ORAL AND PARENTERAL IRON PREPARATIONS

Arun GeorgeOG 4

Iron needs in PregnancyFetus and placenta – 300mgRed cell expansion - 500mgLoss in sweat, urine- 200mgBlood loss at delivery – 200mg

Total need = 1200mgIron saved due to amenorrhoea = 300mgNet need in pregnancy = 900mg

Mukherji J. Iron deficiency anemia in pregnancy. Rational Drug Bull. 2002;12:2–5

Why iron supplementation ? Iron - used during the later half of pregnancy.

the iron requirement increases from a 0.8 mg/day in the first trimester to 6 to 7 mg/day in the second half of pregnancy.

Avg - 2 to 4.8 mg of iron per day

amount of iron absorbed from diet - insufficient to meet the demands imposed by pregnancy.

Therefore, iron supplementation during pregnancy is recommended universally even in non anemic women.

IRON SUPPLEMENTS

Oral preparations

Therapeutic oral iron preparations

Preparations of iron salt • Ferrous sulfate • Ferrous fumarate • Ferrous gluconate • Ferrous glycinesulfate • Ferrous succinate • Ferrous calciumcitrate • Ferrous amoniate

• Ferric ammonium citrate • Ferrous ascorbate

Others •Iron polysaccharide complex (iron polymaltose)• Carbonyl iron• Sodiumferedetate• Combination of iron salts & Vit C, succinate, fructose• Haemoglobin preparations

API, 2008

OralProphylaxis:

Iron supplementation 100mg elemental iron 500mcg folic acid

for 100 days

(national anemia control program)

Standard therapy for iron-deficiency anemia in adults is a 300-mg

tablet of ferrous sulphate (60 mg of iron) 3 times per day.

Although absorption is enhanced when given on an empty stomach, nausea and epigastric pain sometimes results.

Iron supplementation during pregnancy is advisable in developing countries, where women often enter pregnancy with low iron stores.

-Cook JD. Diagnosis and management of iron deficiency anaemia. Best Pract Res Clin Haematol. 2005;18:319–332-WHO guidelines

General principles•Iron is not absorbed in the stomach and is absorbed best from the duodenum and proximal jejunum, where the iron transport proteins (eg, duodenal iron transporter, divalent metal transport protein and the iron export protein to blood, ferroportin) are most strongly expressed.

•Iron salts should not be given with food because phosphates, phytates, and tannates in food bind the iron and impair its absorption.

•A number of other factors can inhibit the absorption of iron salts, including antacids, H receptor blockers, proton pump inhibitors, calcium-containing foods and beverages, calcium supplements, certain antibiotics (eg, quinolones, tetracycline), and the ingestion of iron along with cereals, dietary fiber, tea, coffee, eggs, or milk.

Iron is best absorbed as the ferrous (Fe ) salt in a mildly acidic medium. As a result, we usually add a 250 mg ascorbic acid tablet or a half-glass of orange juice at the time of iron administration to enhance the degree of iron absorption.

The iron preparation used should be based upon cost and effectiveness with minimal side effects.

The least expensive preparation is ferrous sulfate; each tablet contains 325 mg of iron salts, of which 65 mg is elemental iron.

Gastrointestinal tract symptoms (eg, abdominal discomfort, nausea/vomiting, diarrhea/constipation) suffered by some patients seem to be directly related to the amount of elemental iron ingested.

Thus, the reported low incidence of side effects for some preparations can be explained by their low elemental iron content.

Patients with persistent gastric intolerance to oral iron tablets may tolerate ferrous sulfate elixir, which provides 44 mg of elemental iron per 5 mL. Patients can titrate the dose up or down to the level at which the gastrointestinal symptoms become acceptable.

ResponseHemoglobin increases at a rate of

0.1g/dL/day starting from the second week of treatment.

Reticulocytosisfeeling of well being, appetiteNo significant improvement in 3

weeks – further evaluation

Reasons for failure of Rx Various malabsorptive states (eg, celiac disease, Whipple's disease,

bacterial overgrowth syndromes)

In patients with inflammatory bowel disease, the use of oral iron has been associated with worsening of the underlying disease, and may be poorly tolerated and ineffective

inability to absorb oral iron (eg, impaired iron transport, concomitant use of calcium-containing salts, H blockers, phosphate binders, generalized malabsorption).

Gastrointestinal side effects - poor adherence to therapy.

Inflammation-mediated induction of hepcidin, which regulates iron homeostasis, may result in suboptimal gastrointestinal absorption of orally administered iron in iron deficient subjects.

Non-response to oral iron therapy does not rule out iron deficiency in such subjects, since two-thirds of the non-responders to oral iron in one study responded to treatment with intravenous iron (ferric carboxymaltose).

