Introduction to Anaemia

Anaemia is described as a reduction in the proportion of the red blood cells. Anaemia is not a diagnosis, but a presentation of an underlying condition. It is an extremely common disease affecting up to one-third of the global population. The prevalence increases with age and is more common in women of reproductive age, pregnant women, and the elderly.¹

Globally, 40% of children in 6–59 months of age, 37% of pregnant women, and 30% of women 15–49 years of age worldwide are anaemic.²

Indian Scenario

As per the National Family Health Survey-5 (NFHS-5) data, anaemia is prevalent in 57% women (15-49 years), 59% adolescent girls, and 52% pregnant women.³

In a survey from a north Indian village, about 70% women in the postpartum period were found to be anaemic. In India, about 36% of the total maternal deaths are attributable to postpartum haemorrhage or anaemia.⁴

Iron Deficiency Anaemia (IDA)

Approximately 20 mL of senescent erythrocytes are cleared daily, and the 20 mg of iron in those cells is recycled to produce new erythrocytes. Owing to a shorter half-life of circulating erythrocytes in iron deficiency anaemia (IDA), iron is recovered sooner in anaemic patients, but the amount of iron in each microcytic erythrocyte is reduced.⁵

IDA is typically associated with low iron saturation of available transferrin. Iron is loaded onto diferric transferrin from three sources: the gut (diet), macrophages (recycled iron), and the liver (stored ferritin iron). In general, iron stores are reduced or lost before the host develops anaemia. Therefore, dietary, and erythrocyte-recycled iron must meet the demands for erythrocyte production. If iron losses continue, the newly produced erythrocytes will have decreased Hb, causing the amount of iron provided by the same number of senescent erythrocytes to be reduced.⁵

Prevalence

Iron deficiency is the most common form of anaemia affecting up to 50% of the total population. ⁵ IDA is among the five greatest causes of years lived with disability globally, the leading cause of years lived with disability in low-income and middle-income countries (LMICs) and the leading cause of years lived with disability among women across 35 countries.⁶ Subgroups particularly at risk include preschool age children (aged 0–5 years), women of childbearing age, and pregnant women.⁷

Symptoms of IDA

The symptoms of IDA can vary over a wide range. Shortness of breath, fatigue, palpitations, tachycardia and angina can result from reduced blood oxygen levels. This resultant hypoxemia can subsequently cause a compensatory decrease in intestinal blood flow, leading to motility disorder, malabsorption, nausea, weight loss and abdominal pain. Central hypoxia can cause headaches, vertigo and lethargy as well as cognitive impairment with several studies showing an improvement in cognitive functions once anaemia has normalised. It is well known that IDA significantly affects quality of life (QoL) with recent evidence demonstrating that treating IDA improves QoL, regardless of the underlying cause for anaemia.⁸

Diagnosis of IDA⁹

Initial testing for IDA typically includes an assessment of haemoglobin (Hb), hematocrit (Hct), and red blood cell (RBC) indices such as mean corpuscular volume (MCV), followed by serum ferritin (SF).

Red Blood Cell Parameters and Indices - A primary step in the diagnosis of IDA is to consider the complete blood count (CBC) including Hb, MCV, MCH, and MCHC. It is simple, inexpensive, rapid to perform and helpful for early prediction of IDA. The RBC indices are of great value for primary diagnosis which can reduce unnecessary investigative costs. Of all available indices, the Mentzer index (MCV/RBC count) has been shown as the most reliable index with high sensitivity. Mentzer Index >13 indicates IDA and < 13 indicates β-thalassemia.

Table 1: Haemoglobin cut off in pregnancy anaemia (WHO)

Pregnancy state	Normal (g/dL)	Mild (g/dL)	Moderate (g/dL)	Severe (g/dL)
First trimester	> 11	10-10.9	7-9.9	<7
Second trimester	> 10.5
Third trimester	≥ 11	10-10.9	7-9.9	<7

 

Table 2: Haemoglobin cut-off for anaemia (ICMR)

Normal (g/dL)	Mild (g/dL)	Moderate (g/dL)	Severe (g/dL)	Very severe (g/dL)
> 11	10-10.9	7-10	<7	<4

 

Serum Ferritin - Serum ferritin reflects ID in the absence of inflammation. Treatment to be initiated when serum conc. <30µg/L.

Serum Iron, and Total Iron Binding Capacity (TIBC) - The TIBC measures the obtainability of iron-binding sites. Transferrin, a specific carrier protein transports extracellular iron in the body. Therefore, TIBC is the indirect measure of transferrin levels that rises as serum iron concentration (and stored iron) declines.

