Iron supplement

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Iron supplement
Dr Williams' 'Pink Pills', London, England, 1850-1920 Wellcome L0058211.jpg
Iron supplement from the late 19th and early 20th century
Clinical data
Trade names Feosol, Feostat, Feratab, others
Other namesIron pills, iron salts, ferrous salts, ferric salts
AHFS/Drugs.com Monograph
Routes of
administration 		By mouth, by injection
ATC code
Legal status
Legal status
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CAS Number
ChemSpider
  • None

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. [1] [2] For prevention they are only recommended in those with poor absorption, heavy menstrual periods, pregnancy, hemodialysis, or a diet low in iron. [2] [3] Prevention may also be used in low birth weight babies. [2] They are taken by mouth, injection into a vein, or injection into a muscle. [2] While benefits may be seen in days, up to two months may be required until iron levels return to normal. [4]

Contents

Common side effects include constipation, abdominal pain, dark stools, and diarrhea. [4] Other side effects, which may occur with excessive use, include iron overload and iron toxicity. [1] [3] Ferrous salts used as supplements by mouth include ferrous fumarate, ferrous gluconate, ferrous succinate, and ferrous sulfate. [3] Injectable forms include iron dextran and iron sucrose. [3] They work by providing the iron needed for making red blood cells. [4]

Iron pills have been used medically since at least 1681, with an easy-to-use formulation being created in 1832. [5] Ferrous salt is on the World Health Organization's List of Essential Medicines. [6] Ferrous salts are available as a generic medication and over the counter. [1] Slow release formulations, while available, are not recommended. [2] In 2021, ferrous sulfate was the 105th most commonly prescribed medication in the United States, with more than 6 million prescriptions. [7] [8]

Medical uses

Iron supplements are used to treat or prevent iron deficiency and iron-deficiency anemia; [9] parenteral irons can also be used to treat functional iron deficiency, where requirements for iron are greater than the body's ability to supply iron such as in inflammatory states. The main criterion is that other causes of anemia have also been investigated, such as vitamin B12 or folate deficiency, drug induced or due to other poisons such as lead, as often the anemia has more than one underlying cause. [10]

Iron deficiency anemia is classically a microcytic, hypochromic anemia. Generally, in the UK oral preparations are trialled before using parenteral delivery, [11] unless there is the requirement for a rapid response, previous intolerance to oral iron or likely failure to respond. Intravenous iron may decrease the need for blood transfusions however it increases the risk of infections when compared to oral iron. [12] A 2015 Cochrane Collaboration review found that daily oral supplementation of iron during pregnancy reduces the risk of maternal anemia and that effects on infant and on other maternal outcomes are not clear. [13] Another review found tentative evidence that intermittent iron supplements by mouth for mothers and babies is similar to daily supplementation with fewer side effects. [14] Supplements by mouth should be taken on an empty stomach, optionally with a small amount of food to reduce discomfort. [15]

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. [16]

Frequent blood donors

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". [17] 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". [18] 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. [19]

Side effects

Side effects of therapy with oral iron are most often diarrhea or constipation and epigastric abdominal discomfort. Taken after a meal, side effects decrease, but there is an increased risk of interaction with other substances. Side effects are dose-dependent, and the dose may be adjusted.

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(III)-hydroxide polymaltose complex (IPC) [20] [21] [22] or iron bis-glycinate chelate. [23] [24]

Iron overdose has been one of the leading causes of death caused by toxicological agents in children younger than 6 years. [25]

Iron poisoning may result in mortality or short-term and long-term morbidity. [26]

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. [27]

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. [28]

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. [29]

Hemochromatosis

Individuals may be genetically predisposed to excessive iron absorption, as is the case with those with 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. [30] Neither individuals with the homozygous or heterozygous form should take iron supplements. [30]

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. [31] 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.

