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{{Short description|Iron formulation used to prevent or treat iron deficiency anemia}}
{{See also|Ferrous sulfate}}
{{Use dmy dates|date=February 2024}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Infobox drug
| drug_name =▼
| INN =▼
| type =<!-- empty -->▼
| IUPAC_name = ▼
| image = Dr Williams' 'Pink Pills', London, England, 1850-1920 Wellcome L0058211.jpg
| alt =
| caption = Iron supplement from the late 19th and early 20th century
<!-- Clinical data -->
| synonyms = Iron pills, iron salts, ferrous salts, ferric salts▼
| pronounce =
| tradename = Feosol, Feostat, Feratab, others
| Drugs.com = {{
| {{drugs.com|monograph|iron-preparations-oral}} | {{drugs.com|monograph|iron-dextran}}
}}
| MedlinePlus =
|
| pregnancy_AU = B3
| pregnancy_AU_comment =
| pregnancy_US = <!-- A/B/C/D/X/N -->▼
| pregnancy_category=
| routes_of_administration = [[By mouth]],
|
| ATC_prefix = B03▼
| legal_AU_comment =▼
|
| ATC_supplemental =
| legal_DE = <!-- Anlage I, II, III -->▼
<!-- Legal status -->
| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled -->
▲| legal_AU_comment =
| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F -->
| legal_BR_comment =
| legal_CA = Rx-only
| legal_CA_comment = /{{nbsp}}OTC<ref>{{cite web | title=Ferinject Product information | website=[[Health Canada]] | date=11 March 2024 | url=https://health-products.canada.ca/dpd-bdpp/info?lang=eng&code=103479 | access-date=21 June 2024}}</ref><ref>{{cite web | title=Health product highlights 2021: Annexes of products approved in 2021 | website=[[Health Canada]] | date=3 August 2022 | url=https://www.canada.ca/en/health-canada/services/publications/drugs-health-products/health-product-highlights-2021/appendices.html | access-date=25 March 2024}}</ref>
▲| legal_DE = <!-- Anlage I, II, III or Unscheduled -->
| legal_DE_comment =
| legal_NZ_comment =
| legal_UK_comment = <ref name="Cosmofer SmPC" /><ref name="Ferinject SmPC" />
| legal_US = OTC
| legal_US_comment = / Rx-only<ref name="Injectafer FDA label" /><ref name="Drug Approval Package: Accrufer" />
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV-->▼
|
| legal_EU_comment =
▲| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->
| legal_UN_comment =
| legal_status = <!-- For countries not listed above -->
<!-- Pharmacokinetic data -->
| bioavailability =
| protein_bound =
| metabolism =
| metabolites =
| onset =
| elimination_half-life =
| duration_of_action =
| excretion =
<!-- Identifiers -->
| CAS_number = 1332-96-3
|
▲| ATCvet =
▲| ATC_prefix = B03
| ATC_suffix = A▼
| PubChem =
| IUPHAR_ligand =
| DrugBank =
| ChemSpiderID = None
| NIAID_ChemDB =
| PDB_ligand =
▲| synonyms = Iron pills, iron salts, ferrous salts, ferric salts
<!-- Chemical and physical data -->
▲| IUPAC_name =
| chemical_formula_ref =
| chemical_formula =
| C= | H= | Ag= | Al= | As= | Au= | B= | Bi= | Br= | Ca= | Cl= | Co= | F= | Fe= | Gd= | I=
| K= | Li= | Mg= | Mn= | N= | Na= | O= | P= | Pt= | S= | Sb= | Se= | Sr= | Tc= | Zn= | charge=
| molecular_weight =
| molecular_weight_comment =
| SMILES =
| StdInChI =
| StdInChI_comment =
| StdInChIKey =
| density =
| density_notes =
| melting_point =
| melting_high =
| melting_notes =
| boiling_point =
| boiling_notes =
| solubility =
| sol_units =
| specific_rotation =
}}
<!-- Definition and medical uses -->
'''Iron supplements''', also known as '''iron salts''' and '''iron pills''', are a number of [[iron]] formulations used to treat and prevent [[iron deficiency]] including [[iron deficiency anemia]].<ref name=Ric2015>{{cite book|
<!-- Side effects and mechanism -->
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<!-- History and culture -->