Reticulocyte Haemoglobin Content - Reticulocyte Hb concentration determines the amount of iron presented to the bone marrow for uptake into new RBCs. This test is not commonly available. The sensitivity and specificity of this are analogous to those of serum ferritin.

Bone Marrow Biopsy - It should be considered to make a definitive diagnosis of IDA when the diagnosis remains ambiguous even after the analysis of laboratory results. It is indicated when there is no response to treatment or to rule out other conditions.

Trial of Iron Therapy - In situations with low Hb or haematocrit, a presumptive diagnosis of IDA is supported by a response to iron therapy.

Table 3: Indicators in IDA⁹

 

Iron deficiency anaemia is common during pregnancy, high prevalence was seen in late pregnancy, and severity of anaemia is associated with high rate of morbidity and mortality.¹⁰

Role of Iron Supplementation in IDA

Treatment of iron deficiency anaemia primarily aims at replenishing the body's iron stores and providing symptomatic relief. At risk population are women of childbearing age, where monthly menses and pregnancy are a common cause for anaemia. If left untreated, this may lead to adverse events such as poor pregnancy outcomes for expectant mothers.¹¹

The role of iron supplementation is to replace the iron stores and to encourage erythropoiesis and oxygen transportation throughout the body. Iron transport occurs via the divalent metal transporter 1 (DMT1) across the cell membrane, where it is incorporated and stored as ferritin in the macrophage. This form then is converted to an absorbable Fe²⁺ ion, then sequestered by transferrin to various sites in the body, including the bone marrow for RBC synthesis. The iron combines with other components such as porphyrin and globin chains to form Hb, which transports oxygen from the lung to other organs in the body.¹¹

Iron Deficiency Anaemia in Pregnancy - The Grave Consequences¹²

Pregnant women are susceptible to IDA because of foetal and placental requirements, and expansion of red cell mass, over the course of pregnancy. There is rationale to avoid IDA in pregnancy because it is associated with preterm birth, low-birth-weight neonates and higher perinatal mortality. Furthermore, women with moderate to severe anaemia (haematocrit < 30% or Hb < 10 g/dL) at the time of delivery, have a 3-fold increased risk for severe postpartum haemorrhage. To prevent iron deficiency in pregnancy, experts recommend 30 mg of iron daily, which is readily met by most prenatal vitamin formulations. Additional supplementation is required for women entering pregnancy with anaemia.¹²

Oral Iron - Is it a Single Stop Solution for IDA in Pregnancy?¹²

The first-line treatment for iron-deficiency anaemia in pregnancy is supplementation with oral iron.

However, nearly 1 of 2 pregnant women suffer from side-effects of oral iron, such as constipation, nausea, epigastric discomfort, and vomiting, often limiting tolerance and delaying repletion efforts¹²

Iron absorption is regulated by the hepatic peptide hormone hepcidin. Hepcidin also controls iron release from cells that recycle or store iron, thus regulating plasma iron concentrations.¹³ Due to feedback inhibition of hepcidin, attempts to give oral iron more than once daily are also limited because subsequent doses are less effective. Moreover, repletion of iron in pregnancy is time sensitive hence quick replenishment of the depleted stores is required in IDA in pregnancy.¹² Even with increasing the dose, the levels are not attained, and oral iron takes around 3 to 6 months to replete body iron stores and normalize ferritin levels.¹² Lastly, oral iron preparations are also poorly absorbed and badly tolerated, and hence, may not be suitable or effective in all patients.¹⁴

IV Iron Administration - The Need of the Hour

Oral iron therapy is currently the treatment of choice for the majority of patients with iron deficiency anaemia, but it has disadvantages like poor absorption, poor compliance and gastro-intestinal (GI) side effects. Parenteral iron helps in restoring iron stores faster and more effectively than oral iron.⁴

IV iron should be preferred over oral iron due to following reasons: ^12,15.16,17

• Lower rates of adverse events compared oral iron, primarily due to a lower rate of gastrointestinal adverse effects in pregnant women.
• Poor absorption or poor adherence to oral iron
• IV iron is preferred when oral iron supplements and/or dietary interventions may fail to resolve anaemia.
• IV iron should be offered to pregnant women in second trimester when anaemia is severe (< 8 g/dL), or in women with moderate to severe anaemia in third trimester, when there is a need for quick replenishment to prepare for delivery, as well as to reduce the risk of postpartum haemorrhage and blood transfusion.
• Moderate to severe postpartum anaemia when compliance to oral iron and follow up to health care facility is doubtful
• Pre- and post-operative cases

