ (accessed: 27.10.2017). 
71. DeMaeyer E.M. et al. Preventing and controlling iron deficiency anaemia through primary 
health care : a guide for health administrators and programme managers // Prévenir et 
combattre l’ anémie ferriprive dans le cadre des soins de santé primaire : guide à l’ usage 
des administrateurs de la santé et des responsables de programme. 1989. 
72. Mueller A., Geisser P. Properties and pharmacokinetics of oral bivalent and trivalent 
haematinics, // Diagnostica e terapia degli stati ferro-carenziali. 1984. P. 39–50. 
73. Heinrich H.C. Intestinal absorption of 59Fe from neutron-activated commercial oral 
iron(III)-citrate 
and 
iron(III)-hydroxide-polymaltose 
complexes 
in 
man 
// 
Arzneimittelforschung. 1987. Vol. 37, № 1A. P. 105–107. 
74. Bullen J.J., Griffiths E. Chichester. Iron and infection: molecular, physiological, and 
clinical aspects; New York: Wiley, 1988. 325 p. 
75. Membrahtu T. et al. Low-dose daily iron supplementation for 12 months does not increase 
the prevalence of malarial infection or density of parasites in young Zanzibari children // 
J. Nutr. 2004. Vol. 134, № 11. P. 3037–3041. 


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76. Tuomainen T.-P. et al. Serum ferritin concentration is associated with plasma levels of 
cholesterol oxidation products in man // Free Radic. Biol. Med. 2003. Vol. 35, № 8. P. 
922–928. 
77. Tuomainen T.-P. et al. Oral supplementation with ferrous sulfate but not with non-ionic 
iron polymaltose complex increases the susceptibility of plasma lipoproteins to oxidation 
// Nutr. Res. 1999. Vol. 19, № 8. P. 1121–1132. 
78. Milman N. et al. Iron status and iron balance during pregnancy. A critical reappraisal of 
iron supplementation // Acta Obstet. Gynecol. Scand. 1999. Vol. 78, № 9. P. 749–757. 
79. Jacobs P., Fransman D., Coghlan P. Comparative bioavailability of iron polymaltose and 
ferrous sulfate in iron-deficient blood donors //J.Clin. Apheresis. 1993. Vol. 8, № 2. P.89–
95. 
80. Schnell R. Ferrum Hausmann with Iron (III) Hydroxide Polymaltose complex as active 
agent - Efficient iron donors for iron deficiency Anemia // Frankfurt am Main: Der 
Kassenarzt, Kassenarzt-Verlag GmbH. 1998:2-4. 
81. Bogdanova O.M., Paschenko I.G. A comparative study of iron salts vs hydroxide 
polymaltose iron complex efficacy in the treatment of iron deficiency anemia in presenile 
and senile patients. 2004. Vol. 49. P. 29–32. 
82. Jacobs P., Wood L., Bird A.R. Erythrocytes: Better Tolerance of Iron Polymaltose 
Complex Compared with Ferrous sulfate in the Treatment of Anaemia // Hematol. Amst. 
Neth. 2000. Vol. 5, № 1. P. 77–83. 
83. Hercberg S. et al. Consequences of Iron Deficiency in Pregnant Women // Clin. Drug 
Investig. 2000. Vol. 19, № 1. P. 1–7. 
84. Bruner A.B. et al. Randomised study of cognitive effects of iron supplementation in non-
anaemic iron-deficient adolescent girls // Lancet Lond. Engl. 1996. Vol. 348, № 9033. P. 
992–996. 
85. Lozoff B. et al. Poorer behavioral and developmental outcome more than 10 years after 
treatment for iron deficiency in infancy // Pediatrics. 2000. Vol. 105, № 4. P. E51. 
86. Radtke H. et al. Iron supplementation and 2-unit red blood cell apheresis: a randomized, 
double-blind, placebo-controlled study // Transfusion (Paris). 2004. Vol. 44, № 10. P. 
1463–1467. 
87. Steffensen R., Varming K., Jersild C. Determination of gene frequencies for two common 
haemochromatosis mutations in the Danish population by a novel polymerase chain 
reaction with sequence‐specific primers. Tissue antigens, 52(3), 1998, pp. 230-235 
88. Vifor (International) Inc. Staining of teeth caused by iron (lll)-hydroxidepolymaltose 
complex and iron sulfate. 1999: 1-13. 
89. Abraham S.C., Yardley J.H., Wu T.T. Erosive injury to the upper gastrointestinal tract in 
patients receiving iron medication. Am. J. Surg. pathol. 1999; 23:1241-7. 


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90. Kavakli K. et al. Safety profiles of Fe2+ and Fe3+ oral preparations in the treatment of iron 
deficiency anemia in children // Pediatr. Hematol. Oncol. 2004. Vol. 21, № 5. P. 403–410. 
91. Sözmen E.Y. et al. Effects of iron(II) salts and iron(III) complexes on trace element status 
in children with iron deficiency anemia // Biol. Trace Elem. Res. 2003. Vol. 94, № 1. P. 
79–85. 
92. Bothwell T.H., Charlton R.W. Current problems of iron overload // Recent Results Cancer 
Res. Fortschritte Krebsforsch. Progres Dans Rech. Sur Cancer. 1979. Vol. 69. P. 87–95. 
93. Tuomainen T.P. et al. Body iron stores are associated with serum insulin and blood glucose 
concentrations. Population study in 1,013 eastern Finnish men // Diabetes Care. 1997. Vol. 
20, № 3. P. 426–428. 
94. Drug Acting on the blood and the blood forming organs; Section XI, 1494-1497. 
95. Idjradinata P., Watkins W.E., Pollitt E. Adverse effect of iron supplementation on weight 
gain of iron-replete young children // Lancet Lond. Engl. 1994. Vol. 343, № 8908. P. 1252–
1254. 
96. Johnson D.W. et al. Oral versus intravenous iron supplementation in peritoneal dialysis 
patients // Perit. Dial. Int. 2001. Vol. 21, № Suppl 3. P. S231–S235. 
97. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine // 
Nephron. 1976;16(1):31-41. 
 
 


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17 Appendices 
17.1 Appendix 1. Claims 
 
1. 
DEFINITIONS 
Non-compliance with the requirements of investigational medicinal product  (study product and 
reference product) or medical device use may include the following:  
 
1) 
Claims related to the quality of the product/medical device such as 
• 
any fault of quality and/or efficacy e.g. change of visual appearance, change of amount, 
damaged tablets/capsules, presence of particulate matter. 
• 
any fault of the containers and outer packages e.g. surface defect, container leakage, broken 
syringe/plunger, missing contents, device malfunction. 
• 
any fault of the labeling e.g. missing or illegible label. 
• 
any falsification of the medicinal product or medical device e.g. suspected product mix-
up, tampering or counterfeiting. 
 
2) 
Problems related to the transportation of the product, such as damaged packaging for 
transport and/or damaged secondary packaging after receipt of the goods, a lack of quantity of 
medicinal product in the packaging for transport, inadequate transport conditions. 
 
2. 
PROCEDURE 
In case any of the non-compliances listed above are detected or information about these has been 
received, the prepared Non-compliance Report must be sent to the sponsor (principal 
investigator/clinical research manager) within 24 hours. Simultaneously local monitor or CRA of 
the respective study must be informed about the non-compliance. If possible, a photo of the 
affected material should be attached to the report. Affected material should be retained and stored 
according to the storage conditions label and/or returned to sponsor if requested by the Sponsor. 
 
 
 
 
 
 
 
 
 
 
 
 
 


Ferr u m Le k ®  
Pa ge 1 1 5  of 1 1 6  
Pr ot oc ol N o. T E _ 0 0 5 _ F E R _ C H T  
 Versi o n 2 . 0 от 2 0. 0 3. 2 0 1 9  
 
 
 
1 7. 2  A p pe n di x 2. P atie nt di ar y  
Ha n de d o ut at visits 1, 2, a n d 3 
 
T o be fille d i n 
by t he 
p hysici a n:  
P atie nt di ary h a n d -o ut visit:   1   2   3  
P atie nt n u m ber:  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
 
 
 
1. Sc he d ule of i n vesti g ati o n al dr u g  a d mi nistr ati o n bet wee n t he visits   
D a y 
N o.  
D ate  
 
H a ve y o u t a ke n Ferr u m Le k ® / 
M alt ofer
®  acc or di n g t o t he 
me dic al prescri pti o n ?  
C o m me nt aries a n d 
c o m pl ai nts 
1 *  
_ _/ _ _/ _ _ _ _ _  
Yes          N o  
 
2  
_ _/ _ _/ _ _ _ _ _  
Yes          N o  
 
3  
_ _/ _ _/ _ _ _ _ _  
Yes          N o  
 
4  
_ _/ _ _/ _ _ _ _ _  
Yes          N o  
 
5  
_ _/ _ _/ _ _ _ _ _  
Yes          N o  
 
6  
_ _/ _ _/ _ _ _ _ _  
Yes          N o  
 
7  
_ _/ _ _/ _ _ _ _ _  
Yes          N o  
 
8  
_ _/ _ _/ _ _ _ _ _  
Yes          N o  
 
9  
_ _/ _ _/ _ _ _ _ _  
Yes          N o  
 
1 0  
_ _/ _ _/ _ _ _ _ _  
Yes          N o  
 
1 1  
_ _/ _ _/ _ _ _ _ _  
Yes          N o  
 
1 2  
_ _/ _ _/ _ _ _ _ _  
Yes          N o  
 
1 3  
_ _/ _ _/ _ _ _ _ _  
Yes          N o  
 
1 4  
_ _/ _ _/ _ _ _ _ _  
Yes          N o  
 
1 5  
_ _/ _ _/ _ _ _ _ _  
Yes          N o  
 
1 6  
_ _/ _ _/ _ _ _ _ _  
Yes          N o  
 
1 7  
_ _/ _ _/ _ _ _ _ _  
Yes          N o  
 
1 8  
_ _/ _ _/ _ _ _ _ _  
Yes          N o  
 
1 9  
_ _/ _ _/ _ _ _ _ _  
Yes          N o  
 
2 0  
_ _/ _ _/ _ _ _ _ _  
Yes          N o  
 
2 1  
_ _/ _ _/ _ _ _ _ _  
Yes          N o  
 
2 2  
_ _/ _ _/ _ _ _ _ _  
Yes          N o  
 
2 3  
_ _/ _ _/ _ _ _ _ _  
Yes          N o  
 
2 4  
_ _/ _ _/ _ _ _ _ _  
Yes          N o  
 
2 5  
_ _/ _ _/ _ _ _ _ _  
Yes          N o  
 
2 6  
_ _/ _ _/ _ _ _ _ _  
Yes          N o  
 
2 7  
_ _/ _ _/ _ _ _ _ _  
Yes          N o  
 
2 8  
_ _/ _ _/ _ _ _ _ _  
Yes          N o  
 
* Da y 1 – Visit da y.  
 


