Anemias i

Anemias I:Iron Deficiency Anemia, Vitamin B12 Deficiency Anemia, and Folic Acid Deficiency Anemia Sarah Nordberg, Pharm.D. PGY-1 Pharmacy Resident, Valley Health October 22, 2012

Objectives •  Identify pathophysiologic differences between iron deficiency anemia,

vitamin B12 deficiency anemia, and folic acid deficiency anemia and use those differences to predict RBC morphology

•  Identify signs and symptoms of iron deficiency anemia, vitamin B12 deficiency anemia, and folic acid deficiency anemia

•  Given a patient case, determine appropriate pharmacologic and non-pharmacologic treatment for iron deficiency anemia, vitamin B12 deficiency anemia, and folic acid deficiency anemia

•  Be familiar with common side effects for treatments used for iron deficiency anemia, vitamin B12 deficiency anemia, and folic acid deficiency anemia

•  Determine key counseling points and monitoring parameters for medications used to treat iron deficiency anemia, vitamin B12 deficiency anemia, and folic acid deficiency anemia

Classification of Anemias •  Macrocytic anemia

•  Folic acid deficiency anemia •  B12 deficiency anemia

•  Normocytic, normochromic •  Acute blood loss •  Hemolysis •  Anemia of chronic disease

•  Microcytic, hypochromic •  Iron deficiency anemia •  Sickle cell anemia

Introduction to Anemia •  Decrease in hemoglobin (Hgb) or red blood cells (RBCs)

•  Defined by WHO as Hgb <13 g/dL in men and 12 g/dL in women •  Normal hematocrit is 42-50 % in men and 36-45 % in women

•  Reduced oxygen carrying capacity of the blood

•  Many etiologies → results in different types of anemia

•  Classified by morphology of RBCs, etiology, or pathophysiology •  First step is often morphology: RBC size and color

•  Global goals of treatment: alleviate signs/symptoms, correct underlying etiology, prevent recurrence

Introduction: Clinical Presentation

Rapid Onset Anemia •  Tachycardia

•  Palpitations

•  Angina

•  Hypotension

•  Light-headedness

•  Dyspnea

Chronic Anemia •  Fatigue

•  Weakness

•  Headache

•  Sensitivity to cold

•  Vertigo

•  Pallor

Pathophysiology: Erythropoiesis

The survival time of a mature erythrocyte is 120 days

Laboratory Evaluation Test Reference Range

Hemoglobin Men: 14-17.5 g/dL Women: 12.3-15.3 g/dL

Hematocrit Men: 42-50 % Women: 36-45 %

MCV 80-96 fL/cell

MCH 27.5-33.2 pg/cell

MCHC 33.4-35.5 g/dL

RBC Distribution Width (RDW) 11.5-14.5%

RBC 4.5-5.9 million/mm3

Absolute reticulocyte count 0.5-2.5 % of RBC

Serum Iron 50-150 mcg/dL

TIBC 250-410 mcg/dL

Ferritin > 10 – 20 ng/mL

Folate 5-25 mcg/L

Vitamin B12 180-1000 pg/L

Hgb HCT

WBC Plt

Iron Deficiency Anemia (IDA)

IDA: Etiology •  Decreased dietary intake (heme vs. nonheme)

•  Malabsorptive syndromes

•  Situations that increase the demand for iron •  Frequent blood donations •  Endurance sports •  Infancy and adolescence •  Menstruation

•  Pregnancy

•  Blood loss → Dx tool: Fecal occult blood test

•  Medications

**The RDA for iron is 8 mg in adult males and postmenopausal females and 18 mg in menstruating females

Iron Deficiency Anemia (IDA): Clinical Presentation •  Most common nutritional deficiency!