IV Iron - Efficacy and Place in Therapy

A meta-analysis by Govindappagari S. et al demonstrated that pregnant women were 2-3x more likely to achieve desired Hb targets within 4 weeks of starting therapy. The study concluded that IV iron is more efficacious, acts more quickly, and has fewer side effects, when compared with oral iron for treatment of iron deficiency anaemia in pregnancy.¹²

However, not all the IV iron preparations are similar since iron preparations like sodium ferric gluconate and iron sucrose require either multiple administration of low doses to replenish iron stores and some preparations like iron dextran have been associated with hypersensitivity reactions.¹⁴

Since not all IV iron preparations are similar, consider a preparation that rapidly replenish iron stores, with minimal risks of hypersensitivity or other adverse effects.¹⁴

Guidelines Recommendation for IV Iron Use in IDA in Pregnant Women

American Society of Haematology Guideline 2019 recommend use of IV iron when there are no contraindications, when poor response to oral iron is anticipated, when rapid hematologic responses are desired, and/or when there is availability of and accessibility to the product. IV iron is recognized as appropriate first-line therapy in inflammatory bowel disease (adult and paediatric),chronic kidney disease, chemotherapy-induced anaemia, and after bariatric surgery. For surgeries with 6 weeks or more lead time, oral iron once per day or once every other day is recommended; for those with less lead time, IV iron is recommended as safe and efficacious¹⁸. In the first trimester, iron deficiency is treated with oral iron, reserving IV iron for after 13th week. This is in keeping with recommendations of the European Medicine Agency’s Committee of Medicinal Products for Human Use (CHMP). Because IV iron has been shown to improve Hb more rapidly than oral iron, IV iron is preferentially used to treat patients in the second half of the pregnancy.¹⁹

Network for the Advancement of Patient Blood Management, Haemostasis and Thrombosis (NATA) consensus statement from 2017 recommends IV iron be considered in pregnant women that fail to respond to oral iron within 2 to 4 weeks, those with severe anaemia (Hb < 8.0 g/dL), or newly diagnosed iron deficiency anaemia >34 weeks of gestation.¹²

The British Committee for Standards in Haematology 2019 on the management of iron deficiency in pregnancy recommend IV iron to be considered from the 2^nd trimester onwards and postpartum period in women with iron deficiency anaemia who fail to respond to or are intolerant of oral iron (1A). IV iron should be considered in women who present after 34 weeks gestation with confirmed iron deficiency anaemia and an Hb of <100 g/l. ²⁰

The Intensified National Iron Plus Initiative (I-NIPI) 2018 guidelines recommend using IV iron:²¹

• As first line of management in pregnant women with mild (10-10.9 g/dL) or moderate (7–9.9 g/dL) anaemia who are detected to be anaemic late in pregnancy or in whom compliance is likely to be low (high chance of lost to follow-up).
• In severe (5.0–6.9 g/dL) anaemia as the first line of treatment.

Ferric Carboxymaltose (FCM) - Addressing the Unmet Need in IDA

Ferric carboxymaltose is an intravenous iron preparation approved in numerous countries for the treatment of iron deficiency. FCM is more stable than other IV iron preparations like sodium ferric gluconate and iron sucrose. Due to its stability, it is possible to administer much higher single doses of FCM over shorter periods of time than sodium ferric gluconate or iron sucrose, resulting in the need for fewer administrations to replete iron stores.²² Moreover, it does not contain dextran; therefore, the risk of anaphylaxis or serious hypersensitivity reactions is very low, and a test dose is also not required.⁴ FCM elevates serum ferritin and Hb levels and restores iron stores faster than iron sucrose and oral iron with minimal adverse reactions.⁴

FOGSI General Clinical Practice Recommendations in the Management of Iron Deficiency Anaemia in Pregnancy 2017 advocates the use of FCM to be superior to all other parenteral iron supplementation products. FCM administration during postpartum has been found to be safe and effective in improving the mean Hb level. Compared to other parenteral iron preparations FCM has several advantages: It has fewer side-effects; single high dose administration is possible, and it can reduce the frequency of hospital visits.⁹

FCM possess several advantages over other iron preparations due to which FCM may be considered early, while treating patient with iron deficiency anaemia:^4,23,12

• Ultra-short duration of treatment
• No hospitalization required.
• Well tolerated with lesser side-effects
• Quicker iron replacements and consequently a higher success in anaemia correction
• Neutral pH (5.0-7.0) and physiological osmolarity makes it possible to administer its higher single doses over shorter time periods than other parenteral preparations.