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2. Concomitant therapy 
If you took any vitamins or medications at your discretion together with  Ferrum 
Lek® or MALTOFER ®,  please, put them down in the table below and report to 
your physician about them. 
Product name 
Date 
started 
Date ended 
Reason for administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Please return the completed diary to the physician at the next visit 

SAP_001.pdf: 
Official Title: 
Multicenter, Open-label Active-controlled Randomized Study of Efficacy and 
Safety of Ferrum Lek® (Iron (III) Hydroxide Polymaltosate), 100 mg Chewable 
Tablets (Lek d.d., Slovenia) Compared With Maltofer® (Iron (III) Hydroxide 
Polymaltosate), 100 mg Chewable Tablets (Vifor S.A., Switzerland), in 
Treatment of Patients With Mild and Moderate Iron-deficiency Anaemia 
NCT Number: 
NCT03993288 
Document Date: 
Statistical Analysis Plan Version 1.0: 06 April 2020 


Перевод с русского языка на английский язык 
Translation from Russian into English 
 
/Logotype: Research/ 
STATISTICAL ANALYSIS PLAN 
 
-SOP-05-02_RF01 Statistical Analysis Plan_01APR2020_3.0 
 Confidential 
Page 1 of 68 
Statistical Analysis Plan 
 
Sponsor 
Sandoz CJSC 
Protocol title 
A multicenter, open-label, randomized, active-controlled 
study to evaluate the efficacy and safety of Ferrum Lek® 
(iron (III) hydroxide polymaltosate), 100 mg chewable tablets 
(Lek d.d., Slovenia), as compared to Maltofer® (iron (III) 
hydroxide polymaltosate), 100 mg chewable tablets 
(Vifor S.A., Switzerland), in subjects with mild and moderate 
iron deficiency anemia 
Protocol No. 
TE_005_FER_CHT 
 
Author 
 
Statistical Analysis Plan version 
1.0 
Date of version 
April 6, 2020 
 
 


/Logotype: Research/ 
STATISTICAL ANALYSIS PLAN 
 
-SOP-05-02_RF01 Statistical Analysis Plan_01APR2020_3.0 
 Confidential 
Page 2 of 68 
Approved by 
 
Full name 
Position 
Signature 
Date 
/Signature/ 
April 6, 2020 
/Signature/ 
April 6, 2020 
/Signature/ 
April 6, 2020 
/Signature/ 
April 6, 2020 
 
 
Document history 
 
Version 
Reason for change 
Date 
1.0 
Original document 
April 6, 2020 
 
 


/Logotype: Research/ 
STATISTICAL ANALYSIS PLAN 
 
-SOP-05-02_RF01 Statistical Analysis Plan_01APR2020_3.0 
 Confidential 
Page 3 of 68 
Table of contents 
 
1. 
Introduction ............................................................................................................................................... 7 
2. 
Study objectives and design ...................................................................................................................... 7 
2.1. 
Study objectives ................................................................................................................................ 7 
2.1.1. 
Primary objective ................................................................................................................... 7 
2.1.2. 
Secondary objectives .............................................................................................................. 7 
2.2. 
Study design...................................................................................................................................... 7 
4.2.6. Study design flowchart ................................................................................................................. 8 
Description of visits .................................................................................................................................... 8 
2.3. 
Sample size ..................................................................................................................................... 11 
3. 
General analysis values ........................................................................................................................... 13 
3.1. 
General assumptions and baseline conditions ................................................................................. 13 
3.2. 
Processing missing data .................................................................................................................. 13 
4. 
Study participants .................................................................................................................................... 13 
4.1. 
Patient distribution .......................................................................................................................... 13 
4.3. 
Study population ............................................................................................................................. 14 
4.3.1. 
Safety population .................................................................................................................. 14 
4.3.2. 
ITT population receiving treatment ................................................................................... 14 
4.3.3. 
Per protocol set ..................................................................................................................... 14 
5. 
Demographics and baseline characteristics ............................................................................................. 14 
6. 
Concomitant therapy ............................................................................................................................... 15 
6.1. 
Permitted concomitant therapy ....................................................................................................... 15 
6.2. 
Prohibited concomitant therapy ...................................................................................................... 15 
8. 
Efficacy analysis ..................................................................................................................................... 16 
8.1. 
Primary endpoint analysis ............................................................................................................... 16 
8.2. 
Analysis of the secondary endpoint ................................................................................................ 17 
9. 
Safety analysis ......................................................................................................................................... 18 
9.1. 
Adverse events ................................................................................................................................ 18 
9.2. 
Other safety endpoints .................................................................................................................... 19 
10. Exploratory analysis ................................................................................................................................ 19 
11. Interim analysis ....................................................................................................................................... 19 
Appendix 1. Table layouts ............................................................................................................................... 20 
SECONDARY ENDPOINTS .................................................................................................................... 21 
LABORATORY RESULTS ...................................................................................................................... 40 
Table 1. Urinalysis  ...................................................................................................................................  40 
Table 2. Urinalysis statistical test ..............................................................................................................  42 
Table 3. Urinalysis, categorical variables .................................................................................................. 43 
Table 4. Hematology 1 ..............................................................................................................................  43 
Table 5. Hematology 2 ..............................................................................................................................  48 
Table 6. Hematology 3 ............................................................................................................................... 49 
Table 7. Hematology 4 ............................................................................................................................... 51 
Table 8. Hematology, statistical test 1  .....................................................................................................  53 
Table 9. Hematology, statistical test 2  .....................................................................................................  53 
Table 10. Hematology, statistical test 3 ..................................................................................................... 53 
Table 11. Hematology, statistical test 4 ..................................................................................................... 54 
Table 12. Physiological data ...................................................................................................................... 54 
Table 13. Physiological data, statistical test ............................................................................................... 56 
Table 14. Physiological data, categorical data ........................................................................................... 56 
Table 15. Biochemistry 1 ........................................................................................................................... 56 
Table 16. Biochemistry 2 ........................................................................................................................... 59 
Table 17. Biochemistry 3 ........................................................................................................................... 61 
Table 18. Biochemistry, statistical test 1 .................................................................................................... 63 
Table 19. Biochemistry, statistical test 2 .................................................................................................... 63 
Table 20. Biochemistry, statistical test 3 .................................................................................................... 64 
ADVERSE EVENTS ................................................................................................................................ 65 


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Table 1. Adverse events reported in the study ....................................................................................... 65 
Tables N. Is the adverse event ongoing?/ Relatedness to the medicinal product/ Dose adjustment or temporary 
withdrawal of the IMP/ Complete withdrawal of the IMP/ Prescribing a concomitant medicinal product/ 
Prescribing non-drug therapy/ Patient admission to hospital or hospitalization prolongation/ Based on an AE/ Is it 
an SAE?/ Leads to death/ Threatens life/ Requires admission to hospital or hospitalization prolongation/ Leads to 
permanent or significant incapacity for work or disability .................................................................. 66 
 
 


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List of abbreviations and definitions of terms 
 
ANOVA 
Analysis of variance 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HFE 
Hemochromatosis gene 
ICH 
The International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use 
ITT 
Intention-to-treat 
LD100 
Lethal dose, the average dose of the substance in milligrams per kilogram of live 
weight, which causes the death of 100% of experimental animals 
LD50 
Half-lethal dose, the average dose of the substance in milligrams per kilogram of live 
weight, which causes the death of 50% of experimental animals 
MLE 
Maximum likelihood estimation 
PP 
Per protocol 
BP 
Blood pressure 
ALT 
Alanine aminotransferase 
JSC 
Joint-stock company 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical (classification system) 
VAS 
Visual analog scale 
HIV 
Human immunodeficiency virus 
IUS 
Intrauterine system 
IUD 
Intrauterine device 
Hb 
Hemoglobin 
GOST 
State standard 
GOSTR 
State Standard of Russia 
DBP 
Diastolic blood pressure 
ID 
Iron deficiency 
CI 
Confidence interval 
DMPO 
5,5-Dimethyl-1-pyrroline-N-oxide 
IDA 
Iron-deficiency anemia 
GI 
Gastrointestinal 
GI tract 
Gastrointestinal tract 
 
 


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CRF 
Case record form 
CRO 
Contract research organization 
LDL 
Low-density lipoprotein 
MoH 
Ministry of health 
 
MIC 
Minimum inhibitory concentration 
ICD 
International Classification of Diseases 
GCP 
Good Clinical Practice 
IEC 
Independent ethics committee 
AE 
Adverse event 
SmPC 
Summary of Product Characteristics 
PVC 
Polyvinyl chloride 
IHPC 
Iron (III) hydroxide polymaltose complex 
IPC 
Iron polymaltose complex 
PND 
Postnatal days 
PCR 
Polymerase chain reaction 
RMSAH/ 
RSC 
The Russian Medical Society on Arterial Hypertension/ The Russian Society of 
Cardiology 
ITP 
Iron transport proteins 1 and 2 
RE 
Reticuloendothelial (cells) 
RES 
Reticuloendothelial system 
SBP 
Systolic blood pressure 
SAE 
Serious adverse event 
SOD 
Superoxide dismutase 
SOP 
Standard operating procedure 
TF 
Transferrin 
TfR 
Transferrin receptor 
FL 
Federal law 
Full name 
First name, Patronymic, Last name 
CNS 
Central nervous system 
Cp 
Ceruloplasmin 
RR 
Respiration rate 
HR 
Heart rate 
ECG 
Electrocardiography 
 
 