Iron pills have been used medically since at least 1681, with an easy-to-use formulation being created in 1832.<ref>{{cite book|
==Medical uses==
Iron supplements are used to treat or prevent [[Iron deficiency (medicine)|iron deficiency]] and [[iron-deficiency anemia]];<ref name="
Iron deficiency anemia is classically a microcytic, hypochromic anemia. Generally, in the UK oral preparations are trialled before using parenteral delivery,<ref name="pmid21561874">{{cite journal | vauthors = Goddard AF, James MW, McIntyre AS
===Athletes===
Athletes may be at elevated risk of iron deficiency and so benefit from supplementation, but the circumstances vary between individuals and dosage should be based on tested [[ferritin]] levels, since in some cases supplementation may be harmful.<ref name=ferr>{{cite journal | vauthors = Clénin G, Cordes M, Huber A, Schumacher YO, Noack P, Scales J, Kriemler S | title = Iron deficiency in sports
===Frequent blood donors===
{{main|Blood donation}}
Frequent blood donors may be advised to take iron supplements. [[Canadian Blood Services]] recommends discussing "taking iron supplements with your doctor or pharmacist" as "the amount of iron in most multivitamins may not meet your needs and iron supplements may be necessary".<ref>{{cite web |title=What you need to know about iron |url=https://www.blood.ca/en/blood/am-i-eligible/abcs-eligibility/iron |website=Canadian Blood Services |access-date=30 May 2022}}</ref> The [[American Red Cross]] recommends "taking a multivitamin with 18 mg of iron or an iron supplement with 18-38 mg of elemental iron for 60 days after each blood donation, for 120 days after each power red donation or after frequent platelet donations".<ref>{{cite web |title=Frequent Blood Donors and the Importance of Iron |url=https://www.redcrossblood.org/donate-blood/blood-donation-process/before-during-after/iron-blood-donation/iron-informationforfrequentdonors.html |website=American Red Cross Blood Services |access-date=30 May 2022}}</ref> A 2014 [[Cochrane Review]] found that blood donors were less likely to be deferred for low hemoglobin levels if they were taking oral iron supplements, although 29% of those who took them experienced side effects in contrast to the 17% that took a placebo. It is unknown what the long-term effects of iron supplementation for blood donors may be.<ref>{{cite journal |
==Side effects==
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The patient may notice that their stools become black. This is completely harmless, but patients must be warned about this to avoid unnecessary concern. When iron supplements are given in a liquid form, teeth may reversibly discolor (this can be avoided through the use of a straw). Intramuscular injection can be painful, and brown discoloration may be noticed.
Treatments with [[iron(II) sulfate]] have higher incidence of adverse events than [[Iron polymaltose|iron(III)-hydroxide polymaltose complex]] (IPC)<ref name="pmid17691594">{{cite journal |
Iron overdose has been one of the leading causes of death caused by toxicological agents in children younger than
Iron poisoning may result in mortality or short-term and long-term morbidity.<ref>
=== Infection risk ===
Because one of the functions of elevated [[ferritin]] (an acute phase reaction protein) in acute infections is thought to be to sequester iron from bacteria, it is generally thought that iron supplementation (which circumvents this mechanism) should be avoided in patients who have active bacterial infections. Replacement of iron stores is seldom such an emergency situation that it cannot wait for any such acute infection to be treated.