Many other substances decrease the rate of non-heme iron absorption. One example is tannins from foods such as tea [32] and phytic acid. [33] Because iron from plant sources is less easily absorbed than the heme-bound iron of animal sources, vegetarians and vegans should have a somewhat higher total daily iron intake than those who eat meat, fish or poultry. [34] [35]

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, [36] which were named after P. Blaud of Beaucaire, the French physician who introduced and started the use of these medications as a treatment for patients with anemia. [37]

Administration

By mouth

Iron can be supplemented 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. [38]

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. [39]

Another alternative is ferrous glycine sulfate or ferroglycine sulfate, has less gastrointestinal side-effects than standard preparations such as iron fumarate. [40] [ better source needed ] It is unusual among oral preparations of iron supplements in that the iron in this preparation has very high oral bioavailability, especially in the liquid formulation. This option should be evaluated before resorting to parenteral therapy. It is especially useful in iron deficiency anemia associated with autoimmune gastritis and Helicobacter pylori gastritis, where it generally has satisfactory effect. [41]

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. [42]

Due to the frequent intolerance of oral iron and the slow improvement, parenteral iron is recommended in many indications. [43] [44]

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). [45] Parenteral therapy is more expensive than oral iron preparations and is not suitable during the first trimester of pregnancy. [46]

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 (IV) iron infusion may be more effective than oral iron therapy, with fewer people needing to stop treatment early due to adverse effects. [47] 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. [47]

In many cases, use of intravenous iron such as ferric carboxymaltose has lower risks of adverse events than a blood transfusion and as long as the person is stable is a better alternative. [48] Ultimately this always remains a clinical decision based on local guidelines, although National Guidelines are increasingly stipulating IV iron in certain groups of patients. [49] [50]

A Cochrane review of controlled trials comparing 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. [51] 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. [51] 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. [51]

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 ]

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). [52]

Iron sucrose has an occurrence of allergic reactions of less than 1 in 1000. [53] A common side effect is taste changes, especially a metallic taste, occurring in between 1 in 10 and 1 in 100 treated patients. [53] 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. [54]

Iron carboxymaltose is marketed as Ferinject, Injectafer, and Iroprem in various countries. [55] [56] The most common side effects are headaches which occur in 3.3%, and hypophosphatemia, which occurs in more than 35%. [57] [58]

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. [59] [56]

Ferric maltol, marketed as Accrufer and Ferracru, is available in oral and IV 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. [47]

Related Research Articles

<span class="mw-page-title-main">Anemia</span> Reduced ability of blood to carry oxygen

In hematology, anemia or anaemia is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, a reduction in the amount of hemoglobin or hemoglobin abnormalities. The name is derived from Ancient Greek ἀν- (an-) 'not', and αἷμα (haima) 'blood'. When anemia comes on slowly, the symptoms are often vague, such as tiredness, weakness, shortness of breath, headaches, and a reduced ability to exercise. When anemia is acute, symptoms may include confusion, feeling like one is going to pass out, loss of consciousness, and increased thirst. Anemia must be significant before a person becomes noticeably pale. Symptoms of anemia depend on how quickly hemoglobin decreases. Additional symptoms may occur depending on the underlying cause. Preoperative anemia can increase the risk of needing a blood transfusion following surgery. Anemia can be temporary or long term and can range from mild to severe.

<span class="mw-page-title-main">Iron deficiency</span> State in which a body lacks enough iron to supply its needs

Iron deficiency, or sideropenia, is the state in which a body lacks enough iron to supply its needs. Iron is present in all cells in the human body and has several vital functions, such as carrying oxygen to the tissues from the lungs as a key component of the hemoglobin protein, acting as a transport medium for electrons within the cells in the form of cytochromes, and facilitating oxygen enzyme reactions in various tissues. Too little iron can interfere with these vital functions and lead to morbidity and death.

<span class="mw-page-title-main">Intravenous therapy</span> Medication administered into a vein

Intravenous therapy is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrients for those who cannot, or will not—due to reduced mental states or otherwise—consume food or water by mouth. It may also be used to administer medications or other medical therapy such as blood products or electrolytes to correct electrolyte imbalances. Attempts at providing intravenous therapy have been recorded as early as the 1400s, but the practice did not become widespread until the 1900s after the development of techniques for safe, effective use.