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1. Introduction 
This study is planned and carried out to demonstrate the non-inferiority and safety of Ferrum Lek® 
(iron (III) hydroxide polymaltosate), 100 mg chewable tablets (Lek d.d., Slovenia), compared to 
MALTOFER® (Vifor S.A., Switzerland), in subjects with mild and moderate iron deficiency anemia. 
The objective of this Statistical Analysis Plan is more detailed, compared to Section 9 of the study 
protocol, description of the main principles of the protocol-based statistical analysis, description of the 
primary and secondary endpoints analysis methods as well as other data obtained during the study. 
This Plan stipulates for conformance of the scheduled and conducted statistical analysis to the study 
protocol, including the definition of the analysis data sets, transformations and calculations for the 
endpoints, observations quantity needed, etc. 
2. Study objectives and design 
2.1. Study objectives 
2.1.1. Primary objective 
To demonstrate non-inferior therapeutic efficacy of Ferrum Lek® by evaluating its effect on blood 
hemoglobin levels (g/L) when taken as 2 tablets (200 mg) per day for 12 weeks in subjects with mild to 
moderate iron deficiency anemia versus 2 tablets (200 mg) per day of MALTOFER® administered over the 
same period. 
2.1.2. Secondary objectives 
To evaluate the safety of Ferrum Lek® with 2 tablets (200 mg) per day versus MALTOFER® with 2 tablets 
(200 mg) per day by evaluating the rates, characteristics, severity of AEs, and their relation to the prescribed 
treatment. 
2.2. Study design 
This study is a multicenter, randomized, open-label, prospective, comparative, phase III, parallel-group, 
active control study conducted in the Russian Federation. 
The eligible and ineligible subjects will be randomized into two treatment groups at the ratio of 1:1. 
The subjects in the first group (168 subjects) will receive 2 tablets daily (200 mg) of Ferrum Lek® chewable 
tablets, during or right after meals; the daily dose should be administered once daily (as a single dose). The 
subjects in the second group (168 subjects) will receive 2 tablets daily (200 mg) of MALTOFER® chewable 
tablets, during or right after meals; the daily dose should be administered once daily. Subjects will take the 
medicinal products daily for 12 weeks and fill out a diary (see Appendix 17.1), where they will register 
administration of the study medicinal products and concomitant therapy. 
 
 


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All subjects will undergo a complete blood count and blood biochemistry. Therapy under investigation also 
includes an interim Visit 2 (Day 29 ± 2), Visit 3 (Day 57 ± 2), and final Visit 4 (84 ± 2). After the final 
visit, a subject's participation in the study shall be terminated, and further treatment shall be performed by 
a consulting physician. 
The study design is depicted in Figure 1. 
 
4.2.6. Study design flowchart 
 
 
 
Figure 1. Study design flowchart 
 
Study duration 
 
The total duration of the study will be no more than 12 months, including enrollment (9 months), 
treatment (3 months), and follow-up (by phone) 14 days after the completion of the active treatment 
period. 
 
Description of visits 
 
4.2.9.1. Visit 0 (screening, days −7...−1) 
Visit objectives: 
• Signing of the informed consent; 
• Assessment of the inclusion/exclusion criteria; 
 
Days  
−7...−1 
Day 1 
Day 29 ± 2 
Day 57 ± 2 
Day 84 ± 2 
Day 98 ± 2 
Signing of IMP/ICF, 
screening 
Randomization 
(n = 336) 
Ferrum Lek® 
(n = 168) 
MALTOFER® 
(n = 168) 
Treatment for 12 weeks 
Visit 0 
Visit 1 
Follow-up visit 
Visit 2 
Visit 3 
Visit 4 


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• Collection of demographic and anthropometric data; 
• Collection of medical history data on iron deficiency anemia and significant concomitant diseases;  
• Physical examination, blood pressure and heart rate measurement;  
• Laboratory tests: 
o Urinalysis [general properties (color, pH, specific gravity, protein) and sediment 
microscopy]; 
o Urine pregnancy test; 
o HIV antibody test, except for subjects who had an HIV test within the last 6 months; 
o Blood biochemistry (total protein, total and conjugated bilirubin, AST, ALT, alkaline 
phosphatase, creatinine, glucose, CRP); 
o Complete blood count (hemoglobin level, hematocrit, RBC, PLT, WBC, leucogram, ESR); 
o Metabolic parameters of iron (serum ferritin and iron level, transferrin, iron transferrin 
saturation percentage); 
o Determining blood vitamin В9 (folic acid) and vitamin В12 (cyanocobalamin) levels;  
o Determining blood TSH and Т4 levels; 
o Creatinine clearance calculation according to the Cockroft-Gault formula; 
• Evaluation of the concomitant therapy; • Adverse events registration. 
4.2.9.2. Visit 1 (randomization/ start of the treatment, Day 1) 
Visit objectives: 
• Assessment of the inclusion/exclusion criteria; 
• Randomization; 
• Start of the treatment with the investigational medicinal product; 
• Hand-out of the patient diary (Appendix 17.1) and instructions on its completion; 
• Accounting and dispensing of the investigational medicinal product; 
• Evaluation of the concomitant therapy; • Adverse events registration. 
4.2.9.3. Visit 2 (continuation of the treatment, Day 29 ± 2) 
Visit objectives: 
• Physical examination, blood pressure and heart rate measurement; 
 


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• Metabolic parameters of iron (serum ferritin and iron level, transferrin, iron transferrin saturation 
percentage); 
• Complete blood count (hemoglobin level, hematocrit, RBC); 
• Hand-out of the patient diary (Appendix 17.1) and instructions on its completion; 
• Check of a patient diary completion and collection of diaries; 
• Accounting and dispensing of the investigational medicinal product; 
• Evaluation of compliance; 
• Evaluation of the concomitant therapy; 
• Adverse events registration. 
4.2.9.4. Visit 3 (continuation of the treatment, Day 57 ± 2) 
Visit objectives: 
• Physical examination, blood pressure and heart rate measurement; 
• Metabolic parameters of iron (serum ferritin and iron level, transferrin, iron transferrin saturation 
percentage); 
• Complete blood count (hemoglobin level, hematocrit, RBC); 
• Hand-out of the patient diary (Appendix 17.1) and instructions on its completion; 
• Check of a patient diary completion and collection of diaries; 
• Accounting and dispensing of the investigational medicinal product; 
• Evaluation of compliance; 
• Evaluation of the concomitant therapy; 
• Adverse events registration. 
4.2.9.5. Visit 4 (efficacy and safety assessment, Day 84 ± 2) 
Visit objectives: 
• Physical examination, blood pressure and heart rate measurement; 
• Laboratory tests: 
o Urinalysis [general properties (color, pH, specific gravity, protein) and sediment 
microscopy]; 
o Urine pregnancy test; 
 


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o Blood biochemistry (total protein, total and conjugated bilirubin, AST, ALT, alkaline 
phosphatase, creatinine, glucose, CRP); 
o Complete blood count (hemoglobin level, hematocrit, RBC); 
o Metabolic parameters of iron (serum ferritin and iron level, transferrin, iron transferrin 
saturation percentage). 
• Check of a patient diary completion and collection of diaries; 
• Accounting and dispensing of the investigational medicinal product; 
• Evaluation of compliance; 
• Evaluation of the concomitant therapy; 
• Adverse events registration. 
4.2.9.6. Follow-up visit (Visit 5, Day 98 ± 2) 
A follow-up visit shall be conducted by phone to find out about the patient's state and any AEs. It will be 
conducted 14 days after the completion of treatment. 
Follow-up visit procedures (by phone): 
o Evaluation of adverse events. 
In case of adverse events, the patient might be invited to visit the study site. 
 
2.3. Sample size 
The sample size was calculated on the basis of the published articles, where the efficacy of iron (III) 
hydroxide polymaltosate was studied: 
1) Maltofer, Product Information http://www.aspenpharma.com.au/product_info/pi/PI_Maltofer.pdf 
2) Santiago P. Ferrous versus ferric oral iron formulations for the treatment of iron deficiency: a 
clinical overview. Scientific World Journal. 2012;2012:846824. 
3) Geisser P. Safety and efficacy of iron(III)-hydroxide polymaltose complex / a review of over 
25 years' experience. Arzneimittelforschung. 2007;57(6A):439-52; 
4) Toblli JE, Brignoli R. Iron(III)-hydroxide polymaltose complex in iron deficiency anemia/ review 
and meta-analysis. Arzneimittelforschung. 2007;57(6A):431-8); 
5) Reinisch W, Staun M, Tandon RK, Altorjay I, Thillainayagam AV, Gratzer C, Nijhawan S, 
Thomsen LL. A randomized, open-label, non-inferiority study of intravenous iron isomaltoside 
1,000 (Monofer) compared with oral iron for treatment of anemia in IBD (PROCEED). Am J 
Gastroenterol. 2013 Dec;108(12):1877-88. 
 


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6) Zaim M, Piselli L, Fioravanti P, Kanony-Truc C. Efficacy and tolerability of a prolonged release 
ferrous sulphate formulation in iron deficiency anaemia: a non-inferiority controlled trial. Eur J 
Nutr. 2012 Mar;51(2):221-9. 
Based on these publications, the hemoglobin levels increased by an average of 8–15 g/L, with SD of up to 
15 g/L, following 12 weeks of oral administration of iron (III) hydroxide polymaltosate complex 
preparations. Since approximately the same efficiency is assumed in both groups, a zero difference in the 
main efficiency parameter will be used to calculate the sample size. In order to take into account the 
maximum variability of the primary endpoint variable for the study with sufficient statistical power, the 
maximum standard deviation value of 15 g/L was used. 
The value of 5 g/L was chosen as the non-inferiority cut-off (in accordance with the limit established and 
justified in the above publications). 
Thus, the following assumptions were proposed for calculations: 
1) It is assumed that changes in the hemoglobin level in the blood (g/L) after 12 weeks of iron 
deficiency anemia therapy (at the final visit) compared to the initial value (at Screening Visit 0) 
will be approximately the same in the group receiving the investigational medicinal product and 
in the group receiving the reference product (i.e., the expected difference between the two groups 
will be zero). 
2) A pooled standard deviation for the changes in hemoglobin levels was 15 g/L. 
3) The non-inferiority margin is 5 g/L. 
4) The significance level (two-sided, according to the recommendations by the Food and Drug 
Administration) is 95%, which corresponds to a one-sided type I error of 0.05. 
5) The study power is 80%, which corresponds to a type II error of 0.20. 
6) Statistical hypotheses are the demonstration of non-inferiority: 
H0: μA–μB≤5.0 
H1 
:μA–μB>5.0 
7) The ratio between the test and control group sizes is 1:1. 
8) The interim analysis will be conducted when 70% of the total sample size is reached. 
9) The O'Brian-Fleming alpha-spending function will be applied with 80% power for the efficiency 
frontier, which will satisfy the following critical values of the t-test: 2.628 for the intermediate 
analysis (corresponding to p = 0.005) and 1.976 for the final analysis (corresponding to 
p = 0.0245). 
 


