Kovey Oral Hematinics in Pediatrics.pdf - Helen DeVos Children's ...

Oral Hematinics inPediatricsKaren Kovey, Pharm.D., BCPSHelen DeVos Children’s HospitalPediatric Blood ManagementConference 2010 - GVSU

Objectives• Overview of iron absorption, metabolism,distribution and storage• Review physiologic impact of inflammation• Discuss different forms of available oralproducts• Identify expected outcomes with ironreplacement• Optimize oral hematinic therapy with adjunctivemedications

Introduction• Average adult European/American dietprovides 10-20mg iron/day• Approximately 10% of dietary iron isabsorbed/day (1-2mg/day) and• Approximately 1-2mg of iron is lost/day• Females at increased risk of iron deficiency• Requirement for erythropoiesis 20-30mg/day

Iron Absorption• Primary site: duodenum1. Reduction of iron to ferrous state(Fe 2+ ) -inorganic iron2. Apical uptake by DMT13. Intracellular storage by Ferritin4. Basolateral release byFerroportin5. Reuptake by Ferritin in bloodand delivery to RBC precursors

Alteration of Iron Absorption• Competition with other divalent cations (copper,magnesium, zinc, calcium)• pH alteration: proton pump inhibitors, antacids, H2blockers, neonates• Binders: co-administration with tetracyclines, phenoliccompounds, phytates• Impaired Iron Uptake: H. pylori, gastric atrophy• Iron storage status, presence of hypoxia, rate oferythropoiesis• Expression of hepcidin

Iron Distribution &Cycling• Iron is transferrin bound inplasma• Delivered to bone marrow,muscle and liver where it isstored• Iron is released fromtransferrin via pHalternation inside theendosome

Iron Distribution & Cycling

Impact of Chronic Inflammation onIron HomeostasisInt-γ, TNF-α, Interleukins (IL)-1, 6, & 101. Decreased RBC half life2. Impaired erythropoietin (EPO) production3. Impaired responsiveness of erythroid cellsto EPO4. Inhibition of proliferation anddifferentiation of erythroid cells5. Increased iron storage

Impact of Acute Inflammation onIron HomeostasisInterleukins 6 and 8 (major) and TNF-α andIL-1 (minor)1. Perioperative or traumatic blood loss2. Blunted erythropoiesis due to decreased ironbioavailability (hepcidin)

Impact of Inflammation on IronHomeostasis

Enteral Iron Products

Enteral Iron Dosing• Dosing for anemia:• Premature Neonates: 2-4mg elemental Fe/kg/day• Infants and Children:• Severe anemia: 4-6mg elemental Fe/kg/day• Mild/Moderate anemia: 3mg elemental Fe/kg/day• Anemia Prophylaxis: 1-2 mg elemental Fe/kg/day• Adults:• Anemia: 2-3mg elemental Fe/kg/day• Anemia Prophylaxis: 60mg elemental Fe/day

Enteral Iron ProductsInorganic IronSaltsFerrous sulfateFerrous gluconateFerrous fumarateOrganic IronHeme Iron PolypeptidePolysaccharide Iron ComplexChelated Iron ProductsFerrous bis glycinateFerrochel & Sumalate ironElemental IronSaltsCarbonyl Iron

Immediate Release (IR) Preparations1. Ferrous sulfate 300mg or 325mg2. Ferrous gluconate 27mg (Fergon®)3. Ferrous Bis-Glycinate 27mg (Gentle Iron®)4. Carbonyl Iron 45mg or 50mg (Feosol®, PerfectIron®)5. Polysaccharide Iron Complex (PIC) 22mg + HemeIron Polypeptide as Proferrin (HIP) 6mg mixtures(Bifera®)6. Heme Iron Polypeptide 12mg (Proferrin® ES)

Sustained or Extended Release (SRor ER) Preparations1. SlowFe® (ferrous sulfate 45mg elementaliron)2. Ferro-Sequels® (Ferrous fumarate 50mg)

