Parenteral Iron therapy

E. K. ANTIRI

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OUTLINE
• Introduction
• Aetiology of IDA
• Iron metabolism and regulation
• Treatment of IDA
• Parenteral iron therapy
• Bioengineering of IV iron
• Physiochemical differences
• Clinical characteristics of IV iron
• Parenteral iron therapy indications and contraindications
• Metabolism of IV iron
• Side effects of IV iron
• Conclusion
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Introduction
• Iron is the most abundant element on earth,
accounting for 35% of the earth’s mass
Bhandari et al Pharmaceuticals 2018, 11, 82; doi:10.3390/ph11030082

• Human body contains 3–5 g iron

• Iron is an essential trace mineral necessary for

myriad of metabolic reactions in the body. These
include a role in
• Catalytic enzymes and proteins for DNA synthesis
• Transport of oxygen in haemoglobin and myoglobin
• Mitochondrial cell respiration, oxidative
phosphorylation and ATP formation in the
tricarboxylic acid cycle
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Introduction Ctd
• Iron deficiency anaemia (IDA)
• Most common nutritional deficiency worldwide
• Commonest cause of microcytic hypochromic anaemia
• 1.24 billion people are affected globally (a sixth of the global population).

• Oral iron replacement therapy is a simple, inexpensive treatment, but

is limited by gastrointestinal problems and other factors.

• Parenteral iron therapies circumvent most of these problems.

• Allow rapid and complete replacement dosing and are indicated when oral
therapy is ineffective or contraindicated.
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Aetiology of IDA
cause Details
Insufficient uptake Poverty or diet-related (low-iron, vegetarian)
Increased physiological Rapid growth during infancy/adolescence, menstrual blood loss, pregnancy
demand

Chronic blood loss PUD, heavy menstrual bleeding, hookworm and schistosomiasis.

Chronic disease Kidney disease, heart failure, inflammatory bowel disease, gastritis, peptic
ulcer, intestinal cancer and benign tumours

Malabsorption After gastrectomy and in inflammatory bowel diseases

Drug-related Glucocorticoids, salicylates, non-steroidal anti-inflammatory drugs, proton-

pump inhibitors, antacids

Genetic Iron-refractory iron-deficiency anaemia

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Iron metabolism and regulation

12/20/2020 Bhandari et al Pharmaceuticals 2018, 11, 82; doi:10.3390/ph11030082 6

Treatment
• Addressing the underlying cause of the iron deficiency
• Replenishment of iron stores (symptomatic/asymptomatic)
• Oral
• Parenteral (IM/IV)

• More recently, emerging data also suggest benefit in the treatment of

non-anaemic iron deficiency (NAID) with replacement iron

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Treatment Ctd

• Oral iron replacement therapy to treat IDA in the form of iron salts dates to the 17 th
century.

• Oral ferrous salts are the most commonly prescribed iron replacement therapy,
reflecting their efficacy and simplicity of dosing.
• Long-term treatment of up to 6 months to replete iron stores
• Gastrointestinal side-effects that include nausea and pain are common.

• A meta-analysis of 43 randomised, controlled trials of 6831 patients reported

gastrointestinal side-effects in up to 75% of patients. These side effects can be
underestimated regarding their impact on patients and adherence can be
challenging
Bhandari et al Pharmaceuticals 2018, 11, 82; doi:10.3390/ph11030082
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Parenteral iron therapy
• Early 20th century: First parenteral iron preparations to be used clinically in
were colloidal ferric hydroxide preparations.
• Toxicity linked to the release of large amounts of labile (“free”) iron limited their use.
• This prompted the development of preparations composed of an iron core and
carbohydrate shell that prevented rapid release of the elemental iron.

• 1947: Introduction of IV iron saccharide

• 1954: High-molecular-weight dextran (HMWD) iron

• Signalled a major change in perception of IV iron therapy due to their efficacy and relative
safety.
• However, severe hypersensitivity reactions in HMWD - dextran-induced anaphylactic
reactions
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Parenteral iron therapy
• 1990s: Iron gluconate and Iron sucrose developed.
• Used non-dextran carbohydrates complexed with the iron core
• Were associated with markedly fewer severe adverse events (SAE).

• Recently: Third generation IV irons

• Development from new pharmaceutical technologies
• Attempts to circumvent the toxicity issues inherent with earlier preparations and
the posology limitations of iron sucrose products.
• In the last ten years, three third-generation IV iron compounds were licensed for
the treatment of IDA.
• Two are currently approved for use in Europe—ferric carboxymaltose and iron
isomaltoside 1000—and one in the United States—ferumoxytol
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Parenteral iron therapy
• The haematological response to parenteral iron is no faster than to
adequate dosage of oral iron but the stores are replenished faster.