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Calculations were performed using the clinfun package of the R software, in which the calculation of a 
fixed sample size for interim and final analyses was performed using the group sequential design. 
According to the data obtained with the clinfun package, 143 subjects in each group (total: 286 subjects) 
should complete the study to confirm the hypothesis of non-inferiority. For the interim analysis, data for 
200 subjects (100 in each group) that are suitable for analysis should be obtained. Taking into account the 
frequency of premature discontinuation of the study, which is 15%, it is necessary to randomize 336 people 
(168 people in each group). Taking into consideration the withdrawal rate based on the results of the 
screening that equals to 30%, about 480 people should undergo screening to achieve the target level of 
randomization. 
3. 
General analysis values 
3.1. General assumptions and baseline conditions 
Clinical and statistical significance 
All the statistical tests within this study will be performed at a 95% confidence level (threshold value p to 
confirm statistical significance is 0.05). 
3.2. Processing missing data 
A method of filling in the missing data based on maximum likelihood estimation (MLE) for the primary 
endpoint will be applied if needed. 
The analysis of the rest of endpoint types and other parameters will be performed only on the basis of the 
available information without filling in the missing data in view of the short duration of the clinical study. 
4. 
Study participants 
4.1. Patient distribution 
Upon signing of the informed consent for participation in the study, the subjects undergo screening for up 
to 7 days. The eligible and ineligible subjects will be randomized into two treatment groups at the ratio of 
1:1. 
Automated randomization sheets will be generated; randomization will be carried out through an electronic 
CRF system with a randomization module. 
Each randomized patient will receive a unique number for the medicinal product dispensing during the 
study. The patient's number contains R letter and numbers from 001 to 336. Patients numbering does not 
depend on the study site and is consecutive. In addition to the number, the system will indicate the treatment 
group to which the patient is randomized. Randomization will be stratified according to two factors: 1) Sex 
(men vs. women); 2) Hemoglobin level (80–94 g/L versus 95–110 g/L). The randomization number cannot 
be changed during the study. 
 


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The medicinal product is given to the patient according to the information about the treatment group 
received from the CRF system. Study treatment also cannot be changed in the process of the study. 
Serious deviations from the Protocol should be reported as soon as possible to the Sponsor by the site staff 
and/or CRO and Monitor (if they are at the Site). 
The Sponsor must be informed of minor protocol deviations within 10 business days but before the start of 
the next study period or before the start of the bioanalytical/statistical phase. 
Sponsor has the right to terminate the study, and the Investigator has the right to stop subjects recruitment 
at any time. In the case of premature closing of the center/study, all completed as well as unused CRFs 
(including unused pages of partially completed CRFs) and other documents (excluding documents that must 
be kept in the center) must be returned to the Sponsor. Study materials can be destroyed only with the 
consent of the Sponsor. 
4.3. Study population 
4.3.1. Safety population 
All randomized subjects who received at least one dose of the investigational medicinal product and 
completed at least one safety parameters evaluation visit. As distinct from ITT population, the TS 
population will be analyzed depending on actually received treatment (not only prescribed) (in case of 
difference between the prescribed and received therapies). 
4.3.2. ITT population receiving treatment 
All randomized subjects who received at least one dose of the investigational medicinal product and 
completed at least one efficacy parameters evaluation visit. 
4.3.3. Per protocol set 
All randomized subjects who completed participation in the study in accordance with the protocol (have 
completed the prescribed period of treatment and follow-up without significant deviations from the 
protocol). 
5. 
Demographics and baseline characteristics 
All the data obtained in the groups before the study therapy initiation (demographic, laboratory, 
instrumental, and physical examinations data, vital signs, etc.) will be compared between the groups to 
determine the groups' comparability for analysis. 
 
 


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The Fisher's exact test and χ2 (chi-square) will be used to compare the qualitative and serial data, while 
the t-test or the Mann–Whitney test will be used for the quantitative data (depending on the quantitative 
data distribution). 
To assess the normality of the distribution, the Shapiro-Wilk test will be applied. In the event that any of 
the initial data reveal the incomparability of the study groups (statistically significant differences in 
demographic and other initial data between the groups), the analysis of the efficacy and safety parameters 
will be additionally performed, together with the primary planned analysis, using multi-factor statistics 
(ANOVA, ANCOVA, or logistic regression analysis depending on the type of the studied parameter), as 
adjusted for the initial indicator(s) that vary between the groups. 
6. 
Concomitant therapy 
6.1. Permitted concomitant therapy 
Patients will take medications, which they took before the enrollment, for the treatment of concomitant 
diseases during the study. Women that take oral contraceptives may continue taking them during the study. 
It is permitted and recommended to take vitamins (not containing iron), folic acid, and ascorbic acid by 
medical prescription as well as adhere to a diet with products rich in iron. 
It is not recommended to take non-steroidal anti-inflammatory medicinal products groundlessly, including 
selective inhibitors of cyclooxygenase, but these medicinal products may be prescribed by the Investigator 
due to medical indications. 
6.2. Prohibited concomitant therapy 
During the study, the enrolled patients must not take the following products: 
• prescribed for iron deficiency anemia: 
Pharmacotherapeutic groups 
Active substance (INN) 
Vitamin and mineral supplements 
 
Macro- and microelement supplements 
 
Vitamins and pseudovitamins 
Ascorbic acid 
 
 


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Pyridoxine 
Riboflavin 
Vitamin and pseudovitamins in combinations 
Multivitamins + Minerals 
Macro- and microelements 
Iron protein succinylate 
 
Hematogen 
Macro- and microelements in combinations 
Ferrous sulfate + Serine + Folic acid 
Multivitamins + Minerals 
Hematopoiesis-stimulating agents 
Iron (III) hydroxide polymaltosate complex 
Iron (III) hydroxide sucrose complex 
Ferrous gluconate 
Ferric carboxymaltosate 
Iron protein succinylate 
Ferrous sulfate 
Ferrous fumarate 
Ferrous chloride 
Cyanocobalamin 
Hematopoiesis-stimulating agents in 
combinations 
Iron (III) hydroxide polymaltosate complex + Folic 
acid 
Ferrous sulfate + Folic acid + Cyanocobalamin 
Ferrous sulfate + Folic acid 
Ferrous fumarate + Folic acid 
and any other substances affecting hematopoiesis (for example, cytostatic agents, interferons, 
chloramphenicol, streptomycin). 
• Other substances that influence hematopoiesis (epoetins, anabolic steroids, etc.) 
• Medicinal products that slow iron absorption (antacids, calcium supplements), 2 hours before 
administration of the investigational products. It is not recommended to drink strong tea and coffee 
2 hours before the administration of medicinal products. 
During the study, the patients must not undergo physiotherapy or other procedures that potentially affect 
erythropoiesis (for example, Buteyko breathing). 
8. 
Efficacy analysis 
8.1. Primary endpoint analysis 
• Changes in hemoglobin level (g/L) after 12 weeks of iron deficiency therapy (at the final visit) as 
compared to baseline (determined at the screening visit) in the study groups. 


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The covariance analysis (ANCOVA) will be used as the main method for assessing the primary endpoint, 
with the baseline blood hemoglobin level as a covariate, and four fixed factors (treatment group, sex, 
weight, and baseline hemoglobin level (80–94 g/L vs. 95–110 g/L). The method of unrestricted least 
significant differences (LSD) will be applied to ANCOVA results with LS mean values from 95% CI for 
mean values calculated by the method of least squares for differences between the studied groups. Due to 
the obvious dependence of the covariates and the base hemoglobin factor (80–94 g/L compared to 95–
110 g/L), a linear model containing the term of interaction between these variables will be used. 
Non-inferiority will be confirmed if the upper bound of a two-sided confidence interval for the mean value 
calculated by the method of least squares does not exceed the predetermined non-inferiority margin of 
5 g/L. The CI percentage will be determined by the moment of the analysis (interim/final) in accordance 
with clause 2.3 of the Statistical Analysis Plan. 
8.2. Analysis of the secondary endpoint 
• Absolute values and changes in hemoglobin level (g/L) after 4, 8, and 12 weeks of therapy 
(determined at the final visit) between the study groups. 
• Changes in iron metabolism parameters mean values (ferritin, transferrin, percent transferrin 
saturation, serum iron) during the therapy period (from the screening to the study end visit) in the 
study groups. 
• The responder rate (%) was determined as an increase in the hemoglobin level by ≥ 20 g/L after 
12 weeks of treatment (from screening to the study end visit) in the study groups. 
The data will be checked for compliance with the normal distribution law using the Shapiro–Wilk test. 
Intergroup comparison of secondary endpoints related to quantitative scales will be performed using 
Student's t-test for independent samples if the data correspond to the normal distribution law; otherwise, 
the Mann–Whitney U test will be applied to independent samples. 
Intergroup comparisons of secondary endpoints related to categorical scales will be performed using 
Pearson's chi-square test if the number of points in each cell of the crosstab is ≥ 5, or Fisher's exact test if 
at least one of the crosstab cells contains < 5 points. 
The dynamics will be assessed using ANOVA methods with repeated measurements if the data correspond 
to the normal distribution; otherwise, the Friedman test will be applied. 
 