•  If Hgb falls below 9 g/dL: •  Glossal pain •  Smooth tongue •  Reduced salivary flow •  Pica •  Pagophagia •  Koilonychia

IDA: Laboratory Findings and Diagnosis •  ______ mean corpuscular volume (MCV)

•  ______ mean corpuscular hemoglobin (MCH)

•  ______ mean corpuscular hgb concentration (MCHC)

•  ______ serum iron

•  ______ ferritin levels

•  ______ transferrin saturation

•  ______ TIBC

http://www.maleenhancementgroup.com/blog/general-health/107-iron-deficiency-anemia.html

Cells are microcytic & hypochromic

IDA: Laboratory Findings and Diagnosis •  LOW mean corpuscular volume (MCV)

•  ______ mean corpuscular hemoglobin (MCH)





•  ______ TIBC




•  LOW mean corpuscular hemoglobin (MCH)





•  ______ TIBC





•  LOW mean corpuscular hgb concentration (MCHC)




•  ______ TIBC






•  LOW serum iron



•  ______ TIBC







•  LOW ferritin levels


•  ______ TIBC








•  LOW transferrin saturation

•  ______ TIBC








•  LOW transferrin saturation

•  HIGH TIBC



IDA: Treatment •  Non-Pharmacologic: Dietary supplementation

•  Foods high in iron: meat, fish, poultry, broccoli, cereals (Total) •  Foods that increase iron absorption: ascorbic acid (oranges) •  Foods that may reduce iron absorption: milk, tea

•  Pharmacologic: •  Therapeutic iron preparations

•  Oral iron •  Parenteral iron

•  Iron Dextran •  Sodium ferric gluconate •  Iron sucrose •  Ferumoxytol

IDA Treatment: Oral Iron Salt Elemental Iron % Elemental Iron amt

Ferrous gluconate 12% 36 mg per 325 mg tablet

Ferrous sulfate 20% 60-65 mg per 325 mg tablet

Ferrous fumarate 33% 106 mg per 325 mg tablet

Polysaccharide iron complex

100% 50 mg capsule or tablet

Carbonyl iron 100% 50 mg caplet

G/S/F 12/20/33

IDA Treatment: Oral Iron •  Recommendation: 200 mg elemental iron daily in 2-3

divided doses to ensure patient tolerability

•  Best absorbed in reduced Fe2+ form

•  Maximal absorption in duodenum

•  Ideally taken at least 1 hour before meals •  Food reduced absorption by >50%

IDA Treatment: Oral Iron •  Adverse Effects

•  Dark discoloration of feces •  Constipation or diarrhea •  Nausea/vomiting

•  GI side effects are usually dose-related and are similar between the types of iron salts

•  To minimize adverse effects, take with small amount of food or decrease iron dose

IDA Treatment: Oral Iron Oral Iron Drug-Drug Interactions

Decrease absorption of oral iron Drugs affected by oral iron

Al, Mg, and Ca containing antacids Levodopa

MVI or supplements containing Zn, Mn, Cu, or Ca Methyldopa

H2 antagonists Levothyroxine

Proton pump inhibitors Fluoroquinolones

Cholestyramine Tetracycline and doxycycline

IDA Treatment: Oral Iron •  Expected effects and monitoring:

•  Hgb should increase 2-4 g/dL every 3 weeks until Hgb normalizes

•  Modest reticulocytosis should be seen in a few days •  Serum ferritin should return to normal range before

stopping iron supplementation •  Duration of therapy is usually at least 6 months

IDA Treatment: Parenteral Iron •  Indications:

•  Intolerance to oral iron •  Iron malabsorption •  Long-term nonadherence to oral iron •  Patients with significant blood loss who refuse transfusions

and cannot take oral iron therapy •  Dialysis patients (CKD) •  Cancer patients receiving chemotherapy who are taking

erythropoiesis stimulating agents (ESAs)

IDA Treatment: Parenteral Iron •  Does not lead to a quicker hematologic response than oral iron

•  Four different parenteral iron preparations in the US: •  Iron dextran •  Sodium ferric gluconate •  Iron sucrose •  Ferumoxytol

•  Each is efficacious, but differ in molecular size, degradation kinetics, bioavailability, side effect profiles, and toxicity profiles

•  Treatment course is considered 1,000 mg of iron

IDA Treatment: Iron Dextran •  INFed® and DexFerrum® (NOT INTERCHANGEABLE)

•  Complex of Fe3+ hydroxide and dextran

•  50 mg/mL elemental iron

•  Route: IM, slow IV injection (non-diluted), or IV infusion (diluted)

•  FDA Indication: Treatment of patients with documented iron deficiency in whom oral therapy is unsatisfactory or impossible