NEW THERAPEUTIC ALTERNATIVES

• CARBONYL Iron

• Iron ascorbate

ADVANTAGES a) Outstanding GI Tolerance

b) Very safe with no poisoning even in high doses

c) No interaction with food stuffs

d) Delicious with non-metallic taste and don’t stain the patients’ teeth

e) Compliance is very high

PARENTERAL IRON

Indications for parenteral iron therapy

Intolerant or unresponsive to oral Iron

Necessity for faster increase in haemoglobin (Elective surgery)

Malabsorption syndromesAvoidance of allogenic blood

transfusionModerate to severe anemia around

30 weeks in pregnancy(ICMR)

When Should Parenteral Iron be Used in Pregnant Patients?

In most clinical circumstances, oral preparations are appropriate and sufficient.

Guideline for Giving Parenteral Iron Sucrose Hb <8 g% iron. 14 Day oral dose failure. No haemoglobinopathy.

Parental Iron High molecular weight, iron dextrose is NOT recommended for use. Newer preparations like iron sucrose are effective and safe with

minimal adverse reactions. In comparison with patients who take iron dextran, patients who

take ferrous sucrose have fewer allergic reactions (8.7 vs. 3.3 allergic events per 1,000,000 doses) and a significantly lower fatality rate (31 vs. 0, P < 0.001), hence it is the preferred molecule of choice.

Iron sucrose molecule used should have 30,000–60,000 mol wt.Good Clinical Practice Recommendations for Iron Deficiency Anemia in Pregnancy (IDA) in Pregnancy in IndiaJ Obstet Gynaecol India. Oct 2011; 61(5): 569–571.

Parental IronHigh molecular weight, iron dextrose is NOT

recommended for use.Newer preparations like iron sucrose are effective

and safe with minimal adverse reactions.In comparison with patients who take iron

dextran, patients who take ferrous sucrose have fewer allergic reactions (8.7 vs. 3.3 allergic events per 1,000,000 doses) and a significantly lower fatality rate (31 vs. 0, P < 0.001), hence it is the preferred molecule of choice.

Iron sucrose molecule used should have 30,000–60,000 mol wt.

Parenteral ironElemental Fe Requirement (mg)

=

(N Hb – Pt. Hb) X Wt(kg) x 2.21 + 1000

Dosage and Technique of Administration

Fe–sucrose administered as either a bolus (undiluted) over 5–10 min on outpatient basis or short infusion less than 30 min (in 200 ml Nacl (9 g/l)).

Maximum cumulative doses 1,600 mg in pregnancy (200 mg twice per week to a target Hb of 11.0 g/l or for a maximum of 4 weeks), Mean treatment duration 21 days (8–29 days).

Pre-requisites for parenteral therapy• Should be given under proper supervision• After test dose only• Close monitoring required• Inj. Adrenaline, Hydrocortisone and oxygen

to be available for management of anaphylactic reactions.

• Cardiopulmonary resuscitation facility to be available.

• Other indications for parenteral iron therapy are poor compliance or intolerance to oral

iron therapy.

Parenteral preparations:

Intravenous preparationa) Iron dextran (Imferon)b) Iron sucrose c) Sodium ferric gluconate (ferrlecit)

Intramuscular preparationd) Iron Sorbitol Citrate in dextrin(Jectofer)

e) Iron Dextran (imferon)

Iron dextran: 50 mg/mL. Iron sucrose: 20 mg/mL. Ferric gluconate: 12.5 mg/mL

IM ROUTEIron Dextran (1ml contains 50mg elemental

iron & 1amp=2ml)Dose : 100 mg IM OD till the total dose overDrawbacks:

a) Painful injection (less with jactofer).b) Skin discolorationc) Local abscessd) Allergic reactione) Fe over load.f) Category C drugg) Gluteal sarcomah) Test dose needed

AdvantageCan be given in primary care set upAbsolute reticulocyte count increases in 7 daysHemoglobin increases within 1-2 wksWhole dose can be given in single setting

I/V Route :

a)Repeated Injections

b)Total dose infusion

Side effects:

- Anaphylactic reaction.

- Chest pain, rigors, chills, fall in BP, dyspnoea, hemolysis.

Treatment:

a) Stop infusion.

b) Give antihistaminics, corticosteroids & epinephrine.

IRON DEXTRANa) Colloidal solution of ferric

oxyhydroxide complexed with polymersised dextran

b) Advantage : patients total iron requirement is given in one administration

c) Higher rate of adverse effects like delayed hypotension/ arthralgia/abdominal pain

d) Test dose is necessarye) Patients should be monitored 1

hr following a test dose of 25 mgf) Can given as IV infusion with rate

less than 50 mg/ming) Category B drug

FERRIC GLUCONATE COMPLEX IN SUCROSE

1) Given as IV injection/infusion

2) Standard dose of 125 mg may be given IV injection over 10 min

3) Rate should be < 12.5mg/min

4) Dose can be repeated if ferritin < 100ng/ml or saturation < 20%

5) Can be safely given to Dextran sensitive patients

IRON SUCROSECommonly used in chronic kidney diseases

MW 34,000-60,000 DIron hydroxide sucrose complex in water

Given as IV injection/infusionEach ml contains 20 mg of FeAfter IV administration it dissociates into iron & sucrose

T 1/2 is 6hrsCategory B drug

Total iron deficit = Body weight x (Target Hb – Actual Hb) x 2.4 + Iron stores [mg]