Liquid Preparations1. Ferrous sulfate elixir 220mg/5mL (44mgelemental iron/5mL)2. Ferrous sulfate drops 75mg/0.6mL (15mgelemental iron/0.6mL)3. Fer-In-Sol® (ferrous sulfate drops) 75mg/1mL(15mg elemental iron/1mL)4. Poly-Vi-Sol w/Iron Infant Drops – contain10mg elemental iron per 1mL

Prescription Only Iron Supplements

Niferex-150®Iron (elemental iron)• Sumalate®* iron . . . . .. . . . . . . . . . . . . . . . . . . . . . 50 mg• Polysaccharide iron . . . . . . . . . . . . . . . . . . . . . . . 100 mg• Succinic acid . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . 50 mg• Vitamin C• Ester-C ® supplement ... . . . . . . . . . . . . . . . . . . . . 50 mgSumalate®* = ferrous asparto glycinate

Niferex-150 Forte®Iron (elemental iron)• Sumalate® iron . . ... . . . . .. . . . ... . . . . . . . 50 mg• Polysaccharide iron . . . . …. .. ... . . . . . . . 100 mg• Succinic acid . . . . . . . . . . .. .. .. . ... .. . . . . . 50 mg• Vitamin C• Ester-C ® supplement . . ... . . … . . .. . . . . . 60 mg• Folic acid, USP . . . . . . . . . . .. . . . .. .. . . . . . . 1 mg• Vitamin B12 (cyanocobalamin) . . . .. . . . . 25 mcg

Repliva® 21/7Iron (elemental iron)• Ferrochel®………………………………….……………..70 mg• Ferrous fumarate…………………………….....………...81 mg• Succinic acid………………………………………………150 mg• Vitamin C (ascorbic acid)………………………………..140 mg• Vitamin C as Ester-C ®• Ascorbic acid (as calcium ascorbate)………………..…60 mg• Threonic acid (as calcium threonate)………………….0.8 mg• Folic acid, USP……………………………………………....1 mg• Vitamin B 12 (cyanocobalamin)…………………. …….10 mcg• Days 21-28:Succinic acid (purple pill)………………….150 mgFerrochel® = iron bis glycinate chelate

Evaluating Efficacy of IronReplacement Therapy

Van Wyck DB, et al. Venofer Clinical Trials Group2005.Non-dialysis dependent adults with CKD given IV ironsucrose 1000mg in divided doses over 14 days vsFerrous sulfate 325mg TID x 14 days• IV iron group had 44.3% of patients achieve an increasein Hgb ≥ 1 vs. 28% in the PO iron group• Mean Hgb was significantly higher in the IV vs. POgroup• Percent of patients reporting ADE’s same though 4cases of anaphylaxis in IV group

Agarwal R, et al. Am J Nephrol 2006.Non-dialysis dependent adults with CKD given sodiumferric gluconate 250mg IV x 4 doses over 22 days vs.oral ferrous sulfate 325mg TID x 42 days.• Use of ESA excluded• Increase in Hgb was significant with IV iron but not PO ironthough end points for both were similar (mean 11.3 g/dL forIV vs. 10.9 g/dL)• IV iron increased ferritin and TSAT significantly vs. PO• IV iron had higher quality of life scores than PO

Bencaiova G, et al. Eur J Ob Gyn 2009.Pregnant women given iron sucrose 200mg IV x 3doses over 17 weeks vs oral ferrous sulfate 80mgdaily• No significant different between Hgb response between IVand PO group (80% vs. 75% with final Hgb ≥ 11g/dL• Goal ferritin of ≥ 50 mcg/L reached by 49% of women in theIV group vs 14% in the PO group• 60% of the PO group experienced ADE’s vs. 30.8% in the IVgroup• Authors felt non-standard dose of PO iron may havecontributed to outcomes