 

CLINICAL PHARMACOLOGY

Mechanism of Action²⁵

FCM is a polynuclear iron (III)–hydroxide carbohydrate complex designed to mimic physiologic ferritin.

• The carbohydrate shell of FCM is incompletely broken down in the blood by α-amylase after IV administration.
• The macrophages take the FCM by an endocytic mechanism by which the carbohydrate shell and the polynuclear iron core may be completely broken down in the endolysosomes to release Fe³⁺
• Six-transmembrane epithelial antigen of the prostate 3 (Steap3) is likely to reduce the released Fe³⁺ into Fe²⁺
• Fe²⁺ is extruded from the endolysosomes to the cytosolic labile iron pool by the activity of DMT1 and from the cytosol to the plasma by FPN.
• Fe² is transported by transferrin to the liver, bone marrow, and other tissue
  
  Figure 1: Mechanism of action of FCM²⁴

DMT1, divalent metal transporter 1; FP, ferroportin.

Pharmacodynamics²⁵

FCM injection solution for injection/infusion is a colloidal solution of the iron complex ferric carboxymaltose. The complex is designed to provide, in a controlled way, utilisable iron for the iron transport and storage proteins in the body (transferrin and ferritin, respectively).

Pharmacokinetics²⁵

Absorption

Red cell utilisation of ⁵⁹Fe from radiolabelled FCM injection ranged from 91 to 99% in subjects with ID and 61 to 84% in subjects with renal anaemia at 24 days post-dose. FCM injection treatment results in an increase in reticulocyte count, serum ferritin levels and TSAT levels to within normal ranges.

Distribution

Positron emission tomography demonstrated that ⁵⁹Fe and ⁵²Fe from FCM injection was rapidly eliminated from the blood, transferred to the bone marrow, and deposited in the liver and spleen. After administration of a single dose of FCM injection of 100 to 1,000 mg of iron in ID subjects, maximum total serum iron levels of 37 μg/mL up to 333 μg/mL are obtained after 15 minutes to 1.21 hours respectively. The volume of the central compartment corresponds well to the volume of the plasma (approximately 3 litres).

Elimination

The iron injected or infused was rapidly cleared from the plasma. The terminal half-life ranged from 7 to 12 hours, and the mean residence time (MRT) from 11 to 18 hours. Renal elimination of iron was negligible.

CPINK-FCM

Composition²⁵

Each mL contains:

Ferric Carboxymaltose equivalent to Elemental Iron ……………. 50 mg

Water for Injections IP………………………. q.s.

Therapeutic Indications

CPINK-FCM injection is indicated for the treatment of iron deficiency when -

• ·oral iron preparations are ineffective.
• ·oral iron preparations cannot be used.

The diagnosis of iron deficiency must be based on laboratory tests.

Posology and Method of Administration²⁵

Monitor patients carefully for signs and symptoms of hypersensitivity reactions during and following each administration of CPINK-FCM injection. CPINK-FCM injection should only be administered when staff trained to evaluate and manage anaphylactic reactions are immediately available, in an environment where full resuscitation facilities can be assured. The patient should be observed for adverse effects for at least 30 minutes following each CPINK-FCM injection administration.

Posology²⁵

Step 1: Determination of the iron need

The individual iron need for repletion using CPINK-FCM injection is determined based on the patient's body weight and haemoglobin level.

Table 4: Determination of the iron need

Hemoglobin		Patient Body Weight
g/dL	mmol/L	Below 35 kg	35 kg to <70 kg	70 kg and above
<10	<6.2	500 mg	1,500 mg	2,000 mg
10 to <14	6.2 to <8.7	500 mg	1,000 mg	1,500 mg
≥14	≥8.7	500 mg	500 mg	500 mg

Note: Iron deficiency must be confirmed by laboratory tests. A cumulative iron dose of 500 mg should not be exceeded for patients with body weight <35 kg.

Step 2: Calculation and administration of the maximum individual iron dose(s)

Based on the iron need determined as above, the appropriate dose(s) of CPINK-FCM injection should be administered taking into consideration the following:

A single CPINK-FCM injection administration should not exceed -

• 15 mg iron/kg body weight (IV injection) or 20 mg iron/kg body weight (IV infusion)
• 1,000 mg of iron (20 mL CPINK-FCM injection)

The maximum recommended cumulative dose of CPINK-FCM injection is 1,000 mg of iron (20 mL FCM injection) / week.