Administered 100 mg IV over 5 minutes, thrice weekly until 1000 mg

200mg max dose per SittingRate of administration should not

more than 20 mg/minInfusion : 50 mg to be injected

slowly over 2 minutes, wait for 2-3 min ,then give another 50 mg over 2 min

100mg-200 mg to be diluted with 100ml NS, infuse at least 15 min

Marked increase in reticulocyte count expected in 7-14 days

Advantages of IRON SUCROSE over othersa)All iron preparations were capable of

causing tissue peroxidation except iron sucrose

b)Less oxidative injuryc) Less risk of tissue parenchymal injury by

free iron.d)Higher availability for erythropoiesis

than iron Dextran e) IV iron supplementation increases the

erythropoiesis 5 timesf) Safe in dextran sensitive patientsg)Minimal side effects

The Hb rise will be evident in as early as 5 days IV iron sucrose is safe & effective Iron sucrose is given both bolus push & infusionDisadvantage

a)Total dose administered in multiple infusions

b)Needs a set up where anaphylactic reaction can be managed.

NEWEST FAST ACTING IV MOLECULES

Iron III Carboxymaltose (FERRINJECT) :

a)Ferric hydroxide carbohydrate complex which allows for control delivery of iron within cells of the RES (primarily bone marrow) and subsequently delivery to the iron binding proteins ferritin and transferin

b)T1/2 : 16 hrc) Dose : Single dose of 1000

mg over 15 minutes (maximum 15mg/kg by injection or 20 mg/kg by infusion)

IRON III ISOMALTOSE(MONOFER)

a)Strongly bound iron in spheroid iron-carbohydrate particle providing slow release of bioavailale iron to iron binding proteins

b)Rapidly up taken by RES and little risk of free iron for tissue damage

c) Dose : 1000 mg in a single infusion

d)Erythropoietic response seen within days

e)Serum ferritin returns to normal by 3 wks

FERUMOXYTOL

USA FDA approved this drug in 2009 for iron replacement in patients with IDA & CKD

No test dose required

Can be given as large dose (510 mg/vial) in <20 Seconds in single settings

No significant side effects

Not approved in Europe

ORAL Vs IV

Intravenous iron treated iron-deficiency anemia of pregnancy and restored iron stores faster and more effectively than oral iron, with no serious adverse reactions.

Intravenous Versus Oral Iron for Treatment of Anemia in Pregnancy

A Randomized Trial

Ragip A. Al, MD, Eylem Unlubilgin, MD, Omer Kandemir, MD, Serdar Yalvac, MD, Leyla Cakir, MD,

and Ali Haberal, MD

(Obstet Gynecol 2005;106:1335–40)

Management of anaemia on the basis of haemoglobin levels among pregnant and lactating women

UNICEF INDIA – National Iron Plus initiative Guidelines for Control of IDA

Hb level between 9–11 gm/dl

• 2 IFA tablets (1 in the morning and 1 in the evening) per day for at least 100 days (at least 200 tablets of IFA).

• Hb levels should preferably be reassessed at monthly

intervals. If on testing, Hb has come up to normal level,

discontinue the treatment.

Hb level between 8–9 gm/dl

Before starting the treatment, the woman should be investigated to detect the cause of anaemia.

Oral IFA supplementation as for Hb level 9–11 gm/dl.

Hb testing to be done every month. Depending on the response to

treatment, same course of action as prescribed for Hb level between 9–11 gm/dl.

Hb level between 7–8 gm/dl Before starting the treatment, the woman should be

investigated to diagnose the cause of anaemia.

Injectable IM iron preparations (parenteral iron) should be given if iron deficiency is found to be the cause of anaemia.

IM iron therapy in divided doses along with oral folic acid daily if women do not have any obstetric or systemic complication; repeat Hb after 8 weeks.

If the woman has become non-anaemic, no further medication is required:

if Hb level is between 9–11 gm/dl, same regimen of oral IFA prescribed for this range.

Multiple dose regimeIntramuscular (IM) - Test dose of

0.5 ml given deep IM and woman observed for 1 hour.

Iron dextran or iron sorbitol citrate complex given as 100 mg (2 ml) deep IM in gluteal region daily. Recommended dose is 1500–2000 mg (IM in divided doses) depending upon the body weight and Hb level

Hb level between 5-7 gm/dlContinue parenteral iron therapy as for Hb

level between 7–8 gm/dl. Hb testing to be done after 8 weeks

If the woman becomes non-anaemic, no further medication is required: if Hb level is between 9–11 gm/dl, same regimen of oral IFA prescribed for this range

Depending on the further response to treatment, same course of action as prescribed for Hb level between 9–11 gm/dl

Hb level less than 5 gm/dl• Evidence for injectable IV sucrose

preparation: under Randomised Control Trial of GOI• Immediate hospitalisation irrespective

of period of gestation in hospitals where round-the-

clock specialist care is available for intensive

personalised care and decision for blood transfusion (packed cell transfusion)

Thank you

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