IDA Treatment: Iron Dextran IM •  Administered via Z-tract injection technique into

buttock

•  Each dose is limited to 2 mL (100 mg of iron)

•  Daily IM doses should not exceed •  25 mg in patients < 5 kg •  50 mg in patients < 10 kg •  100 mg in all other patients

•  Adverse reactions: discomfort, unpredictable delivery, sterile abscesses, tissue necrosis, and atrophy

IDA Treatment: Iron Dextran IV •  Dosing:

•  Adults and children over 15 kg •  Dose (mL) = 0.0442 (desired Hgb – observed Hgb) x IBW + (0.26 x

IBW) •  Children 5-15 kg

•  Use actual body weight instead of IBW •  Remember IBW equations:

•  IBW (males) = 50 + 2.3 (inches over 5 feet) •  IBW (females) = 45.5 + 2.3 (inches over 5 feet)

*Weight in all equations is in kg

IDA Treatment: Iron Dextran IV •  Administration:

•  IV bolus not to exceed 50 mg/minute and 100 mg (2mL) daily •  Total dose IV infusion diluted in 250-1,000 mL NS or 5%

dextrose in water infused over 4-6 hours

•  Adverse reactions: •  Staining of the skin •  Pain at injection site •  Allergic reaction → BBW •  Total dose infusions: arthralgias, myalgias, flushing, malaise,

fever

Iron Dextran: BLACK BOX WARNING! •  Must receive test dose prior to ANY dose of iron dextran

due to anaphylactic type reactions

•  Test dose = 25 mg IM or IV or a 5-10 minute infusion of the diluted solution

•  Patient is to be observed for 1 hour

•  Lack of reaction to a test dose does not ensure that an anaphylactic reaction will not occur when the therapeutic dose is administered

IDA Treatment: Sodium Ferric Gluconate •  Ferrlecit®

•  Complex of iron bound to 1 gluconate and 4 sucrose molecules

•  62.5 mg/5 mL elemental iron

•  Route: IV

•  FDA Indication: Treatment of IDA in patients undergoing chronic hemodialysis who are receiving supplemental erythropoietin therapy

IDA Treatment: Sodium Ferric Gluconate •  Dosing:

•  125 mg/10 mL diluted in 100 mL NS infused over 60 minutes

•  Can also be given as slow IV injection (undiluted) over at least 10 minutes

•  Given at each dialysis session

•  Administration: •  Diluted doses infused over 1 hour •  Undiluted doses infused slowly at a rate of 12.5 mg/

min

IDA Treatment: Sodium Ferric Gluconate •  Adverse reactions:

•  Cramps •  Nausea/vomiting •  Flushing •  Hypotension •  Intense upper gastric pain •  Rash •  Pruritis

•  Test dose not required, but still recommended (no BBW)

IDA Treatment: Iron Sucrose •  Venofer®

•  Iron hydroxide in sucrose complex

•  20 mg/mL elemental iron

•  Route: IV

•  FDA Indication: Treatment of IDA in patients undergoing chronic hemodialysis who are receiving supplemental epoetin alfa therapy

IDA Treatment: Iron Sucrose Dosing

Patients Undergoing Hemodialysis

Patients Undergoing Peritoneal Dialysis

Patients Not Dialysis-Dependent

•  100 mg over 2-5 minutes given 1-3 times/week during dialysis

•  No more than 3 times/week adding up to a total cumulative dose of 1,000 mg (10 doses)

•  May also be given via infusion diluted in NS and infused over 15 minutes (no test dose)

•  Two infusions of 300 mg each over 1.5 hours 14 days apart followed by a single 400 mg infusion over 2.5 hours 14 days later

•  Total cumulative dose of 1,000 mg in 3 divided doses

•  200 mg slow injection over 2-5 minutes on 5 different occasions within a 14-day period

•  Total cumulative dose of 1,000 mg in a 14-day period

IDA Treatment: Iron Sucrose •  Adverse Reactions:

•  Leg cramps •  Hypotension •  Nausea/vomiting

•  Well-tolerated

•  Reduces the absorption of oral iron → do not administer concomitantly

IDA Treatment: Ferumoxytol •  Feraheme®

•  30 mg/mL

•  Route: IV

•  FDA Indication: Treatment of IDA in adults with chronic kidney disease who are on or off dialysis