Step 3: Post-iron repletion assessments

Re-assessment should be performed by the clinician based on the individual patient's condition. The haemoglobin level should be re-assessed no earlier than 4 weeks after final CPINK-FCM injection administration to allow adequate time for erythropoiesis and iron utilisation. In the event the patient requires further iron repletion, the iron need should be recalculated as given in table 4.

Method and Administration²⁵

CPINK-FCM injection must only be administered by the intravenous route - by injection, or by infusion, or during a haemodialysis session, given undiluted directly into the venous limb of the dialyser.

CPINK-FCM injection must not be administered by the subcutaneous or intramuscular route.

Intravenous Injection

CPINK-FCM may be administered by intravenous injection using undiluted solution. The maximum single dose is 15 mg iron/kg body weight but should not exceed 1,000 mg iron. The administration rates are as shown in Table 5.

Table 5: Administration Rates for Intravenous Injection of CPINK-FCM Injection

 

Intravenous Infusion

CPINK-FCM injection may be administered by intravenous infusion, in which case it must be diluted. The maximum single dose is 20 mg iron/kg body weight but should not exceed 1,000 mg iron.

For infusion, CPINK-FCM injection must only be diluted in sterile 0.9% m/V sodium chloride solution.

Table 6: Dilution Plan for Intravenous Infusion of CPINK-FCM Injection

Volume of FCM Injection Required	Equivalent Iron Dose	Maximum Amount of Sterile 0.9% m/V Sodium	Minimum Administration Time
2 to 4 mL	100 to 200 mg	50 mL	No minimal prescribed time
>4 to 10 mL	>200 to 500 mg	100 mL	6 minutes
>10 to 20 mL	>500 to 1,000 mg	250 mL	15 minutes

Note: For stability reasons, dilutions to concentrations < 2 mg iron/mL are not permissible.

Inspect vials visually for sediment and damage before use. Use only those containing sediment-free, homogeneous solution.

Each vial of CPINK-FCM Injection is intended for single use only. Any unused product or waste material should be disposed of in accordance with local requirements. CPINK-FCM Injection must only be mixed with sterile 0.9% sodium chloride solution. No other intravenous solutions and therapeutic agents should be used, as there is the potential for precipitation and/or interaction. From a microbiological point of view, preparations for parenteral administration should be used immediately after dilution with sterile 0.9% sodium chloride solution.

Contraindications²⁵

• Hypersensitivity to the active substance, to FCM injection, or any of its excipients.
• Known serious hypersensitivity to other parenteral iron products.
• Anaemia not attributed to iron deficiency, e.g., other microcytic anaemia.
• Evidence of iron overload or disturbances in the utilisation of iron
• Pregnancy in the first trimester.

Warnings and Precautions²⁵

Hypersensitivity Reactions

Parenterally administered iron preparations can cause hypersensitivity reactions, including serious and potentially fatal anaphylactic/anaphylactoid reactions. Hypersensitivity reactions have also been reported after previously uneventful doses of parenteral iron complexes. There have been reports of hypersensitivity reactions that progressed to Kounis syndrome (acute allergic coronary arteriospasm that can result in myocardial infarction). The risk is enhanced for patients with known allergies (drug allergies as well), including patients with a history of severe asthma, eczema or other atopic allergy. There is also an increased risk of hypersensitivity reactions to parenteral iron complexes in patients with immune or inflammatory conditions (e.g., systemic lupus erythematosus, rheumatoid arthritis).

FCM injection should only be administered when staff trained to evaluate and manage anaphylactic reactions are immediately available, in an environment where full resuscitation facilities can be assured. Each patient should be observed for adverse effects for at least 30 minutes following each FCM injection administration. If hypersensitivity reactions or signs of intolerance occur during administration, the treatment must be stopped immediately. Facilities for cardio-respiratory resuscitation and equipment for handling acute anaphylactic/anaphylactoid reactions should be available, including an injectable 1:1,000 adrenaline solution. Additional treatment with antihistamines and/or corticosteroids should be given as appropriate.

Hypophosphataemic Osteomalacia

Symptomatic hypophosphataemia leading to osteomalacia and fractures requiring clinical intervention, including surgery, has been reported in the post marketing setting. Patients should be asked to seek medical advice if they experience worsening fatigue with myalgias or bone pain. Serum phosphate should be monitored in patients who receive multiple administrations at higher doses or long-term treatment, and those with existing risk factors for hypophosphataemia. In case of persisting hypophosphataemia, treatment with FCM should be re-evaluated.

Infection

Parenteral iron must be used with caution in case of acute or chronic infection, asthma, eczema or atopic allergies. It is recommended that the treatment with FCM injection is stopped in patients with ongoing bacteraemia. Therefore, in patients with chronic infection a benefit/risk evaluation has to be performed, taking into account the suppression of erythropoiesis.