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9. 
Safety analysis 
Safety evaluation of the study therapy will be performed throughout the study and will be based on the 
detection of any adverse events occurring during the study. The following will be performed: 
• Physical examination, including measurement of blood pressure and heart rate, and gastrointestinal 
disorders identification (at the screening, during the second visit, and the final visit). 
• Complete blood count (at screening and in 4, 8, and 12 weeks of treatment); 
• Blood biochemistry (at screening and after 12 weeks of treatment); 
• Clinical urinalysis, pregnancy test (at screening and in 12 weeks); 
• Registration of concomitant therapy (at each visit). 
9.1. Adverse events 
The safety assessment will include determining the total number, frequency, and severity of: 
1. Adverse events (AEs), regardless of their relation to the treatment; 
2. AEs associated or potentially associated with the medicinal product; 
3. AEs requiring treatment discontinuation. 
Adverse events will be coded using the MedDRA nomenclature in the latest version. These will be 
represented by the preferred term (PT) and systemic organ class (SOC). 
Methods of descriptive statistics will be used to represent the results. Comparison of the incidence of new 
cases of AE in the study groups will be carried out using Fisher's exact test or Pearson's χ2 test, depending 
on the number of observations in one cell (< 5 or ≥ 5). 
Changes in the results of laboratory tests over time and the incidence of abnormal test results (based on the 
reference values of the central laboratory) will be summarized by groups, and a comparison will be made 
between the groups using appropriate tests for quantitative and qualitative data. 
Safety data will be analyzed using the methods designated for the application of efficacy data evaluation. 


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9.2. Other safety endpoints 
No other safety endpoints are foreseen in this study. 
 
10. Exploratory analysis 
In the course of this study, exploratory analysis is not envisaged. 
 
11. 
Interim analysis 
One interim analysis is planned to assess the primary and secondary efficacy endpoints when a group of 
patients with available data on the primary endpoint will include at least 200 subjects [100 patients in each 
treatment group: in the main treatment group of patients taking Ferrum Lek® (iron (III) hydroxide 
polymaltosate complex) and in the control group of patients taking MALTOFER® (iron (III) hydroxide 
polymaltosate complex]. Safety and efficacy will be assessed in all patients who have received at least one 
dose of randomized therapy at the time of the interim analysis. Based on the results of the interim analysis 
of the primary and secondary statistical endpoints of efficacy and safety, the Sponsor may decide to 
discontinue the study if the endpoints of the study are achieved in accordance with the protocol based on 
the results of the interim analyses or the sample size can be recalculated using the results of the interim 
analysis. 
 


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Appendix 1. Table layouts 
 
PRIMARY ENDPOINT 
 
Parameter 
Coef. 
Standard error 
t-value 
p-value 
CI 
Constant (intercept) 
 
 
 
 
 
 
Group R versus Group T 
 
 
 
 
 
 
Gender M versus F 
 
 
 
 
 
 
Weight 
 
 
 
 
 
 
Base hemoglobin factor (80–94 g/L compared to 95–110 g/L) 
 
 
 
 
 
 
Hemoglobin level at screening 
 
 
 
 
 
 
Interactions 
 
 
 
 
 
 
 


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SECONDARY ENDPOINTS 
 
Table 1. Hemoglobin, frequency analysis of the treatment efficacy after 12 weeks 
 
Hemoglobin (g/L) 
Group 
Parameter 
Value 
R – Maltofer® 
Total observations 
 
Responders, n 
 
Responders, % 
 
95% CI 
 
T – Ferrum Lek® 
Total observations 
 
Responders, n 
 
Responders, % 
 
95% CI 
 
Group comparison 
Pearson's chi-square test, p-value 
 
 
 


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Table 2. Results of analysis of variance 
 
Coefficients 
Evaluation Standard error 
t-value 
p-value 
(Intercept) 
 
 
 
 
V1_CB_LBORRES_HB 
 
(Hemoglobin level at screening) 
 
 
 
 
Group T – Ferrum Lek® 
 
(Test to reference group factor) 
 
 
 
 
 
 
Table 3. Hemoglobin, absolute values, g/L 
 
Hemoglobin (g/L) 
Group 
Parameter 
Screening 
Week 4 
Week 8 
Week 12 
R – Maltofer® 
Number of observations 
 
 
 
 
Number of missing values 
 
 
 
 
Mean value 
 
 
 
 
95% CI 
 
 
 
 
Standard deviation 
 
 
 
 
Median 
 
 
 
 
Minimum value 
 
 
 
 
Maximum value 
 
 
 
 
 
 


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1st quartile 
 
 
 
 
3rd quartile 
 
 
 
 
Interquartile range 
 
 
 
 
p-value 
(Shapiro–Wilk test) 
 
 
 
 
T – Ferrum Lek® 
Number of observations 
 
 
 
 
Number of missing values 
 
 
 
 
Mean value 
 
 
 
 
95% CI 
 
 
 
 
Standard deviation 
 
 
 
 
Median 
 
 
 
 
Minimum value 
 
 
 
 
Maximum value 
 
 
 
 
1st quartile 
 
 
 
 
3rd quartile 
 
 
 
 
Interquartile range 
 
 
 
 
p-value 
(Shapiro–Wilk test) 
 
 
 
 
Group 
comparison 
Criterion 
 
 
 
 
p-value 
 
 
 
 
 
 


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Table 4. Hemoglobin, changes, g/L 
 
Hemoglobin (g/L) 
Group 
Parameter 
Week 4 – Screening 
Week 8 – Screening Week 12 – Screening 
R – Maltofer® 
Number of observations 
 
 
 
Number of missing values 
 
 
 
Mean value 
 
 
 
95% CI 
 
 
 
Standard deviation 
 
 
 
Median 
 
 
 
Minimum value 
 
 
 
Maximum value 
 
 
 
1st quartile 
 
 
 
3rd quartile 
 
 
 
Interquartile range 
 
 
 
p-value 
(Shapiro–Wilk test) 
 
 
 
T – Ferrum Lek® 
Number of observations 
 
 
 
Number of missing values 
 
 
 
Mean value 
 
 
 
95% CI 
 
 
 
Standard deviation 
 
 
 
Median 
 
 
 
Minimum value 
 
 
 
 
 


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Maximum value 
 
 
 
1st quartile 
 
 
 
3rd quartile 
 
 
 
Interquartile range 
 
 
 
p-value 
(Shapiro–Wilk test) 
 
 
 
Group comparison 
Criterion 
 
 
 
p-value 
 
 
 
 
 
Table 5. Blood serum iron, absolute values, μmol/L 
 
Serum iron level (μmol/L) 
Group 
Parameter 
Screening 
Week 4 
Week 8 
Week 12 
R – Maltofer® 
Number of observations 
 
 
 
 
Number of missing values 
 
 
 
 
Mean value 
 
 
 
 
95% CI 
 
 
 
 
Standard deviation 
 
 
 
 
Median 
 
 
 
 
Minimum value 
 
 
 
 
Maximum value 
 
 
 
 
 
 


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1st quartile 
 
 
 
 
3rd quartile 
 
 
 
 
Interquartile range 
 
 
 
 
p-value 
(Shapiro–Wilk test) 
 
 
 
 
T – Ferrum Lek® 
Number of observations 
 
 
 
 
Number of missing values 
 
 
 
 
Mean value 
 
 
 
 
95% CI 
 
 
 
 
Standard deviation 
 
 
 
 
Median 
 
 
 
 
Minimum value 
 
 
 
 
Maximum value 
 
 
 
 
1st quartile 
 
 
 
 
3rd quartile 
 
 
 
 
Interquartile range 
 
 
 
 
p-value 
(Shapiro–Wilk test) 
 
 
 
 
Group comparison 
Criterion 
 
 
 
 
p-value 
 
 
 
 
 
 


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Table 6. Blood serum iron, changes, μmol/L 
 
Serum iron level (μmol/L) 
Group 
Parameter 
Week 4 – 
Screening 
Week 8 – 
Screening 
Week 12 – 
Screening 
R – Maltofer® 
Number of observations 
 
 
 
Number of missing values 
 
 
 
Mean value 
 
 
 
95% CI 
 
 
 
Standard deviation 
 
 
 
Median 
 
 
 
Minimum value 
 
 
 
Maximum value 
 
 
 
1st quartile 
 
 
 
3rd quartile 
 
 
 
Interquartile range 
 
 
 
p-value 
(Shapiro–Wilk test) 
 
 
 
T – Ferrum Lek® 
Number of observations 
 
 
 
Number of missing values 
 
 
 
Mean value 
 
 
 
95% CI 
 
 
 
Standard deviation 
 
 
 
Median 
 
 
 
Minimum value 
 
 
 
 
 


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Maximum value 
 
 
 
1st quartile 
 
 
 
3rd quartile 
 
 
 
Interquartile range 
 
 
 
p-value 
(Shapiro–Wilk test) 
 
 
 
Group comparison 
Criterion 
 
 
 
p-value 
 
 
 
 
 


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Table 7. Transferrin, absolute values, g/L 
 
Transferrin (g/L) 
Group 
Parameter 
Screening 
Week 4 
Week 8 
Week 12 
R – Maltofer® 
Number of observations 
 
 
 
 
Number of missing values 
 
 
 
 
Mean value 
 
 
 
 
95% CI 
 
 
 
 
Standard deviation 
 
 
 
 
Median 
 
 
 
 
Minimum value 
 
 
 
 
Maximum value 
 
 
 
 
1st quartile 
 
 
 
 
3rd quartile 
 
 
 
 
Interquartile range 
 
 
 
 
p-value (Shapiro–Wilk test) 
 
 
 
 
T – Ferrum Lek® 
Number of observations 
 
 
 
 
Number of missing values 
 
 
 
 
Mean value 
 
 
 
 
95% CI 
 
 
 
 
Standard deviation 
 
 
 
 
Median 
 
 
 
 
 
 


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Minimum value 
 
 
 
 
Maximum value 
 
 
 
 
1st quartile 
 
 
 
 
3rd quartile 
 
 
 
 
Interquartile range 
 
 
 
 
p-value (Shapiro–Wilk test) 
 
 
 
 
Group 
comparison 
Criterion 
 
 
 
 
p-value 
 
 
 
 
 
 


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Table 8. Transferrin, changes, g/L 
 
Transferrin (g/L) 
Group 
Parameter 
Week 4 – Screening 
Week 8 – Screening Week 12 – Screening 
R – Maltofer® 
Number of observations 
 
 
 
Number of missing values 
 
 
 
Mean value 
 
 
 
95% CI 
 
 
 
Standard deviation 
 
 
 
Median 
 
 
 
Minimum value 
 
 
 
Maximum value 
 
 
 
1st quartile 
 
 
 
3rd quartile 
 
 
 
Interquartile range 
 
 
 
p-value 
(Shapiro–Wilk test) 
 
 
 
T – Ferrum Lek® 
Number of observations 
 
 
 
Number of missing values 
 
 
 
Mean value 
 
 
 
95% CI 
 
 
 
Standard deviation 
 
 
 