IDA Treatment: Ferumoxytol •  Dosing:

•  510 mg IV dose followed by a second 510 mg dose 3-8 days later (rate of 30 mg/second)

•  Administration: •  Undiluted at a rate of ≤ 1 mL/second (30 mg iron/second)

•  Adverse Reactions •  Hypotension •  Dizziness

•  No test dose required, but anaphylaxis can occur → observe patient for 30 minutes after dose

Summary: Parenteral Iron IV Iron Indication Route Dose ADRs

Iron dextran ($37.70/vial)

Tx of patients with documented IDA in

whom oral therapy is unsatisfactory or

impossible

IM, IV IM: <5 kg: 20 mg <10 kg: 50 mg

>10 kg: 100 mg IV: Weight based

ANAPHYLAXIS Staining of skin Pain at inj site

Sodium ferric gluconate

($43/ampule)

Tx of IDA for patients undergoing chronic

HD who are receiving supplemental ESAs

IV 125 mg Cramps N/V

Flushing Hypotension

Rash Pruritis

Iron sucrose ($68.80/vial)

Tx of IDA for patients undergoing chronic

HD who are receiving supplemental epoetin

alfa therapy

IV Based on dialysis dependence

Leg cramps Hypotension

Ferumoxytol ($400/vial)

Tx of IDA for adults with CKD

IV 510 mg followed by 510 mg 3-8 days

later

Dizziness Hypotension Periph edema Diarrhea/Const

Nausea

IDA: Parenteral Iron Monitoring •  Monitor for iron overload or toxicity

•  Elevated LFTs •  Serum ferritin > 800 ng/mL •  Transferrin saturation > 50%

•  Measure serum ferritin and transferrin the first week after doses of 100-200 mg and 2 weeks after larger IV doses, then monthly

•  Hgb and Hct should be measured weekly

•  Obtain serum iron levels 48 hours after IV administration

IDA: Patient Case – RK •  S: RK is a 23 yo female who presents to you with a chief

complaint of, “I feel tired all the time”. She also says her tongue hurts. She is a strict vegetarian and has 4 cups of coffee per day to stay awake for studying. Her past medical history includes heavy menses. She is not taking any medications. NKDA. FH noncontributory.

•  O: 70 kg, 64 inches, RBC 4.0 million/mm3, Hgb 9.9 g/dL, Hct 29%, MCV 65 fL/cell, MCH 20 pg/cell, serum iron 30 mcg/dL, TIBC 500 mcg/dL

IDA: Patient Case – RK •  What is RK’s likely diagnosis and why?

•  How would you treat RK?

•  What counseling points would you tell RK?


•  Dx is IDA. Low iron, low MCV, low MCH, high TIBC, low H/H, heavy menses, vegetarian, 4 cups of coffee

•  How would you treat RK?




•  How would you treat RK? •  Oral iron → any of the 3 with a total of 200 mg elemental iron daily in 2-3





•  How would you treat RK? •  Oral iron → any of the 3 with a total of 200 mg elemental iron daily in 2-3


•  What counseling points would you tell RK? •  Increase iron in diet, try to cut back on coffee •  Oral iron may have some unpleasant GI adverse effects – try to take 1 hour

before eating but if you must, you can take it will some food or decrease the dose

•  You will probably be on it for 6 months or more

IDA: Patient Case – RK •  RK returns 2 weeks later and states she simply

cannot tolerate the oral iron supplements and refuses to take them.

•  What options are available for the patient?

IDA: Patient Case – RK •  Iron Dextran Dosing → Adults >15 kg

•  Dose (mL) = 0.0442 (desired Hgb – observed Hgb) x IBW + (0.26 x IBW) •  IBW = 45.5 + 2.3 (4 inches over 5 ft) = 54.7 kg

•  Dose (mL) = 0.0442 (12 g/dL – 9.7 g/dL) x 54.7 kg + (0.26 x 54.7 kg) = 19.8 mL

•  Dose (mg) = 50 mg elemental iron/mL x 19.8 mL = 990 mg

•  Remember to GIVE PATIENT A TEST DOSE!