Extravasation

Caution should be exercised to avoid paravenous leakage when administering FCM injection. Paravenous leakage of FCM injection at the administration site may lead to irritation of the skin and potentially long-lasting brown discolouration at the site of administration. In case of paravenous leakage, the administration of FCM injection must be stopped immediately.

Fertility

There are no data on the effect of FCM injection on human fertility. Fertility was unaffected following FCM injection treatment in animal studies.

Excipients

FCM IV injection contains up to 5.5 mg (0.24 mmol) sodium per mL of undiluted solution, equivalent to 0.3% of the World Health Organization (WHO) recommended maximum daily intake of 2 g sodium for an adult.

Drug Interactions²⁵

The absorption of oral iron is reduced when administered concomitantly with parenteral iron preparations. Therefore, if required, oral iron therapy should not be started for at least 5 days after the last administration of FCM injection.

Use in Special Populations²⁵

Hepatic Impairment

In patients with liver dysfunction, parenteral iron should only be administered after careful benefit/risk assessment. Parenteral iron administration should be avoided in patients with hepatic dysfunction where iron overload is a precipitating factor, particularly porphyria cutanea tarda. Careful monitoring of iron status is recommended to avoid iron overload.

Renal Impairment

No safety data on haemodialysis-dependent chronic kidney disease patients receiving single doses of more than 200 mg iron are available.

Pregnant Women

There are limited data from the use of FCM injection in pregnant women. A careful benefit/risk evaluation is required before use during pregnancy and FCM injection should not be used during pregnancy unless clearly necessary. Iron deficiency occurring in the first trimester of pregnancy can in many cases be treated with oral iron. Treatment with FCM injection should be confined to the second and third trimester if the benefit is judged to outweigh the potential risk for both the mother and the foetus. Foetal bradycardia may occur following administration of parenteral iron. It is usually transient and a consequence of a hypersensitivity reaction in the mother. The unborn baby should be carefully monitored during intravenous administration of parenteral iron to pregnant women. Animal data suggest that iron released from FCM injection can cross the placental barrier and that its use during pregnancy may influence skeletal development in the foetus.

Lactating Women

Clinical studies showed that transfer of iron from FCM injection to human milk was negligible (≤1%). Based on limited data on breastfeeding women, it is unlikely that FCM injection represents a risk to the breastfed child.

Paediatric Patients

The use of FCM injection has not been studied in children and, therefore, is not recommended in children under 14 years of age.

Effects on Ability to Drive and Use Machines

Ferric carboxymaltose injection is unlikely to impair the ability to drive and use machines.

Undesirable Effects²⁵

Below table presents the adverse drug reactions (ADRs) reported during clinical studies in which >8,000 subjects received FCM injection, as well as those reported from the post-marketing experience.

The most commonly reported ADR is nausea (occurring in 2.9% of the subjects), followed by injection-/infusion-site reactions, hypophosphataemia, headache, flushing, dizziness and hypertension. Injection-/infusion-site reactions comprise several ADRs that, individually, are either uncommon or rare.

The most serious ADR is anaphylactoid/anaphylactic reactions (rare); fatalities have been reported.

Table 7 : ADRs Observed during Clinical Trials and Post-marketing Experience

System organ class	Common (≥1/100 to < 1/10)	Uncommon (≥1/1,000 to < 1/100)	Rare (≥1/10,000 to < 1/1,000)	Frequency not known (1)
Immune system disorders		Hypersensitivity	Anaphylactoid/anaphylactic reactions
Metabolism and nutritional disorders	Hypophosphataemia
Nervous system disorders	Headache, dizziness	Paraesthesia, dysgeusia		Loss of consciousness (1)
Psychiatric disorders			Anxiety (2)
Cardiac disorders		Tachycardia		Kounis syndrome (1)
Vascular disorders	Flushing, hypertension	Hypotension	Phlebitis, syncope (2), presyncope (2)
Respiratory, thoracic and mediastinal disorders		Dyspnea	Bronchospasm (2)
Gastrointestinal disorders	Nausea	Vomiting, dyspepsia, abdominal pain, constipation, diarrhea	Flatulence
Skin and subcutaneous tissue disorders		Pruritus, urticaria, erythema, rash (3)	Angioedema (2), pallor (2), distant skin discoloration (2)	Face oedema (1)
Musculoskeletal and connective tissue disorders		Myalgia, back pain, arthralgia, pain in extremity, muscle spasms		Hypophosphataemic Osteomalacia (1)
General disorders and administration site conditions	Injection/infusion site reactions (4)	Pyrexia, fatigue, chest pain, oedema peripheral, chills	Malaise, influenza like illness (whose onset may vary from a few hours to several days) (2)
Investigations		Alanine aminotransferase increased, aspartate aminotransferase increased, gamma-glutamyl transferase increased, blood lactate dehydrogenase increased, blood alkaline phosphatase increased

 

⁽¹⁾ ADRs exclusively reported in the post-marketing setting; estimated as rare.