<span class="mw-page-title-main">Pernicious anemia</span> Anemia caused by vitamin B12 deficiency

Pernicious anemia is a disease where not enough red blood cells are produced due to a deficiency of vitamin B12. Those affected often have a gradual onset. The most common initial symptoms are feeling tired and weak. Other symptoms may include shortness of breath, feeling faint, a smooth red tongue, pale skin, chest pain, nausea and vomiting, loss of appetite, heartburn, numbness in the hands and feet, difficulty walking, memory loss, muscle weakness, poor reflexes, blurred vision, clumsiness, depression, and confusion. Without treatment, some of these problems may become permanent.

<span class="mw-page-title-main">Iron-deficiency anemia</span> Medical condition

Iron-deficiency anemia is anemia caused by a lack of iron. Anemia is defined as a decrease in the number of red blood cells or the amount of hemoglobin in the blood. When onset is slow, symptoms are often vague such as feeling tired, weak, short of breath, or having decreased ability to exercise. Anemia that comes on quickly often has more severe symptoms, including confusion, feeling like one is going to pass out or increased thirst. Anemia is typically significant before a person becomes noticeably pale. Children with iron deficiency anemia may have problems with growth and development. There may be additional symptoms depending on the underlying cause.

<span class="mw-page-title-main">Pagophagia</span> Medical condition

Pagophagia is the compulsive consumption of ice or iced drinks. It is a form of the disorder known as pica, which in Latin refers to a magpie that eats everything indiscriminately. Its medical definition refers to the persistent consumption of nonnutritive substances for over a period of at least one month. However, different studies have included alternative definitions including "daily consumption of 2-11 full glasses of ice (480-2640g)" or "the purposeful ingestion of at least one ordinary tray of ice daily for a period in excess of two months." Pagophagia has been shown to be associated with iron-deficiency anemia and responsive to iron supplementation, leading some investigators to postulate that some forms of pica may be the result of nutritional deficiency.

<span class="mw-page-title-main">Microcytic anemia</span> Medical condition

Microcytic anaemia is any of several types of anemia characterized by smaller than normal red blood cells. The normal mean corpuscular volume is approximately 80–100 fL. When the MCV is <80 fL, the red cells are described as microcytic and when >100 fL, macrocytic. The MCV is the average red blood cell size.

Anemia of chronic disease (ACD) or anemia of chronic inflammation is a form of anemia seen in chronic infection, chronic immune activation, and malignancy. These conditions all produce elevation of interleukin-6, which stimulates hepcidin production and release from the liver. Hepcidin production and release shuts down ferroportin, a protein that controls export of iron from the gut and from iron storing cells. As a consequence, circulating iron levels are reduced. Other mechanisms may also play a role, such as reduced erythropoiesis. It is also known as anemia of inflammation, or anemia of inflammatory response.

<span class="mw-page-title-main">Sideroblastic anemia</span> Medical condition

Sideroblastic anemia, or sideroachrestic anemia, is a form of anemia in which the bone marrow produces ringed sideroblasts rather than healthy red blood cells (erythrocytes). In sideroblastic anemia, the body has iron available but cannot incorporate it into hemoglobin, which red blood cells need in order to transport oxygen efficiently. The disorder may be caused either by a genetic disorder or indirectly as part of myelodysplastic syndrome, which can develop into hematological malignancies.

<span class="mw-page-title-main">Human iron metabolism</span> Iron metabolism in the body

Human iron metabolism is the set of chemical reactions that maintain human homeostasis of iron at the systemic and cellular level. Iron is both necessary to the body and potentially toxic. Controlling iron levels in the body is a critically important part of many aspects of human health and disease. Hematologists have been especially interested in systemic iron metabolism, because iron is essential for red blood cells, where most of the human body's iron is contained. Understanding iron metabolism is also important for understanding diseases of iron overload, such as hereditary hemochromatosis, and iron deficiency, such as iron-deficiency anemia.