•  Counsel on adverse reactions

Questions? Next up: megaloblastic anemias

Megaloblastic Anemias •  Vitamin B12 deficiency anemia and folate deficiency anemia

•  Macrocytic anemias

•  Deficiency in vitamin B12 and/or folate results in abnormal DNA metabolism = macrocytosis

•  Can also be caused by medications •  Hydroxyurea, methotrexate, azathioprine, 6-

mercaptopurine

Megaloblastic Anemias: Pathophysiology

✖↘

↖

Vitamin B12 Deficiency Anemia: Clinical Presentation •  Neurologic symptoms

•  Numbness and paresthesia •  Peripheral neuropathy •  Ataxia and abnormal gait

•  Psychiatric symptoms •  Depression •  Dementia-like symptoms

•  Pallor

•  Mildly icteric (jaundice)

Vitamin B12 Deficiency Anemia: Etiology •  3 major causes:

1.  Inadequate intake •  Vegans, chronic alcoholics, elderly

2.  Malabsorption syndromes •  Gastrectomy, atrophic gastritis, prolonged acid

suppression therapy

3.  Inadequate utilization •  Tapeworm, intestinal resections, inflammatory bowel

disease

Vitamin B12 Deficiency Anemia: Labs and Diagnosis •  _____ MCV

•  _____ MCH

•  _____ MCHC

•  _____ serum vitamin B12 level

•  _____ homocysteine

•  _____ methylmalonic acid (MMA)

Vitamin B12 Deficiency Anemia: Labs and Diagnosis •  HIGH MCV

•  _____ MCH

•  _____ MCHC





•  HIGH MCH

•  NORMAL MCHC





•  HIGH MCH

•  NORMAL MCHC

•  LOW serum vitamin B12 level




•  HIGH MCH

•  NORMAL MCHC


•  HIGH homocysteine



•  HIGH MCH

•  NORMAL MCHC



•  HIGH methylmalonic acid (MMA)

Vitamin B12 Deficiency Anemia: Non-Pharmacological Treatment •  Goals of treatment: Reverse hematological manifestations,

replace body stores, resolve neurological symptoms

•  Diet •  Foods high in vitamin B12

•  Beef liver •  Fortified cereals •  Trout, salmon, haddock, tuna •  Clams, oysters •  Beef, chicken •  Milk, yogurt

Vitamin B12 Deficiency Anemia: Pharmacological Treatment •  Oral vitamin B12 → 1-2 mg daily

•  Parenteral vitamin B12

•  Cyanocobalamin 1,000 mcg IM daily x 1 week, then 1,000 mcg IM weekly x 1 month, then 1,000 mcg IM monthly thereafter

•  IM → oral, initiate 1 mg on due date of next injection

•  Intranasal •  Nascobal®: 500 mcg in one nostril once weekly •  CaloMist™: maintenance of 25 mcg in each nostril daily,

may increase to 50 mcg in each nostril if not responding •  Space 1 hour from ingestion of hot food/drinks

Vitamin B12 Deficiency Anemia: Monitoring •  Symptomatic improvement within days

•  Reticulocytosis within 3-5 days

•  Hgb rises after 1 week and normalized within 1-2 months

•  Homocysteine and MMA levels decrease within 1-2 weeks

•  Draw CBC and serum cobalamin level at 1-2 months after initiation of therapy and then 3-6 months thereafter

Folic Acid (FA) Deficiency Anemia: Clinical Presentation •  Symptoms similar to those seen in vitamin B12

deficiency anemia

•  BUT FA deficiency anemia does not present with neurological symptoms •  NO:

•  Numbness and paresthesia✖ •  Peripheral neuropathy✖ •  Ataxia and abnormal gait✖

FA Deficiency Anemia: Etiology •  4 major causes:

1.  Inadequate intake •  Elderly, teenagers, alcoholics, impoverished

2.  Decreased absorption •  Malabsorption syndromes, medications, alcohol

3.  Hyperutilization •  Pregnancy, growth spurts, chronic inflammatory disease, cancer

4.  Inadequate utilization •  Methotrexate

FA Deficiency Anemia: Labs and Diagnosis •  HIGH MCV

•  HIGH MCH

•  NORMAL MCHC

•  LOW serum vitamin B12 level → Normal

•  LOW serum folate levels (normal 1.8 – 16 ng/mL)