Some studies have found that iron supplementation can lead to an increase in [[infectious disease]] morbidity in areas where bacterial infections are common. For example, children receiving iron-enriched foods have demonstrated an increased rate in [[diarrhea]] overall and enteropathogen shedding. Iron deficiency protects against infection by creating an unfavorable environment for bacterial growth. Nevertheless, while iron deficiency might lessen infections by certain pathogenic diseases, it also leads to a reduction in resistance to other strains of viral or bacterial infections, such as ''[[Salmonella typhimurium]]'' or ''[[Entamoeba histolytica]]''. Overall, it is sometimes difficult to decide whether iron supplementation will be beneficial or harmful to an individual in an environment that is prone to many infectious diseases; however this is a different question than the question of supplementation in individuals who are already ill with a bacterial infection.<ref>{{cite journal | vauthors = Oppenheimer SJ | title = Iron and its
Children living in areas prone for malarial infections are also at risk of developing anemia. It was thought that iron supplementation given to such children could increase the risk of malarial infection in them. A Cochrane systematic review published in 2016 found high quality evidence that iron supplementation does not increase the risk of clinical malaria in children.<ref>{{cite journal |
==Contraindications==
Contraindications often depend on the substance in question. Documented [[hypersensitivity]] to any ingredients and anemias without proper work-up (i.e., documentation of iron deficiency) is true of all preparations. Some can be used in iron deficiency, others require iron deficiency anaemia to be present. Some are also contraindicated in [[rheumatoid arthritis]].<ref name="Cosmofer SmPC">
===Hemochromatosis===
Individuals may be genetically predisposed to excessive iron absorption, as is the case with those with [[HFE hereditary haemochromatosis|HFE hereditary hemochromatosis]]. Within the general population, 1 out of 400 people has the homozygous form of this genetic trait, and 1 out of every 10 people has its heterozygous form.<ref name="Nielson">{{
== Interactions ==
Non-[[heme]] iron forms an insoluble complex with several other drugs, resulting in decreased absorption of both iron and the other drug. Examples include [[tetracycline]], [[penicillamine]], [[methyldopa]], [[levodopa]], [[bisphosphonates]] and [[quinolones]]. The same can occur with elements in food, such as [[calcium]], which impacts both heme and non-heme iron absorption.<ref>{{cite journal |last1=Zjip |first1=Itske |last2=Korver |first2=Onno |last3=Tijburg |first3=Lillian |title=Effect of Tea and Other Dietary Factors on Iron Absorption |journal=Critical Reviews in Food Science and Nutrition |date=2000 |volume=40 |issue=5 |pages=371–398 |doi=10.1080/10408690091189194 |pmid=11029010 |s2cid=12423113 |url=https://www.tandfonline.com/doi/abs/10.1080/10408690091189194 |access-date=31 May 2022}}</ref> Absorption of iron is better at a low pH (i.e. an acidic environment), and absorption is decreased if there is a simultaneous intake of antacids.▼
▲Non-[[heme]] iron forms an insoluble complex with several other drugs, resulting in decreased absorption of both iron and the other drug. Examples include [[tetracycline]], [[penicillamine]], [[methyldopa]], [[levodopa]], [[bisphosphonates]] and [[quinolones]]. The same can occur with elements in food, such as [[calcium]], which impacts both heme and non-heme iron absorption.<ref>{{cite journal |
Many other substances decrease the rate of non-heme iron absorption. One example is [[tannins]] from foods such as [[tea]]<ref>{{cite journal |last1=Delimont |first1=Nicole |last2=Haub |first2=Mark |last3=Lindshield |first3=Brian |title=The Impact of Tannin Consumption on Iron Bioavailability and Status: A Narrative Review |journal=Current Developments in Nutrition |date=2017 |volume=1 |issue=2 |pages=e000042 |doi=10.3945/cdn.116.000042 |pmid=29955693 |pmc=5998341 }}</ref> and [[phytic acid]].<ref name="Reddy 1996">{{cite journal |last1=Reddy |first1=MB |last2=Hurrell |first2=RF |last3=Juillerat |first3=MA |last4=Cook |first4=JD |title=The influence of different protein sources on phytate inhibition of nonheme-iron absorption in humans |journal=American Journal of Clinical Nutrition |date=1996 |volume=63 |issue=2 |pages=203–207 |doi=10.1093/ajcn/63.2.203|pmid=8561061 }}</ref> Because iron from plant sources is less easily absorbed than the heme-bound iron of animal sources, [[vegetarian]]s and [[vegan]]s should have a somewhat higher total daily iron intake than those who eat meat, fish or poultry.<ref>[[Reed Mangels|Mangels, Reed]]. [http://www.vrg.org/nutrition/iron.htm Iron in the vegan diet]. The Vegetarian Resource Group.</ref><ref name="Henjum 2021">{{cite journal |last1=Henjum |first1=Sigrun |last2=Groufh-Jacobsen |first2=Synne |last3=Stea |first3=Tonja Holte |last4=Tonheim |first4=Live Edvardsen |last5=Almendingen |first5=Kari |last6=Nurchi |first6=Valeria |title=Iron Status of Vegans, Vegetarians and Pescatarians in Norway |journal=Biomolecules |date=2021 |volume=11 |issue=3 |page=454 |doi=10.3390/biom11030454|pmid=33803700 |pmc=8003004 |doi-access=free }}</ref>▼
▲Many other substances decrease the rate of non-heme iron absorption. One example is [[tannins]] from foods such as [[tea]]<ref>{{cite journal |
Taken after a meal, there are fewer side effects but there is also less absorption because of interaction and pH alteration. Generally, an interval of 2–3 hours between the iron intake and that of other drugs seems advisable, but is less convenient for patients and can impact on compliance.