<span class="mw-page-title-main">Hepcidin</span> Protein-coding gene in the species Homo sapiens

Hepcidin is a protein that in humans is encoded by the HAMP gene. Hepcidin is a key regulator of the entry of iron into the circulation in mammals.

<span class="mw-page-title-main">Copper deficiency</span> Insufficient level of copper in the body, leading to anaemia and nervous symptoms

Copper deficiency, or hypocupremia, is defined either as insufficient copper to meet the needs of the body, or as a serum copper level below the normal range. Symptoms may include fatigue, decreased red blood cells, early greying of the hair, and neurological problems presenting as numbness, tingling, muscle weakness, and ataxia. The neurodegenerative syndrome of copper deficiency has been recognized for some time in ruminant animals, in which it is commonly known as "swayback". Copper deficiency can manifest in parallel with vitamin B12 and other nutritional deficiencies.

<span class="mw-page-title-main">Iron sucrose</span> Intravenous Treatment for Anemia

Intravenous iron sucrose is a commonly used treatment for iron deficiency anemia. Iron sucrose replaces iron in the blood to foster red blood cell production in patients with chronic kidney disease. Iron sucrose has the trade name Venofer.

Magnesium salts are available as a medication in a number of formulations. They are used to treat magnesium deficiency, low blood magnesium, eclampsia, and several other conditions. Magnesium is an essential nutrient.

Latent iron deficiency (LID), also called iron-deficient erythropoiesis, is a medical condition in which there is evidence of iron deficiency without anemia. It is important to assess this condition because individuals with latent iron deficiency may develop iron-deficiency anemia. Additionally, there is some evidence of a decrease in vitality and an increase in fatigue among individuals with LID.

Iron(III)-hydroxide polymaltose complex is a medication used to treat iron deficiency / iron deficiency anemia and belongs to the group of oral iron preparations. The preparation is a macromolecular complex, consisting of iron(III) hydroxide (trivalent iron, Fe3+, Fe(OH)3·H2O) and the carrier polymaltose and is available in solid form as a film-coated or chewable tablet and in liquid form as a syrup, drinkable solution, or drops. It is used for treating iron deficiency without anemia (latent iron deficiency) or with anemia (apparent iron deficiency). Prior to administration, the iron deficiency should be diagnostically established and verified via laboratory tests (e.g., low ferritin concentration, low transferrin saturation).

Anemia is a condition in which blood has a lower-than-normal amount of red blood cells or hemoglobin. Anemia in pregnancy is a decrease in the total red blood cells (RBCs) or hemoglobin in the blood during pregnancy. Anemia is an extremely common condition in pregnancy world-wide, conferring a number of health risks to mother and child. While anemia in pregnancy may be pathologic, in normal pregnancies, the increase in RBC mass is smaller than the increase in plasma volume, leading to a mild decrease in hemoglobin concentration referred to as physiologic anemia. Maternal signs and symptoms are usually non-specific, but can include: fatigue, pallor, dyspnea, palpitations, and dizziness. There are numerous well-known maternal consequences of anemia including: maternal cardiovascular strain, reduced physical and mental performance, reduced peripartum blood reserves, increased risk for peripartum blood product transfusion, and increased risk for maternal mortality.

Intravenous (IV) iron infusion is a therapy in which a combination of iron and saline solution is delivered directly into the bloodstream through a vein, in patients suffering iron deficiency, iron-deficiency anaemia and chronic kidney disease. IV iron infusions are recommended when oral iron supplementation fails to adequately restore iron and haemoglobin levels in the blood. The intravenous method is a fast and effective way of delivering iron throughout the body, used as iron can be administered instantly rather than gradually over time.

<span class="mw-page-title-main">Ferric maltol</span> Chemical compound

Ferric maltol, sold under the brand names Accrufer (US) and Feraccru (EU), is an iron containing medication for the treatment of adults with low iron stores. It is taken by mouth.

Iron preparation is the formulation for iron supplements indicated in prophylaxis and treatment of iron-deficiency anemia. Examples of iron preparation include ferrous sulfate, ferrous gluconate, and ferrous fumarate. It can be administered orally, and by intravenous injection, or intramuscular injection.

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