•  LOW RBC folate levels


FA Deficiency Anemia: Non-Pharmacologic Treatment •  Goals of treatment: hematologic remission, replace

body stores, resolve signs and symptoms

•  Diet •  Chicken liver •  Cereal •  Lentils, chickpeas, asparagus, spinach, brussel

sprouts •  Pasta, white rice •  Black beans, kidney beans, lima beans •  Oranges

FA Deficiency Anemia: Pharmacologic Treatment •  1 mg oral folic acid daily

•  In cases of malabsorption syndromes, may need 1 – 5 mg daily

•  Continue treatment for 4 months (longer in chronic conditions)

•  Pregnancy •  400 mcg folic acid daily in low-risk women •  4 mg folic acid daily in women who have previously given

birth to offspring with neural tube defects (NTD) or with family history of NTD

FA Deficiency Anemia: Monitoring •  Symptomatic improvement early during the course of

treatment

•  Reticulocytosis within 2-3 days and peaks within 5-8 days after treatment

•  Hct rises within 2 weeks and reaches normal levels within 2 months

Megaloblastic Anemias: Patient Case - TG •  S: TG is a 68 yo male who presents to you with a chief complaint of, “I

don’t know where I am or what is going on. I can’t remember anything!”. He is on a “tea and toast” diet and denies alcohol use. His past medical history includes GERD and HTN. He is taking lisinopril 40 mg daily and omeprazole 20 mg daily. NKDA. FH noncontributory.

•  O: 88 kg, 67 inches, RBC 4.0 million/mm3, Hgb 9.7 g/dL, Hct 29%, MCV 116 fL/cell, MCH 38 pg/cell, homocysteine and MMA elevated •  ROS/PE: positive for numbness, decreased sensation, ataxia

Megaloblastic Anemias: Patient Case - TG •  What is the likely diagnosis and why?

•  How would you treat TG?

•  What counseling points would you relay to TG?

•  His pregnant granddaughter also says, “I just want to double-check with a pharmacist, how much folic acid should I be taking daily”?


•  Vitamin B12 deficiency anemia – neurological symptoms in addition to other symptoms, labs, elevated homocysteine AND MMA.

•  How would you treat TG?





•  How would you treat TG? •  Because all of his levels are affected, he needs rapid relief of neurological

symptoms, and he is elderly, could argue to start cyanocobalamin 1,000 mcg IM injections daily x 1 week, then weekly x 1 month, then monthly







•  What counseling points would you relay to TG? •  Eat more vitamin B12-rich foods, no side effects, will be on therapy for

upwards of 6 months






•  What counseling points would you relay to TG? •  Eat more vitamin B12-rich foods, no side effects, will be on therapy for upwards of 6

months

•  His pregnant granddaughter also says, “I just want to double-check with a pharmacist, how much folic acid should I be taking daily”? 400 mcg folic acid daily unless there is Hx of NTDs → then 4 mg

Email: [email protected]

References •  Cook K, Ineck BA, Lyons W. Anemias In: DiPiro JT, Talbert RL, Yee GC, et al. Pharmacotherapy: a

phathophysiologic approach, 8th ed. New York, NT; McGraw-Hill; 2011.

•  Schrier SL. Diagnosis and treatment of vitamin B12 and folic acid deficiency. 2012. http://www.uptodate.com/online. Accessed 20 Aug 2012.

•  Schrier SL. Causes and diagnosis of anemia due to iron deficiency 2011. http://www.uptodate.com/online. Accessed 20 Aug 2012.

•  Alleyne M, Horne MK, Miller, JL. Individualized treatment for iron-deficiency anemia in adults. Am J of Med 2008 (121); 943-948.

•  Silverstein SB, Rodgers GM. Parenteral iron therapy options. Am J Hematol 2004;76:74-78.

•  Lexi-Comp.- Iron Dextran. http://online.lexi.com Accessed 25 Aug 2012.

•  Lexi-Comp.- Sodium Ferric Gluconate. http://online.lexi.com Accessed 25 Aug 2012.

•  Lexi-Comp.- Iron Sucrose. http://online.lexi.com Accessed 25 Aug 2012.

•  Lexi-Comp.- Cyanacobalamin. http://online.lexi.com Accessed 25 Aug 2012.

Anemias i

Health & Medicine

Transcript of Anemias i