==History==
The first pills were commonly known as Blaud's pills,<ref>
==Administration==
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===By mouth===
{{redirect|Proferrin|the pupil dilator|Prefrin}}
Iron can be supplemented [[oral route|by mouth]] using various forms, such as [[iron(II) sulfate]]. This is the most common and well studied soluble iron [[salt]] sold under brand names such as Feratab, Fer-Iron, and Slow-FE. It is in complex with [[gluconate]], [[dextran]], [[carbonyl iron]], and other salts. [[Ascorbic acid]], vitamin C, increases the absorption of non-heme sources of iron.<ref>{{cite journal |
Heme iron polypeptide (HIP) (e.g. Proferrin ES and Proferrin Forte) can be used when regular iron supplements such as ferrous sulfate or ferrous fumarate are not tolerated or absorbed. A clinical study demonstrated that HIP increased serum iron levels 23 times greater than ferrous fumarate on a milligram-per-milligram basis.<ref>{{cite journal |
Another alternative is
Since iron stores in the body are generally depleted, and there is a limit to what the body can process (about 2–6 mg/kg of body mass per day; i.e. for a 100 kg/220 lb man this is equal to a maximum dose of 200–600 mg/per day) without [[iron poisoning]], this is a chronic therapy which may take 3–6 months.<ref>
Due to the frequent intolerance of oral iron and the slow improvement, parenteral iron is recommended in many indications.<ref>{{cite book |author=National Clinical Guideline Centre |title=Anaemia Management in Chronic Kidney Disease |location=London |publisher=Royal College of Physicians |year=2015 |series=NICE Guideline, No. 8 |url=https://www.ncbi.nlm.nih.gov/books/NBK299242/ |pmid=26065064 |url-status=live |archive-url=https://web.archive.org/web/20170918183856/https://www.ncbi.nlm.nih.gov/books/NBK299242/ |archive-date=
===By injection===
Iron therapy (intravenously or intramuscular) is given when therapy by mouth has failed (not tolerated), oral absorption is seriously compromised (by illnesses, or when the person cannot swallow), benefit from oral therapy cannot be expected, or fast improvement is required (for example, prior to elective surgery).<ref name="pmid9070014">{{cite journal |
There are cases where parenteral iron is preferable over oral iron. These are cases where oral iron is not tolerated, where the [[haemoglobin]] needs to be increased quickly (e.g. post partum, post operatively, post transfusion), where there is an underlying inflammatory condition (e.g. inflammatory bowel disease) or renal patients, the benefits of parenteral iron far outweigh the risks.