⁽²⁾ ADRs reported in the post-marketing setting that are also observed in the clinical setting.

⁽³⁾ Includes the following preferred terms: rash (individual ADR determined to be uncommon) and rash erythematous, generalised, macular, maculo-papular, pruritic (all individual ADRs determined to be rare).

⁽⁴⁾ Includes, but is not limited to, the following preferred terms: injection-/infusion-site pain, haematoma, discolouration, extravasation, irritation, reaction, (all individual ADRs determined to be uncommon) and paraesthesia (individual ADR determined to be rare).

Clinical Studies

Phase IV Study Comparing Safety and Effectiveness of FCM with Iron Sucrose ²⁶

In this randomized trial to evaluate the effectiveness and safety of IV FCM (1000 mg) compared to Iron Sucrose (IS; 200 mg), 200 women with IDA were enrolled and randomly allocated in a 1:1 ratio to receive either FCM or IS.

Change in the laboratory parameters such as Hb, mean corpuscular value (MCV), and serum ferritin (SF) levels at 2 weeks and 4 weeks interval after the treatment was recorded. Well-being of the patients was evaluated through a questionnaire for health-related quality of life (HRQOL).

Results: Figure 2: Comparison of Hb levels before and after FCM and iron sucrose

FCM was better as compared to iron sucrose in IDA management.

Table 8: Baseline versus 4^th Week clinical data comparison

Parameter	Iron Sucrose (N=93)		FCM (N=94)		P value
	Baseline	4th week	Baseline	4th week
Mean Corpuscular Volume–– fL	66.82	86.76	68.05	93.8	0·0001
Serum Iron–– μg/dL	32.75	75.4	34.46	127.54	0·0001
Serum Ferritin–– μg/dL	18.13	34.99	18.29	119.02	0·0001
Total Iron Binding Capacity–– μg/dL	474.18	332.61	457.94	315.13	0·0001
Transferrin Saturation –– %	7.02	22.76	7.67	40.59	0·0001

 

Conclusion

This Phase IV study in Indian women with IDA demonstrated that a single dose of 1000 mg IV FCM infusion is safe and effective. FCM improved laboratory biomarkers i.e., Hb, MCV, SI, SF, TIBC, TS% levels and restored the iron stores in short duration of time as compared to IS.

Patient compliance was better with FCM as compared to IS as FCM reduced the number of hospital visits. FCM is ideally suited for treatment of patients with IDA who require rapid replenishment of iron stores.

Evaluation of a Single Dose of FCM in Fatigued, Iron-Deficient Women²⁷

A randomized, placebo-controlled, single-blinded study evaluated the efficacy and tolerability of a single infusion of FCM in improving fatigue symptoms, QoL, and cognitive function in iron-deficient, premenopausal women.

Fatigued women (N=290) with Piper Fatigue Scale [PFS] score ≥5 and with iron deficiency and normal or borderline Hb (≥115g/L) were randomized to FCM 1000 mg (N=144) or placebo (N=146) infusion.

Result: Figure 3: Proportion of patients with ≥1 point reduction in PFS

The percentage of patients with improved total PFS score (≥1 point decrease from baseline to Day 56) was statistically significantly higher in the FCM arm (65.3%) than in the placebo arm (52.7%) (P=0.03).

Conclusion

A single infusion of FCM improved fatigue, mental quality-of-life, cognitive function, and erythropoiesis in iron-deficient women with normal or borderline Hb.

Ferric Carboxymaltose for Anaemic Perioperative Populations: A Systematic Literature Review of Randomized Controlled Trials²⁸

A systematic literature review was conducted to determine the efficacy and safety of the use of IV FCM (dose range 500-2000 mg) for the treatment of perioperative anaemia in preoperative, intraoperative, and postoperative elective surgical care.

