Medications Causing Blood Count Abnormalities - PowerPoint Presentation

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Medications Causing Blood Count Abnormalities

Brooke

Bernhardt,

Pharm.D

.,

MS

, BCOP, BCPPS

Slide2

ObjectivesRecognize medications that may cause various blood count abnormalities

Identify appropriate monitoring approaches for patients on medications that may cause

aberrant

blood count

abnormalities

Summarize key patient education tips for patients on medications that may cause blood count abnormalities

Slide3

WarningI’m a Pediatric Hematology/Oncology Pharmacist…

But this

presentation is

NOT

[just] about chemotherapy!

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This presentation is about:

Idiosyncratic

reactions

not

directly related to

pharmacology

The most common drug-induced hematologic disordersAplastic anemiaAgranulocytosis Hemolytic anemiaMegaloblastic anemia

Thrombocytopenia

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Audience PollHave you ever made a referral (or performed a consultation) for a patient with a suspected medication-induced hematologic abnormality?

What symptomatology prompted you to investigate the hematologic disease?

What medications were incriminated in the drug-induced abnormality, and what were the hematologic changes observed?

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Aplastic AnemiaInherited

Fanconi’s

anemia

Dyskeratosis

congenital

Blackfan

Diamond anemiaAcquired

Medications

Radiation

Viruses

Chemical exposure

Drug-induced, acquired aplastic anemia is perhaps the most serious drug-induced hematologic abnormality, carrying a mortality rate as high as 50% with a mean onset about 6.5 weeks after initiating the offending agent.

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Drug-Induced, Acquired Aplastic Anemia

Diagnosis

involves

Bone marrow aspirate and biopsy

Review of medication history to exclude prior exposure to cytotoxic agents or

radiation

No evidence of increased peripheral blood cell destructionCharacterized by absence or significant reduction of hematopoietic stem cells and increase in fat cells on bone marrow evaluation

At least two of the following criteria

WBC ≤3,500 cells/mm

3

Platelets ≤55,000

cells/mm

3

Hemoglobin ≤10 g/

dL

Reticulocyte count ≤30,000 cells/mm

3

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Drug-Induced, Acquired Aplastic Anemia

Moderate aplastic anemia (MAA)

At least two of the following:

Neutrophils < 1,500

cells/mm

3

Platelets < 50,000 cells/mm3Hemoglobin < 10 g/dL

Severe aplastic anemia (SAA)

At least two of the following:

Neutrophils <

500

cells/mm

3

Platelets

<

20,000

cells/mm

3

Reticulocytes < 1%

Very severe aplastic anemia (VSAA)

SAA with neutrophils < 200 cells/mm

3

Often neutropenia develops first, followed by thrombocytopenia, then anemia. Initial symptoms may be related to thrombocytopenia (

petechiae

, increased bleeding risk, bruising)

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Drug-Induced, Acquired Aplastic Anemia

Direct toxicity

Metabolite-driven toxicity

Intermediate metabolites bind to proteins/DNA and induce marrow failure

Intra-patient genetic variability may in part be responsible for reactive metabolite formation and seemingly idiopathic nature of the risk

Immune-mediated toxicity

Most common cause

Antigenic (drug) exposure activates the immune cascade resulting in stem cell death

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Direct Toxicity AAChemo and radiation

Drug-specific and dose-dependent bone marrow suppression

Consider “maximum tolerated dose” of conventional cycles of chemotherapy vs. autologous or allogenic stem cell transplantation

Direct

injury

Chloramphenicol

is prototypical for dose-dependent, reversible marrow suppression; typically with anemia first, once a cumulative dose of 20 grams have been administered.

This

is not necessarily associated with subsequent development of AA

.

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Metabolite-Driven AA: Chloramphenicol

Antibiotic still used throughout the world and rarely in multi-drug resistant infections

AA may occur on therapy, or weeks to months after discontinuation

Nitrobenzene ring metabolized to

nitroso

group that interacts with DNA, causing chromosomal damage

Gastrointestinal bacteria metabolize the agent to toxic metabolites

Highest risk of AA is with ORAL chloramphenicol

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Metabolite-Driven AA: AntiepilepticsPhenytoin

and carbamazepine

are metabolized to potentially

toxic

arene

oxide intermediates

Gerson WT, et al. Blood 1983;61:889-93.Case report evaluating a patient and his mother demonstrated that a possible defect in detoxification of these metabolites may be responsible for the drug-related toxicity

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Immune-Mediated AAAntigenic (drug) exposure activates the immune cascade resulting in stem cell death

Support for this hypothesis is driven by positive response of AA to immunosuppression

Steroids

A

ntilymphocyte

globulin

Perhaps most importantly…cyclosporine

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Treatment of AARemove the offending agent, if knownProvide supportive care as needed

Transfusions (not growth factors)

Antimicrobial or antifungal prophylaxis (ANC <500)