Median 
 
 
 
 
 


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Minimum value 
 
 
 
Maximum value 
 
 
 
1st quartile 
 
 
 
3rd quartile 
 
 
 
Interquartile range 
 
 
 
p-value 
(Shapiro–Wilk test) 
 
 
 
Group comparison 
Criterion 
 
 
 
p-value 
 
 
 
 
 
Table 9. Percentage of transferrin saturation with iron, absolute values (%) 
 
Percentage of transferrin saturation with iron (%) 
Group 
Parameter 
Screening 
Week 4 
Week 8 
Week 12 
R – Maltofer® 
Number of observations 
 
 
 
 
Number of missing values 
 
 
 
 
Mean value 
 
 
 
 
95% CI 
 
 
 
 
Standard deviation 
 
 
 
 
Median 
 
 
 
 
Minimum value 
 
 
 
 
Maximum value 
 
 
 
 
 
 


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1st quartile 
 
 
 
 
3rd quartile 
 
 
 
 
Interquartile range 
 
 
 
 
p-value 
(Shapiro–Wilk test) 
 
 
 
 
T – Ferrum Lek® 
Number of observations 
 
 
 
 
Number of missing values 
 
 
 
 
Mean value 
 
 
 
 
95% CI 
 
 
 
 
Standard deviation 
 
 
 
 
Median 
 
 
 
 
Minimum value 
 
 
 
 
Maximum value 
 
 
 
 
1st quartile 
 
 
 
 
3rd quartile 
 
 
 
 
Interquartile range 
 
 
 
 
p-value 
(Shapiro–Wilk test) 
 
 
 
 
Group comparison 
Criterion 
 
 
 
 
p-value 
 
 
 
 
 
 


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Table 10. Percentage of transferrin saturation with iron, changes (%) 
 
Percentage of transferrin saturation with iron (%) 
Group 
Parameter 
Week 4 – 
Screening 
Week 8 – 
Screening 
Week 12 – 
Screening 
R – Maltofer® 
Number of observations 
 
 
 
Number of missing values 
 
 
 
Mean value 
 
 
 
95% CI 
 
 
 
Standard deviation 
 
 
 
Median 
 
 
 
Minimum value 
 
 
 
Maximum value 
 
 
 
1st quartile 
 
 
 
3rd quartile 
 
 
 
Interquartile range 
 
 
 
p-value (Shapiro–Wilk test) 
 
 
 
T – Ferrum Lek® 
Number of observations 
 
 
 
Number of missing values 
 
 
 
Mean value 
 
 
 
95% CI 
 
 
 
Standard deviation 
 
 
 
Median 
 
 
 
 
 


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Minimum value 
 
 
 
Maximum value 
 
 
 
1st quartile 
 
 
 
3rd quartile 
 
 
 
Interquartile range 
 
 
 
p-value (Shapiro–Wilk test) 
 
 
 
Group comparison 
Criterion 
 
 
 
p-value 
 
 
 
 
 


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Table 11. Ferritin, absolute values, μg/L 
 
Serum ferritin level (μg/L) 
Group 
Parameter 
Screening 
Week 4 
Week 8 
Week 12 
R – Maltofer® 
Number of observations 
 
 
 
 
Number of missing values 
 
 
 
 
Mean value 
 
 
 
 
95% CI 
 
 
 
 
Standard deviation 
 
 
 
 
Median 
 
 
 
 
Minimum value 
 
 
 
 
Maximum value 
 
 
 
 
1st quartile 
 
 
 
 
3rd quartile 
 
 
 
 
Interquartile range 
 
 
 
 
p-value 
(Shapiro–Wilk test) 
 
 
 
 
T – Ferrum Lek® 
Number of observations 
 
 
 
 
Number of missing values 
 
 
 
 
Mean value 
 
 
 
 
95% CI 
 
 
 
 
 
 


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Standard deviation 
 
 
 
 
Median 
 
 
 
 
Minimum value 
 
 
 
 
Maximum value 
 
 
 
 
1st quartile 
 
 
 
 
3rd quartile 
 
 
 
 
Interquartile range 
 
 
 
 
p-value 
(Shapiro–Wilk test) 
 
 
 
 
Group comparison 
Criterion 
 
 
 
 
p-value 
 
 
 
 
 
 


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Table 12. Ferritin, changes, μg/L 
 
Serum ferritin level (μg/L) 
Group 
Parameter 
Week 4 – 
Screening 
Week 8 – 
Screening 
Week 12 – 
Screening 
R – Maltofer® 
Number of observations 
 
 
 
Number of missing values 
 
 
 
Mean value 
 
 
 
95% CI 
 
 
 
Standard deviation 
 
 
 
Median 
 
 
 
Minimum value 
 
 
 
Maximum value 
 
 
 
1st quartile 
 
 
 
3rd quartile 
 
 
 
Interquartile range 
 
 
 
p-value 
(Shapiro–Wilk test) 
 
 
 
T – Ferrum Lek® 
Number of observations 
 
 
 
Number of missing values 
 
 
 
Mean value 
 
 
 
95% CI 
 
 
 
Standard deviation 
 
 
 
Median 
 
 
 
 
 


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Minimum value 
 
 
 
Maximum value 
 
 
 
1st quartile 
 
 
 
3rd quartile 
 
 
 
Interquartile range 
 
 
 
p-value (Shapiro–Wilk test) 
 
 
 
Group comparison 
Criterion 
 
 
 
p-value 
 
 
 
 


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LABORATORY RESULTS 
 
Table 1. Urinalysis 
 
Visit 
Group 
Parameter 
pH 
Protein 
Specific gravity 
RBC 
V1 
Treatment group: 
R – Maltofer® 
N 
 
 
 
 
Missed 
 
 
 
 
Beyond the limit of 
detection 
 
 
 
 
Mean 
 
 
 
 
95% CI 
 
 
 
 
SD 
 
 
 
 
Median 
 
 
 
 
Min 
 
 
 
 
Max 
 
 
 
 
Q1.25% 
 
 
 
 
Q3.75% 
 
 
 
 
IQR.75% 
 
 
 
 
Treatment group: 
T – Ferrum Lek® 
N 
 
 
 
 
Missed 
 
 
 
 
Beyond the limit of 
detection 
 
 
 
 
Mean 
 
 
 
 
 
 


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Visit 
Group 
Parameter 
pH 
Protein 
Specific gravity 
RBC 
 
 
95% CI 
 
 
 
 
SD 
 
 
 
 
Median 
 
 
 
 
Min 
 
 
 
 
Max 
 
 
 
 
Q1.25% 
 
 
 
 
Q3.75% 
 
 
 
 
IQR.75% 
 
 
 
 
V5 
Treatment group: 
R – Maltofer® 
N 
 
 
 
 
Missed 
 
 
 
 
Beyond the limit of 
detection 
 
 
 
 
Mean 
 
 
 
 
95% CI 
 
 
 
 
SD 
 
 
 
 
Median 
 
 
 
 
Min 
 
 
 
 
Max 
 
 
 
 
Q1.25% 
 
 
 
 
Q3.75% 
 
 
 
 
IQR.75% 
 
 
 
 
 
N 
 
 
 
 
 
 


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Visit 
Group 
Parameter 
pH 
Protein 
Specific gravity 
RBC 
 
Treatment group: 
T – Ferrum Lek® 
Missed 
 
 
 
 
Beyond the limit of 
detection 
 
 
 
 
Mean 
 
 
 
 
95% CI 
 
 
 
 
SD 
 
 
 
 
Median 
 
 
 
 
Min 
 
 
 
 
Max 
 
 
 
 
Q1.25% 
 
 
 
 
Q3.75% 
 
 
 
 
IQR.75% 
 
 
 
 
 
Table 2. Urinalysis statistical test 
 
Visit 
V1 
V5 
V1 
V5 
V1 
V5 
V1 
V5 
Variable 
pH 
Protein 
Specific gravity 
RBC 
Shapiro–Wilk test, p-value 
Treatment group: 
R – Maltofer® 
 
 
 
 
 
 
 
 
Treatment group: 
T – Ferrum Lek® 
 
 
 
 
 
 
 
 
Student's t-test, p-value 
 
 
 
 
 
 
 
 
Wilcoxon–Mann–Whitney test, p-value 
 
 
 
 
 
 
 
 
 
 


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Table 3. Urinalysis, categorical variables 
Visit 
Variable 
Group 
Distribution of responses 
Chi-square test, p-value 
V1 
WBC 
Treatment group: 
R – Maltofer® 
 
 
Treatment group: 
T – Ferrum Lek® 
 
Color 
Treatment group: 
R – Maltofer® 
 
 
Treatment group: 
T – Ferrum Lek® 
 
V5 
WBC 
Treatment group: 
R – Maltofer® 
 
 
Treatment group: 
T – Ferrum Lek® 
 
Color 
Treatment group: 
R – Maltofer® 
 
 
Treatment group: 
T – Ferrum Lek® 
 
 
Table 4. Hematology 1 
Visit 
Group 
Parameter 
Hematocrit (%) 
Hemoglobin 
RBC 
V1 
Treatment group: 
R – Maltofer® 
N 
 
 
 
Missed 
 
 
 
Beyond the limit of detection 
 
 
 
Mean 
 
 
 
 
 


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Visit 
Group 
Parameter 
Hematocrit (%) 
Hemoglobin 
RBC 
 
 
95% CI 
 
 
 
SD 
 
 
 
Median 
 
 
 
Min 
 
 
 
Max 
 
 
 
Q1.25% 
 
 
 
Q3.75% 
 
 
 
IQR.75% 
 
 
 
Treatment group: 
T – Ferrum Lek® 
N 
 
 
 
Missed 
 
 
 
Beyond the limit of detection 
 
 
 
Mean 
 
 
 
95% CI 
 
 
 
SD 
 
 
 
Median 
 
 
 
Min 
 
 
 
Max 
 
 
 
Q1.25% 
 
 
 
Q3.75% 
 
 
 
IQR.75% 
 
 
 
V3 
Treatment group: 
R – Maltofer® 
N 
 
 
 
Missed 
 
 
 
 
 


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Visit 
Group 
Parameter 
Hematocrit (%) 
Hemoglobin 
RBC 
 
 
Beyond the limit of detection 
 
 
 
Mean 
 
 
 
95% CI 
 
 
 
SD 
 
 
 