Findings

Total 1975 patients were studied, of whom 943 were randomized to FCM, of whom 914 received FCM treatment. The 10 studies included elective surgical populations for colorectal, gastric, orthopaedic, abdominal, urologic, plastic, neck, gynaecologic, and otolaryngologic procedures, and these reported statistically greater changes in haemoglobin concentration, serum ferritin, and/or transferrin saturation with FCM treatment compared with comparators (placebo, oral iron, standard care, or a combination of these). Two studies reported statistically significant differences in transfusion rate and 2 studies reported significant differences in length of hospital stay between FCM and its comparator(s).

Conclusions

FCM in preoperative and postoperative settings improved hematologic parameters and reduced transfusion rate and length of stay as reported in several studies.

The preoperative correction of anaemia and other haematological parameters with IV FCM appears to be a viable intervention to mitigate known risks associated with postsurgical anaemia and consequent events such as the need for transfusion.

Comparison of Ferric Carboxymaltose and iron sucrose complex for treatment of iron deficiency anaemia in pregnancy- randomised controlled trial²⁹

A randomized clinical trial compared IV FCM with IV Iron sucrose complex (ISC) for treatment of moderate to severe iron deficiency anaemia in pregnancy (N=100).

Results

Mean rise in Hb at 12 weeks was significantly higher in FCM group (29 g/L vs 22 g/L; p < 0.01). FCM was associated with greater improvement in fatigue scores. Number of visits were significantly less in FCM group. No serious adverse events were noted in either group.

Figure 4: Rise in haemoglobin at 12 weeks from baseline

Conclusion

FCM is a safe IV agent in pregnancy and is non-inferior to the current standard therapy (iron sucrose complex) for the treatment of iron deficiency anaemia in pregnancy. FCM has the advantage of a large dose administration per sitting, early rise in Hb level, lesser total number of required doses (convenient dosing), hence lesser number of hospital visits and total cost involved in transportation, equipment required for infusion and the discomfort caused to the patient due to multiple needle pricks. Improvement in fatigue scores were better with FCM over 12 weeks.

Ferric Carboxymaltose Injection in Postpartum Iron Deficiency Anaemia ³⁰

A real-world clinical practice study was conducted in 535 postpartum iron deficiency anaemia patients treated with IV FCM. Safety and efficacy were assessed by adverse events and change in Hb from baseline, respectively at 1 week after treatment.

Results

No serious adverse events (AE) were reported. Only 4 patients (<1%) reported AE (mild nausea, n=1; shivering, n=1; palpitation, n=1; pruritus and breathlessness, n=1). Safety and efficacy of FCM was rated by physicians as ‘very good and good’ in 99% patients.

Figure 5: Mean change in Hb (g/dL)

 

Table 9: Assessment of efficacy of FCM as per severity of anaemia

Patient Categories	N	Baseline Hb (g/dL)	Hb after FCM treatment (g/dL)	Mean change in Hb from baseline (g/dL)	P' value vs baseline
Mild anaemia (9.1-10 g/dL)	139	9.55 ± 0.28	11.0± 0.73	1.45 ± 0.75	<0.001
Moderate anaemia (7.1-9 g/dL)	272	8.25 ± 0.57	10.36 ± 0.86	2.11 ± 0.88	<0.001
Severe anaemia (<7 g/dL)	87	6.61 ± 0.49	9.56± 1.02	2.95 ± 1.08	<0.001

 

Conclusion

IV FCM was safe and well tolerated without any serious adverse event. It was found to increase Hb significantly in a shorter period of time in patients with post-partum iron deficiency anaemia including patients with severe anaemia.

Summary

• FCM is a robust and stable molecule with similar characteristics to ferritin, which minimizes the release of free iron during its administration, this allows greater iron delivery to tissues and a faster repletion of iron stores by a single infusion, with favourable cost effectiveness.
• FCM appears to be a safe and effective treatment for iron-deficiency anaemia in various conditions, such as menorrhagia, postpartum anaemia, and pregnancy.
• It is well-tolerated and does not appear to be associated with any significant safety concerns.
• Single dose of FCM has been found to improve fatigue in iron-deficient, non-anaemic premenopausal women.
• Superiority of FCM is justified by the large amount of iron that can be administered through a small number of injections i.e., 15 mg/kg: maximum of 1000 mg/infusion in a single and rapid session in 15-minute infusion.
• The therapeutic efficacy of IV FCM has been evaluated in several randomized, Phase III, open-label, controlled, multicentre trials in a diverse range of conditions associated with absolute or functional iron deficiency with or without anaemia.
• FCM leads to faster and quick replenishment of iron compared to iron sucrose.
• Overall, FCM is considered an optimal treatment for parenteral iron administration, providing a very efficient and convenient means of delivering iron in patients with IDA.

 

 

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