• Found to increase functional capacity and quality of life in some

patients with congestive heart failure even in the absence of anaemia.

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Bioengineering of IV Iron
• IV iron preparations:
• Bioengineered as iron-carbohydrate complexes to deliver high doses of
iron in a stable, non-toxic form
• Consist of colloidal suspensions of iron oxide nanoparticles with a
polynuclear Fe(III)-oxyhydroxide/oxide core surrounded by a carbohydrate
ligand
• Behave as prodrugs, retaining ionic iron until the iron–carbohydrate
complex is metabolised.

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Physicochemical differences
• The physicochemical differences
between the IV irons include:

• Size
• Mineral composition
• Crystalline structure
• Conformation
• Molecular weight
• Carbohydrate ligand - key point of
difference between IV iron products.
Influences complex stability, iron release
and immunogenicity, and is a unique
feature of each drug.
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Comparison of physicochemical characteristics and
pharmacokinetics of currently available IV irons

12/20/2020 Bhandari et al Pharmaceuticals 2018, 11, 82; doi:10.3390/ph11030082 14

Clinical characteristics of currently available
IV irons

12/20/2020 Bhandari et al Pharmaceuticals 2018, 11, 82; doi:10.3390/ph11030082 15

Clinical differences between generations
Earlier Generation IV irons Third generation IV irons
Lower complex stability Greater complex stability (keeps iron tightly bound)
Release larger amounts of non-transferrin-bound iron (NTBI) Release small amounts of labile, non-transferrin-bound iron
into the blood into the blood before macrophage uptake.

Cant achieve maximal single dose and complete iron Complete iron replacement in 15–60 min (although processing
replacement after an infusion. and distribution of the iron will obviously take longer).

Longer administration times, multiple infusions Rapid administration, less frequencies

Risk of dextran-related immune reactions. No risk

Increased clinical hypersensitivity reactions though rare Decrease clinical hypersensitivity reactions.

Labile iron contributes to formation of reactive oxygen species and reactive nitrogen species in an uncontrolled way -------→

Results in oxidative and/or nitrosative stress that upsets normal cellular signalling mechanisms. Involved in many diseases
including heart failure, and Alzheimer’s disease, Friedreich’s ataxia and Parkinson’s disease
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IM VERSUS IV
Intramuscular route Intravenous route
Muscular route Venous route
Given in small doses Can be given in large doses.
Repetitive doses (multiple times) Single dose possible or multiple doses (lesser frequency)

Greater discomfort due to multiple injections Less discomfort due to fewer injections
Multiple injections a problem in the malnourished patient No problem associated
with limited muscle mass.

Increased risk of bleeding, staining of the skin, formation of Less risk

sterile abscesses, tissue necrosis or atrophy, ulceration and
sarcoma formation.

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Precautions
• Administered when appropriately trained staff and resuscitation facilities are immediately available.

• Monitor after an initial standard test dose.

• ? Administer pre-med - IV hydrocortisone, IV methylprednisolone

• Monitored closely for signs of hypersensitivity during and for at least 30 minutes after every
administration.
• If occurs, treatment should be stopped immediately and appropriate management initiated.

• Risk of hypersensitivity increased in patients with known allergies, immune or inflammatory

conditions, or those with a history of severe asthma, eczema, or other atopic allergy;
• Only use if the benefits outweigh the risks.

• Intravenous iron should be avoided in the first trimester of pregnancy and used in the second or
third trimesters only if the benefit outweighs the potential risks for both mother and foetus.
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Failure of response to oral iron has several possible causes
which should be considered before parenteral iron is used.

• Continuing haemorrhage

• Failure to take tablets

• Wrong diagnosis – especially thalassaemia trait and sideroblastic anaemia

• Mixed deficiency- associated folate or vitamin b 12 deficiency

• Another cause of anaemia (malignancy, inflammation, renal or hepatic failure)

• Malabsorption – coeliac disease, atrophic gastritis, Helicobacter infection

• Use12/20/2020
of slow release preparation 20
Parenteral iron therapy indications
• Severe adverse side effects to oral therapy. GIT symptoms

• Non compliance

• Intolerability to oral iron e. g. gastrointestinal disease such as inflammatory bowel

disease.

• Malabsorption in gluten-induced enteropathy e.g. Coeliac disease.

• To replenish body stores rapidly e.g. Severe IDA in late pregnancy.

• When oral iron cannot keep pace with continuing haemorrhage e.g. in patients with
hereditary haemorrhagic telangiectasia-severe GIT bleeding
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Parenteral iron therapy indications

• In patients with chronic renal failure:

• Functional iron deficiency in patients with CRF on erythropoietin.
• Increased red cell loss at dialysis contributes to iron needs.
• Reduced clearance contribute to erythropoietin resistance.