Median 
 
 
 
Min 
 
 
 
Max 
 
 
 
Q1.25% 
 
 
 
Q3.75% 
 
 
 
IQR.75% 
 
 
 
Treatment group: 
T – Ferrum Lek® 
N 
 
 
 
Missed 
 
 
 
Beyond the limit of detection 
 
 
 
Mean 
 
 
 
95% CI 
 
 
 
SD 
 
 
 
Median 
 
 
 
Min 
 
 
 
Max 
 
 
 
Q1.25% 
 
 
 
Q3.75% 
 
 
 
 
 


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Visit 
Group 
Parameter 
Hematocrit (%) 
Hemoglobin 
RBC 
 
 
IQR.75% 
 
 
 
V4 
Treatment group: 
R – Maltofer® 
N 
 
 
 
Missed 
 
 
 
Beyond the limit of detection 
 
 
 
Mean 
 
 
 
95% CI 
 
 
 
SD 
 
 
 
Median 
 
 
 
Min 
 
 
 
Max 
 
 
 
Q1.25% 
 
 
 
Q3.75% 
 
 
 
IQR.75% 
 
 
 
Treatment group: 
T – Ferrum Lek® 
N 
 
 
 
Missed 
 
 
 
Beyond the limit of detection 
 
 
 
Mean 
 
 
 
95% CI 
 
 
 
SD 
 
 
 
Median 
 
 
 
Min 
 
 
 
 
 


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Visit 
Group 
Parameter 
Hematocrit (%) 
Hemoglobin 
RBC 
 
 
Max 
 
 
 
Q1.25% 
 
 
 
Q3.75% 
 
 
 
IQR.75% 
 
 
 
V5 
Treatment group: 
R – Maltofer® 
N 
 
 
 
Missed 
 
 
 
Beyond the limit of detection 
 
 
 
Mean 
 
 
 
95% CI 
 
 
 
SD 
 
 
 
Median 
 
 
 
Min 
 
 
 
Max 
 
 
 
Q1.25% 
 
 
 
Q3.75% 
 
 
 
IQR.75% 
 
 
 
Treatment group: 
T – Ferrum Lek® 
N 
 
 
 
Missed 
 
 
 
Beyond the limit of detection 
 
 
 
Mean 
 
 
 
95% CI 
 
 
 
 
 


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Visit 
Group 
Parameter 
Hematocrit (%) 
Hemoglobin 
RBC 
 
 
SD 
 
 
 
Median 
 
 
 
Min 
 
 
 
Max 
 
 
 
Q1.25% 
 
 
 
Q3.75% 
 
 
 
IQR.75% 
 
 
 
 
Table 5. Hematology 2 
Visit 
Group 
Parameter 
WBC 
Lymphocytes 
Lymphocytes (%) 
V1 
Treatment group: 
R – Maltofer® 
N 
 
 
 
Missed 
 
 
 
Beyond the limit of detection 
 
 
 
Mean 
 
 
 
95% CI 
 
 
 
SD 
 
 
 
Median 
 
 
 
Min 
 
 
 
Max 
 
 
 
Q1.25% 
 
 
 
Q3.75% 
 
 
 
IQR.75% 
 
 
 
 
 


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Visit 
Group 
Parameter 
WBC 
Lymphocytes 
Lymphocytes (%) 
 
Treatment group: 
T – Ferrum Lek® 
N 
 
 
 
Missed 
 
 
 
Beyond the limit of detection 
 
 
 
Mean 
 
 
 
95% CI 
 
 
 
SD 
 
 
 
Median 
 
 
 
Min 
 
 
 
Max 
 
 
 
Q1.25% 
 
 
 
Q3.75% 
 
 
 
IQR.75% 
 
 
 
 
Table 6. Hematology 3 
Visit 
Group 
Parameter 
Neutrophils 
Neutrophils (%) 
Stab neutrophils (%) 
Segmented neutrophils 
(%) 
V1 
Treatment group: 
R – Maltofer® 
N 
 
 
 
 
Missed 
 
 
 
 
Beyond the limit of 
detection 
 
 
 
 
Mean 
 
 
 
 
95% CI 
 
 
 
 
SD 
 
 
 
 
 
 


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Visit 
Group 
Parameter 
Neutrophils 
Neutrophils (%) 
Stab neutrophils (%) 
Segmented neutrophils 
(%) 
 
 
Median 
 
 
 
 
Min 
 
 
 
 
Max 
 
 
 
 
Q1.25% 
 
 
 
 
Q3.75% 
 
 
 
 
IQR.75% 
 
 
 
 
Treatment group: 
T – Ferrum Lek® 
N 
 
 
 
 
Missed 
 
 
 
 
Beyond the limit of 
detection 
 
 
 
 
Mean 
 
 
 
 
95% CI 
 
 
 
 
SD 
 
 
 
 
Median 
 
 
 
 
Min 
 
 
 
 
Max 
 
 
 
 
Q1.25% 
 
 
 
 
Q3.75% 
 
 
 
 
IQR.75% 
 
 
 
 
 
 


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Table 7. Hematology 4 
Visit 
Group 
Parameter 
Basophils 
Basophils (%) 
ESR 
Platelets 
Eosinophils 
Eosinophils 
(%) 
V1 
Treatment group: 
R – Maltofer® 
N 
 
 
 
 
 
 
Missed 
 
 
 
 
 
 
Beyond the limit of 
detection 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
95% CI 
 
 
 
 
 
 
SD 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
Min 
 
 
 
 
 
 
Max 
 
 
 
 
 
 
Q1.25% 
 
 
 
 
 
 
Q3.75% 
 
 
 
 
 
 
IQR.75% 
 
 
 
 
 
 
Treatment group: 
T – Ferrum Lek® 
N 
 
 
 
 
 
 
Missed 
 
 
 
 
 
 
Beyond the limit of 
detection 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
95% CI 
 
 
 
 
 
 
SD 
 
 
 
 
 
 
 
 


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Visit 
Group 
Parameter 
Basophils 
Basophils (%) 
ESR 
Platelets 
Eosinophils 
Eosinophils 
(%) 
 
 
Median 
 
 
 
 
 
 
Min 
 
 
 
 
 
 
Max 
 
 
 
 
 
 
Q1.25% 
 
 
 
 
 
 
Q3.75% 
 
 
 
 
 
 
IQR.75% 
 
 
 
 
 
 
 
 


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Table 8. Hematology, statistical test 1 
Visit 
V1 
V3 
V4 
V5 
V1 
V3 
V4 
V5 
V1 
V3 
V4 
V5 
Variable 
Hematocrit (%) 
Hemoglobin 
RBC 
Shapiro– 
Wilk test, p-
value 
Treatment 
group: R – 
Maltofer® 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
group: T – 
Ferrum Lek® 
 
 
 
 
 
 
 
 
 
 
 
 
Student's t-test, p-value 
 
 
 
 
 
 
 
 
 
 
 
 
Wilcoxon–Mann–Whitney test, p-
value 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 9. Hematology, statistical test 2 
Visit 
V1 
Variable 
WBC 
Lymphocytes Lymphocytes 
(%) 
Shapiro– 
Wilk test, p-value 
Treatment group: 
R – Maltofer® 
 
 
 
Treatment group: 
T – Ferrum Lek® 
 
 
 
Student's t-test, p-value 
 
 
 
Wilcoxon–Mann–Whitney test, p-value 
 
 
 
Table 10. Hematology, statistical test 3 
Visit 
V1 
 
 


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Variable 
Neutrophils 
Neutrophils (%) 
Stab neutrophils (%) 
Segmented neutrophils 
(%) 
Shapiro– 
Wilk test, p-value 
Treatment group: 
R – Maltofer® 
 
 
 
 
Treatment group: 
T – Ferrum Lek® 
 
 
 
 
Student's t-test, p-value 
 
 
 
 
Wilcoxon–Mann–Whitney test, p-value 
 
 
 
 
 
Table 11. Hematology, statistical test 4 
Visit 
V1 
Variable 
Basophils 
Basophils 
(%) 
ESR 
Platelets 
Eosinophils 
Eosinophils (%) 
Shapiro–Wilk test, p-value 
Treatment group: 
R – Maltofer® 
 
 
 
 
 
 
Treatment group: 
T – Ferrum Lek® 
 
 
 
 
 
 
Student's t-test, p-value 
 
 
 
 
 
 
Wilcoxon–Mann–Whitney test, p-value 
 
 
 
 
 
 
 
Table 12. Physiological data 
Visit 
Group 
Parameter 
Weight 
Age 
BMI 
Height 
V1 
Treatment group: 
R – Maltofer® 
N 
 
 
 
 
Missed 
 
 
 
 
 
 


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Visit 
Group 
Parameter 
Weight 
Age 
BMI 
Height 
 
 
Beyond the limit of 
detection 
 
 
 
 
Mean 
 
 
 
 
95% CI 
 
 
 
 
SD 
 
 
 
 
Median 
 
 
 
 
Min 
 
 
 
 
Max 
 
 
 
 
Q1.25% 
 
 
 
 
Q3.75% 
 
 
 
 
IQR.75% 
 
 
 
 
Treatment group: 
T – Ferrum Lek® 
N 
 
 
 
 
Missed 
 
 
 
 
Beyond the limit of 
detection 
 
 
 
 
Mean 
 
 
 
 
95% CI 
 
 
 
 
SD 
 
 
 
 
Median 
 
 
 
 
Min 
 
 
 
 
Max 
 
 
 
 
Q1.25% 
 
 
 
 
Q3.75% 
 
 
 
 
 
 


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Visit 
Group 
Parameter 
Weight 
Age 
BMI 
Height 
 
 
IQR.75% 
 
 
 
 
 
Table 13. Physiological data, statistical test 
Visit 
V1 
Variable 
Weight 
Age 
BMI 
Height 
Shapiro– 
Wilk test, p-value 
Treatment group: 
R – Maltofer® 
 
 
 
 
Treatment group: 
T – Ferrum Lek® 
 
 
 
 
Student's t-test, p-value 
 
 
 
 
Wilcoxon–Mann–Whitney test, p-value 
 
 
 
 
 
Table 14. Physiological data, categorical data 
Visit 
Variable 
Group 
Distribution of responses 
Chi-square test, p-value 
V1 
Gender 
Treatment group: 
R – Maltofer® 
 