Low-certainty evidence suggests that IBD-related anemia treatment with [[Intravenous iron infusion|Intravenous (IV) iron infusion]] may be more effective than [[Oral iron|oral iron therapy]], with fewer people needing to stop treatment early due to adverse effects.<ref name=":0">{{cite journal | vauthors = Gordon M, Sinopoulou V, Iheozor-Ejiofor Z, Iqbal T, Allen P, Hoque S, Engineer J, Akobeng AK | title = Interventions for treating iron deficiency anaemia in inflammatory bowel disease | journal = The Cochrane Database of Systematic Reviews | volume = 1 | issue = 1 | pages = CD013529 | date = January 2021 | pmid = 33471939 | pmc = 8092475 | doi = 10.1002/14651858.CD013529.pub2 }}</ref> The type of iron preparation may be an important determinant of clinical benefit. Moderate-certainty evidence suggests response to treatment may be higher when IV [[ferric carboxymaltose]], rather than IV [[iron sucrose]] preparation is used, despite very-low certainty evidence of increased adverse effects, including bleeding, in those receiving ferric carboxymaltose treatment.<ref name=":0" />
A Cochrane review of controlled trials comparing [[Intravenous iron infusion|intravenous (IV) iron therapy]] with oral iron supplements in people with [[chronic kidney disease]], found low-certainty evidence that people receiving IV-iron treatment were 1.71 times as likely to reach their target [[hemoglobin]] levels.<ref name=":1">{{cite journal | vauthors = O'Lone EL, Hodson EM, Nistor I, Bolignano D, Webster AC, Craig JC | title = Parenteral versus oral iron therapy for adults and children with chronic kidney disease | journal = The Cochrane Database of Systematic Reviews | volume = 2019 | issue = 2 | pages = CD007857 | date = February 2019 | pmid = 30790278 | pmc = 6384096 | doi = 10.1002/14651858.CD007857.pub3 | collaboration = Cochrane Kidney and Transplant Group }}</ref> Overall, hemoglobin was 0.71g/dl higher than those treated with oral iron supplements. Iron stores in the liver, estimated by serum [[ferritin]], were also 224.84 μg/L higher in those receiving IV-iron.<ref name=":1" /> However, there was also low-certainty evidence that allergic reactions were more likely following IV-iron therapy. It was unclear whether type of iron therapy administration affects the risk of death from any cause, including cardiovascular, nor whether it may alter the number of people who may require a blood transfusion or dialysis.<ref name=":1" />
Soluble iron salts have a significant risk of adverse effects and can cause toxicity due to damage to cellular macromolecules. Delivering iron parenterally has utilised various different molecules to limit this. This has included [[dextrans]], [[sucrose]], carboxymaltose and more recently Isomaltoside 1000.{{citation needed|date=July 2015}}▼
▲Soluble iron salts have a significant risk of adverse effects and can cause toxicity due to damage to cellular macromolecules. Delivering iron parenterally has utilised various different molecules to limit this. This has included [[dextrans]], [[sucrose]], carboxymaltose, and
One formulation of parenteral iron is ''iron dextran'' which covers the old high molecular weight (trade name ''DexFerrum'') and the much safer low molecular iron dextrans (tradenames including Cosmofer and Infed).<ref>{{cite journal |last1=Chertow |first1=Glenn M. |last2=Mason |first2=Phillip D. |last3=Vaage-Nilsen |first3=Odd |last4=Ahlmén |first4=Jarl |title=On the relative safety of parenteral iron formulations |journal=Nephrology Dialysis Transplantation |volume=19 |issue=6 |pages=1571–5 |year=2004 |pmid=15150356 |doi=10.1093/ndt/gfh185 |doi-access=free }}</ref>▼
▲One formulation of parenteral iron is