• Improve functional capacity and quality of life in patients with congestive heart failure and iron
deficiency, even in the absence of anaemia.

• As an option to blood transfusion on Religious basis (Jehovah Witness).

• Effective in acutely or chronically unwell patients as compared to oral iron because of the raised
hepcidin levels. (APR which blocks the enteral absorption of iron and its use within the body)
bypasses the enteral absorption.

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Contraindications
• Allergic disorders
• Eczema
• Hepatic dysfunction
• Immune conditions
• Infection (discontinue if ongoing bacteraemia)
• Inflammatory conditions
• Severe asthma

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Metabolism of IV iron
• IV irons after infusion are processed in macrophages and release functional iron
from the carbohydrate ligand.

• The iron complex is endocytosed by macrophages within the RES.

• Endosome–lysosome fusion creates an acidic endolysosome and, combined with

endogenous iron-binding due to other iron-complexing agents present in the
lysosomes, drives iron release from the iron–carbohydrate complex.

• Important factors for iron liberation:

• Low pH of the endolysosome
• Type and concentration of low-molecular-weight iron-ligands present in the endolysosome
• Stabilities of the different IV iron-carbohydrate structures.
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Metabolism of IV iron
• Iron is subsequently transported into the labile iron pool in the
macrophage cytoplasm, where it can be stored, or exported into the
plasma by ferroportin.

• The mechanism by which intracellular iron is delivered to ferroportin for

export is not well characterised.

• Upon export, iron is immediately oxidised by ferroxidases, binds plasma

transferrin for transport to erythroid precursor cells for haemoglobin
synthesis or to other iron-requiring cells, or for liver storage in the form
of ferritin
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 • Systemic
Side effects • Immediate
• Anaphylactoid reaction(life threatening)
• Hypotension
• Local • Hypertension
• Pain at site of injection • bronchospasm
• Discolouration of skin • Hypophosphatemia
• Headache, dizziness, flushing, malaise, nausea
• Tender lymph nodes
• Urticaria
• Thrombophlebitis • Metallic taste in mouth
• Flushing • Peripheral oedema
• Infection/Abscess(sterile/pyogenic) • Delayed
• Lymphadenopathy
• Myalgia
• Arthralgia
• Iron overload syndrome

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Journal review on side effects
• An extensive meta-analysis of >10,000 patients derived from 103 clinical
trials offers important insights into the overall safety profile and allows
comparison between IV and oral iron. IV iron was not associated with an
increase in serious AEs (SAE) when compared to oral iron and placebo.
SAE were rare, estimated to occur in 1:200,000 doses with no fatal or
anaphylactic reactions reported. Although the study confirmed that
minor infusion reactions do occur, the frequency of these adverse events
must be considered in the context of the use of blood transfusions.

Bhandari et al Pharmaceuticals 2018, 11, 82; doi:10.3390/ph11030082

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In conclusion
• IDA is a common medical condition that leads to chronic fatigue,
reduced quality of life (QOL), increased risk of complications and
increased mortality.

• Treatment of IDA falls into two main categories, oral and parenteral
iron formulations.

• Clinical practice guidelines identify the benefits of parenteral iron

preparations as a treatment option for patients with IDA who lack a
response to, are non-compliant with, or are intolerant of oral iron
treatment, as well as those who have severe iron deficiency and
require rapid replenishment of available iron and Hb levels.
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• Various IV iron forms exist, each one with its own unique structure and
physiochemical characteristics .

• These characteristics have implications for therapy, impacting the maximum

amount of iron that can be infused, the rate of infusion, the risk of minor
infusion reactions, the risk of immune-mediated hypersensitivity reactions,
and wider negative effects linked to the toxicity of labile iron.

• The third generation of IV irons are characterised by unique carbohydrate

ligands forming strongly bound iron–carbohydrate complexes.

• The risk of infusion reactions is diminished compared with previous IV iron

formulations, and these drugs are clinically well-tolerated at high doses to
allow rapid, high-dose infusion that offers the potential for complete iron
repletion in 15–60 min.
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references
• Paul, B.T.; Manz, D.H.; Torti, F.M.; Torti, S.V. Mitochondria
and iron: Current questions. Expert Rev. Hematol.2017, 10,
65–79. [CrossRef] [PubMed]
• Sunil Bhandari, Dora I. A. Pereira, Helen F. Chappell and Hal
Drakesmith. Intravenous Irons: From Basic Science to Clinical
Practice. Pharmaceuticals 2018, 11, 82;
doi:10.3390/ph11030082
• BNF 78 September 2019 – March 2020 . Iron (Injectable).
1020-1024
• DexFerrum (iron dextran) product informatio. American
Regent Laboratories, Inc.; Shirley, NY, 2001
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• Thank you. Any questons?

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