 
Treatment group: 
T – Ferrum Lek® 
 
 
Table 15. Biochemistry 1 
Visit 
Group 
Parameter 
ALT 
AST 
Total protein 
Total bilirubin 
C-reactive protein 
V1 
Treatment group: 
R – Maltofer® 
N 
 
 
 
 
 
 
Missed 
 
 
 
 
 
 
 


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Visit 
Group 
Parameter 
ALT 
AST 
Total protein 
Total bilirubin 
C-reactive protein 
 
 
Beyond the limit of 
detection 
 
 
 
 
 
Mean 
 
 
 
 
 
95% CI 
 
 
 
 
 
SD 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
Q1.25% 
 
 
 
 
 
Q3.75% 
 
 
 
 
 
IQR.75% 
 
 
 
 
 
Treatment group: 
T – Ferrum Lek® 
N 
 
 
 
 
 
Missed 
 
 
 
 
 
Beyond the limit of 
detection 
 
 
 
 
 
Mean 
 
 
 
 
 
95% CI 
 
 
 
 
 
SD 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
Q1.25% 
 
 
 
 
 
 
 


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Visit 
Group 
Parameter 
ALT 
AST 
Total protein 
Total bilirubin 
C-reactive protein 
 
 
Q3.75% 
 
 
 
 
 
IQR.75% 
 
 
 
 
 
V5 
Treatment group: 
R – Maltofer® 
N 
 
 
 
 
 
Missed 
 
 
 
 
 
Beyond the limit of 
detection 
 
 
 
 
 
Mean 
 
 
 
 
 
95% CI 
 
 
 
 
 
SD 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
Q1.25% 
 
 
 
 
 
Q3.75% 
 
 
 
 
 
IQR.75% 
 
 
 
 
 
Treatment group: 
T – Ferrum Lek® 
N 
 
 
 
 
 
Missed 
 
 
 
 
 
Beyond the limit of 
detection 
 
 
 
 
 
Mean 
 
 
 
 
 
95% CI 
 
 
 
 
 
SD 
 
 
 
 
 
 
 


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Visit 
Group 
Parameter 
ALT 
AST 
Total protein 
Total bilirubin 
C-reactive protein 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
Q1.25% 
 
 
 
 
 
Q3.75% 
 
 
 
 
 
IQR.75% 
 
 
 
 
 
 
Table 16. Biochemistry 2 
Visit 
Group 
Parameter 
Conjugated bilirubin 
Creatinine level 
Alkaline phosphatase 
V1 
Treatment group: 
R – Maltofer® 
N 
 
 
 
Missed 
 
 
 
Beyond the limit of detection 
 
 
 
Mean 
 
 
 
95% CI 
 
 
 
SD 
 
 
 
Median 
 
 
 
Min 
 
 
 
Max 
 
 
 
Q1.25% 
 
 
 
Q3.75% 
 
 
 
IQR.75% 
 
 
 
 
 


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Visit 
Group 
Parameter 
Conjugated bilirubin 
Creatinine level 
Alkaline phosphatase 
 
Treatment group: 
T – Ferrum Lek® 
N 
 
 
 
Missed 
 
 
 
Beyond the limit of detection 
 
 
 
Mean 
 
 
 
95% CI 
 
 
 
SD 
 
 
 
Median 
 
 
 
Min 
 
 
 
Max 
 
 
 
Q1.25% 
 
 
 
Q3.75% 
 
 
 
IQR.75% 
 
 
 
V5 
Treatment group: 
R – Maltofer® 
N 
 
 
 
Missed 
 
 
 
Beyond the limit of detection 
 
 
 
Mean 
 
 
 
95% CI 
 
 
 
SD 
 
 
 
Median 
 
 
 
Min 
 
 
 
 
 


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Visit 
Group 
Parameter 
Conjugated bilirubin 
Creatinine level 
Alkaline phosphatase 
 
 
Max 
 
 
 
Q1.25% 
 
 
 
Q3.75% 
 
 
 
IQR.75% 
 
 
 
Treatment group: 
T – Ferrum Lek® 
N 
 
 
 
Missed 
 
 
 
Beyond the limit of detection 
 
 
 
Mean 
 
 
 
95% CI 
 
 
 
SD 
 
 
 
Median 
 
 
 
Min 
 
 
 
Max 
 
 
 
Q1.25% 
 
 
 
Q3.75% 
 
 
 
IQR.75% 
 
 
 
 
Table 17. Biochemistry 3 
Visit 
Group 
Parameter 
T4 
Vitamin B12 
Creatinine index 
TSH 
Folic acid (B9) 
V1 
Treatment group: 
R – Maltofer® 
N 
 
 
 
 
 
Missed 
 
 
 
 
 
 
 


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Visit 
Group 
Parameter 
T4 
Vitamin B12 
Creatinine index 
TSH 
Folic acid (B9) 
 
 
Beyond the limit of 
detection 
 
 
 
 
 
Mean 
 
 
 
 
 
95% CI 
 
 
 
 
 
SD 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
Q1.25% 
 
 
 
 
 
Q3.75% 
 
 
 
 
 
IQR.75% 
 
 
 
 
 
Treatment group: 
T – Ferrum Lek® 
N 
 
 
 
 
 
Missed 
 
 
 
 
 
Beyond the limit of 
detection 
 
 
 
 
 
Mean 
 
 
 
 
 
95% CI 
 
 
 
 
 
SD 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
Q1.25% 
 
 
 
 
 
 
 


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Visit 
Group 
Parameter 
T4 
Vitamin B12 
Creatinine index 
TSH 
Folic acid (B9) 
 
 
Q3.75% 
 
 
 
 
 
IQR.75% 
 
 
 
 
 
 
Table 18. Biochemistry, statistical test 1 
Visit 
V1 
V5 
V1 
V5 
V1 
V5 
V1 
V5 
V1 
V5 
Variable 
ALT 
AST 
Total protein 
Total bilirubin 
C-reactive protein 
Shapiro– 
Wilk test, p-value 
Treatment group: 
R – Maltofer® 
 
 
 
 
 
 
 
 
 
 
Treatment group: 
T – Ferrum Lek® 
 
 
 
 
 
 
 
 
 
 
Student's t-test, p-value 
 
 
 
 
 
 
 
 
 
 
Wilcoxon–Mann–Whitney test, p-value 
 
 
 
 
 
 
 
 
 
 
 
Table 19. Biochemistry, statistical test 2 
Visit 
V1 
V5 
V1 
V5 
V1 
V5 
Variable 
Conjugated bilirubin 
Creatinine level 
Alkaline phosphatase 
Shapiro– 
Wilk test, p-value 
Treatment group: 
R – Maltofer® 
 
 
 
 
 
 
Treatment group: 
T – Ferrum Lek® 
 
 
 
 
 
 
Student's t-test, p-value 
 
 
 
 
 
 
Wilcoxon–Mann–Whitney test, p-value 
 
 
 
 
 
 
 
 


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Table 20. Biochemistry, statistical test 3 
Visit 
V1 
Variable 
T4 
Vitamin B12 
Creatinine index 
TSH 
Folic acid (B9) 
Shapiro– 
Wilk test, p-value 
Treatment group: 
R – Maltofer® 
 
 
 
 
 
Treatment group: 
T – Ferrum Lek® 
 
 
 
 
 
Student's t-test, p-value 
 
 
 
 
 
Wilcoxon–Mann–Whitney test, p-value 
 
 
 
 
 
 
 


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ADVERSE EVENTS 
Table 1. Adverse events reported in the study 
Adverse events 
Group 
Amount 
% of the total number of 
AEs 
% of the number of AEs by 
the medicinal product 
p-value, Fisher's test 
All adverse events 
T 
 
 
 
 
R 
 
 
 
SOC... 
T 
 
 
 
 
R 
 
 
 
PT... 
T 
 
 
 
 
R 
 
 
 
PT... 
T 
 
 
 
 
R 
 
 
 
 
T 
 
 
 
 
R 
 
 
 
SOC... 
T 
 
 
 
 
R 
 
 
 
PT... 
T 
 
 
 
 
R 
 
 
 
PT... 
T 
 
 
 
 
R 
 
 
 
 
T 
 
 
 
 
R 
 
 
 
 
 


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Tables N. Is the adverse event ongoing?/ Relatedness to the medicinal product/ Dose adjustment or temporary withdrawal of the IMP/ Complete 
withdrawal of the IMP/ Prescribing a concomitant medicinal product/ Prescribing non-drug therapy/ Patient admission to hospital or 
hospitalization prolongation/ Based on an AE/ Is it an SAE?/ Leads to death/ Threatens life/ Requires admission to hospital or hospitalization 
prolongation/ Leads to permanent or significant incapacity for work or disability 
Adverse events 
Group 
{variable name] 
Amount 
% of the number of AEs by 
the medicinal product 
p-value, Fisher's test 
All adverse events 
T 
value 
 
 
1 
value 
 
 
value 
 
 
R 
value 
 
 
value 
 
 
value 
 
 
SOC... 
T 
value 
 
 
1 
value 
 
 
value 
 
 
R 
value 
 
 
value 
 
 
value 
 
 
PT... 
T 
value 
 
 
1 
value 
 
 
value 
 
 
R 
value 
 
 
value 
 
 
value 
 
 
 
 


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Adverse events 
Group 
{variable name] 
Amount 
% of the number of AEs by 
the medicinal product 
p-value, Fisher's test 
PT... 
T 
value 
 
 
1 
value 
 
 
value 
 
 
R 
value 
 
 
value 
 
 
value 
 
 
 
T 
value 
 
 
1 
value 
 
 
value 
 
 
R 
value 
 
 
value 
 
 
value 
 
 
SOC... 
T 
value 
 
 
1 
value 
 
 
value 
 
 
R 
value 
 
 
value 
 
 
value 
 
 
PT... 
T 
value 
 
 
1 
value 
 
 
value 
 
 
R 
value 
 
 
 
 


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Adverse events 
Group 
{variable name] 
Amount 
% of the number of AEs by 
the medicinal product 
p-value, Fisher's test 
 
 
value 
 
 
 
value 
 
 
PT... 
T 
value 
 
 
1 
value 
 
 
value 
 
 
R 
value 
 
 
value 
 
 
value 
 
 
 
T 
value 
 
 
1 
value 
 
 
value 
 
 
R 
value 
 
 
value 
 
 
value