Pieracci FM, et al. Surgical Infections2009.Adult SICU patients given ferrous sulfate 325mg TID +500mg Ascorbic Acid TID + Folic Acid 1mg daily + B121mg daily vs Placebo until discharge (≥ 5 days)• Excluded: chronic inflammatory disease, ESRD and unableto receive blood transfusions• Physician discretion was allowed regarding initiation oferythropoietin therapy• Average treatment course: 19 days• No difference in final Hct, serum iron level, ferritin level, eZPPconcentration and rate of infection.• Treatment group required significantly less RBC transfusionsand less erythropoietin

McClung JP, et al. Am J Clin Nutr 2009.Female US Army soldiers given 8 weeks of 100 mgferrous sulfate PO daily vs placebo.• Serum ferritin levels rose 87% in the treatment group vs. 66%in the placebo group.• Serum Hgb levels rose in the treatment vs. placebo groupthough were not significantly different between groups at theend of the study• Vigor and 2-mile run time improved in treatment group

Kovey KL, Kaaya BM, Baard J and Hassan N.2009.High dose oral iron (≥6 mg elem. Fe/kg/day) foriron deficiency anemia in children 2-8 yearsold in Namibia, Africa• Case series of 5 children treated with 6-10mg elementalFe/kg/day (ferrous fumerate or ferrous gluconate) + VitaminC 200-400mg/day + Folic acid 5mg/day• Average increase in Hgb of 4.2 g/dL at day 7-14 (average 9.8days). This was a average increase of 100% over baseline.• No reported side effects and no child had to stop treatment.

Hb LevelKovey KL, Kaaya BM, Baard J andHassan N. 2009.High Dose Iron Replacement Therapy in ChildrenCase 1: 6mg/kg x 7d; 10mg/kg/dCase 3: 10mg/kg/dCase5: 10mg/kg/dCase 7: 8mg/kg/dCase 2: 8mg/kg/dCase 4: 6mg/kg/dCase 6: 10mg/kg/d121086425.885.284.793.17.935.864.953.412.63.875.823.828.167.869.649.29.427.019.4411.100 2 4 6 8 10 12 14 16 18Days of Therapy

Adjuvants for Erythropoiesis• Folic Acid: absorbed in small intestine, for nucleic acidsynthesis• Dosing: Age10 years: 1-3mg daily• Cyanocobalamin (Vitamin B12): requires intrinsic factorfrom stomach for absorption in the terminal ileum, fornucleic acid synthesis• Dosing: Weight < 10kg: 100mcg IM monthlyWeight > 10kg: 200mcg IM monthly• Vitamin E: 25-50 IU orally daily, required for neonatalenteral iron supplementation to protect against ironinducedlipid oxidation

Adjuvants for Erythropoiesis• Ascorbic Acid (Vitamin C)• Prevents formation of insoluble iron complexes• Reduces iron to ferrrous state (Fe 2+ ) forabsorption• Dosing Recommendation:• Children < 10kg: 250mg/day divided and given withiron• Children > 10kg: 500mg/day divided and given withiron

Summary

References1. Munoz M et al. World J Gastroenterol 2009;15:4617-26.2. Taketomo CK, et al. Pediatric Dosage Handbook 16 th ed. Lexi-Comp,Hudson, OH; 2009-20103. Product Information: Repliva 21/7 Tablets, Ther-Rx Corp. St. Louis, MO;03/10.4. McClung JP, et al. Am J Clin Nutr 2009;90:124-31.5. Pieracci FM, et al. Surgical Infections 2009;10:9-19.6. Agarwal R, et al. Am J Nephrol 2006;26:445-54.7. Van Wyck DB, et al. Kidney International 2005;68:2646-56.8. Andrews NC. Disorders of iron metabolism. N Engl J Med1999;341(26):1986-95.9. Weiss G, et al. N Engl J Med 2005;325(10):1011-23.10. Ganz T. Blood 2003;102:783-88.