''Iron [[sucrose]]'' has an occurrence of allergic reactions of less than 1 in 1000.<ref name=fass-venofer>[http://www.fass.se/LIF/produktfakta/artikel_produkt.jsp?NplID=20000211000213&DocTypeID=7 Venofer] {{webarchive|url=https://web.archive.org/web/20111001011331/http://www.fass.se/LIF/produktfakta/artikel_produkt.jsp?NplID=20000211000213&DocTypeID=7 |date=2011-10-01 }} in [[FASS (drug formulary)]], translated from Swedish "Allergiska reaktioner (inträffar hos färre än 1 av 1 000 patienter)" and "Vanliga (inträffar hos färre än 1 av 10 patienter): Tillfälliga smakförändringar (speciellt metallsmak)."</ref> A common side effect is taste changes, especially a [[metallic taste]], occurring in between 1 in 10 and 1 in 100 treated patients.<ref name=fass-venofer/> It has a maximum dose of 200 mg on each occasion according to the SPC, but it has been given in doses of 500 mg. Doses can be given up to 3 times a week.<ref>{{cite web |url=https://www.medicines.org.uk/emc/medicine/24168 |title=Venofer (iron sucrose) - Summary of Product Characteristics (SmPC) - (eMC) |access-date=2017-03-07 |url-status=live |archive-url=https://web.archive.org/web/20170308044906/https://www.medicines.org.uk/emc/medicine/24168 |archive-date=2017-03-08 }}</ref>▼
▲
Iron carboxymaltose is marketed as Ferinject,<ref name="Ferinject SmPC" /> Injectafer,<ref name="Injectafer FDA label" /><ref>{{cite web | title=Drug Approval Package: Injectafer (ferric carboxymaltose) Injection NDA #203565 | website=U.S. [[Food and Drug Administration]] (FDA) | date=4 September 2013 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/203565Orig1s000TOC.cfm | access-date=8 February 2024}}</ref> and Iroprem in various countries.<ref name="CançadoMuñoz2011"/> The most common side effects are [[headaches]] which occur in 3.3%, and hypophosphatemia, which occurs in more than 35%.<ref name="Ferinject SmPC" /><ref name="Injectafer FDA label">{{cite web | title=Injectafer- ferric carboxymaltose injection injection, solution; Injectafer- ferric carboxymaltose injection, solution | website=DailyMed | date=1 May 2023 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=517b4a19-45b3-4286-9f6a-ced4e10447de | access-date=8 February 2024}}</ref>
''Iron Isomaltoside 1000'' (Trade name ''Monofer'') is a newer formulation of parenteral iron that has a matrix structure that results in very low levels of free iron and labile iron. It can be given at high doses – 20 mg/kg in a single visit – no upper dose limit. This formulation has the benefit of giving a full iron correction in a single visit.<ref>{{cite journal |last1=Jahn |first1=Markus R. |last2=Andreasen |first2=Hans B. |last3=Fütterer |first3=Sören |last4=Nawroth |first4=Thomas |last5=Schünemann |first5=Volker |last6=Kolb |first6=Ute |last7=Hofmeister |first7=Wolfgang |last8=Muñoz |first8=Manuel |last9=Bock |first9=Klaus |last10=Meldal |first10=Morten |last11=Langguth |first11=Peter |title=A comparative study of the physicochemical properties of iron isomaltoside 1000 (Monofer®), a new intravenous iron preparation and its clinical implications |journal=European Journal of Pharmaceutics and Biopharmaceutics |volume=78 |issue=3 |pages=480–91 |year=2011 |pmid=21439379 |doi=10.1016/j.ejpb.2011.03.016 }}</ref><ref name="CançadoMuñoz2011">{{cite journal |last1=Cançado |first1=Rodolfo Delfini |last2=Muñoz |first2=Manuel |title=Intravenous iron therapy |journal=Revista Brasileira de Hematologia e Hemoterapia |volume=33 |issue=6 |pages=461–9 |year=2011 |pmid=23049364 |pmc=3459360 |doi=10.5581/1516-8484.20110123 }}</ref>▼
▲
[[Ferric maltol]], marketed as Accrufer<ref name="Drug Approval Package: Accrufer">{{cite web | title=Drug Approval Package: Accrufer | website=U.S. [[Food and Drug Administration]] (FDA) | date=14 August 2019 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212320Orig1s000TOC.cfm | access-date=8 February 2024}}</ref> and Ferracru, is available in oral and intravenous preparations. When used as a treatment for IBD-related anemia, very low certainty evidence suggests a marked benefit with oral ferric maltol compared with placebo. However it was unclear whether the IV preparation was more effective than oral ferric maltol.<ref name=":0" />
== References ==
{{reflist}}
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