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Treatment of SAA/VSAAAllogeneic stem cell transplantation Preferred: matched sibling donor

Immunosuppressive therapy

Antithymocyte

globulin (equine ATG, ATGAM) plus cyclosporine and corticosteroids

Cyclosporine should be given over at least 12 months following response and tapered very slowly

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Drug-Induced AgranulocytosisReduction in mature myeloid cells (white blood cells, granulocytes and bands) to ≤ 500 cells/mm

3

Onset from time of drug exposure to symptomatology is typically 1 month of more (median: 19 to 60 days)

Incidence

1 to 5 cases per million persons

Associated with medications in 70% of cases

Only 10% of all cases are seen in children and young adults

Drug-induced/idiosyncratic 1 in 10,000 to 100,000

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Drug-Induced AgranulocytosisTypically resolves with time

Time to neutrophil recovery is 4 to 24 days

Infectious prophylaxis and treatment of known infections has significantly reduced mortality

Highest risk agents

Antithyroid

drugs (

methimazole, propylthiouracil

)

Sulfasalazine,

cotrimoxazole

C

lomipramine

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Drug-Induced AgranulocytosisDirect toxicity

Chlorpromazine

Procainamide

Clozapine

Sulfonamides,

dapsone

Carbamazepine, phenytoin

Indomethacin, diclofenac

Immune-mediated

Antibody-mediated cytotoxicity

Hapten

mechanism

Penicillin, gold compounds

Immune-complex mechanism

Quinidine, quinine

Autoimmune mechanism

Levamisole

(off the market, but in cocaine)

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Drug-Induced AgranulocytosisDeferapironeOral iron chelator

Possible mechanisms:

Interaction with essential metal atoms (e.g., copper)

Inhibition of granulocyte-macrophage colony-forming units in the marrow

Arrest of granulocyte development

Clozapine

Possible mechanisms:

Oxidative stress due to formation of unstable,

nitrenium

ion metabolite

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Treatment of Agranulocytosis

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Drug-Induced Hemolytic AnemiaImmune mechanisms

Hapten

/drug adsorption mechanism

Penicillins

, cephalosporins, minocycline

Immune complex/innocent bystander mechanism

Drugs bind to IgM (or other antibody) to form an immune complex, which reversibly binds to the RBC membrane (with low affinity), activates complement, and causes hemolysisRBC antibody production

Methyldopa,

fludarabine

,

cladribine

Non-immunologic protein adsorption (NIPA) to RBC membranes

Cisplatin,

oxaliplatin

, beta lactamase inhibitors

Metabolic/enzyme deficiencies

Glucose-6-phosphate dehydrogenase (G6PD) deficiency

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Treatment of Hemolytic Anemia

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Drug –Induced Megaloblastic AnemiaPhenytoin, phenobarbital, primidone

May increase folate catabolism or inhibit folate absorption

D

oes folic acid supplementation decrease the effectiveness of

antiepileptics

?

MethotrexateIrreversibly inhibits dihydrofolate

reductase, DNA precursors and synthesis

Cotrimazole

May be caused by similar mechanism as methotrexate, but to a lesser degree and may be potentially corrected with oral leucovorin

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Drug-Induced Thrombocytopenia

Platelet count <100,000 cells/mm

3

OR >50% decline from baseline

Mechanisms of toxicity

Direct toxicity via suppression of

thrombopoiesisChemotherapy

Immune mediated

Hapten

-mediated

Penicillins

, cephalosporins

Drug-dependent antibodies

Vancomycin

Platelet-specific autoantibodies

Procainamide

Immune complex-induced thrombocytopenia

Heparin

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Patient Assessment and MonitoringTake a detailed history, not only of prescription medications,

but also

:

Over the counter medications, including international products

Alternative/herbal products

Vaccinations

Beverages and foods (e.g., tonic water)

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Patient Assessment and Monitoring

FDA REMS Program: Clozapine

http

://

www.clozapinerems.com

“No Blood, No Drug”Wholesalers/distributors must enroll in the Clozapine REMS program to be able to

distribute

Pharmacies must

be certified

to dispense

Providers

must be

certified to prescribe

Patients must be enrolled in the Clozapine REMS

program

ANC must be checked

before the first prescription and at

least:

Weekly for

the

first 6 months

Every

2 weeks for the next 6

months, if ANC

stays

normal

Every

4 weeks after the

first year, if ANC

stays normal

“

No Blood, No Drug

”

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Patient Assessment and Monitoring

FDA Boxed Warning:

Deferiprone

Agranulocytosis

//Neutropenia: [US Boxed

Warning]

Monitor ANC:Prior to treatment initiation and weekly during

therapy

Interrupt treatment if neutropenia (ANC <1,500/mm

3

)

Monitor

CBC, corrected WBC, ANC, and platelets daily until ANC recovery

If ANC <500/mm

3

, consider hospitalization (and other clinically appropriate management)

If

infection develops, interrupt treatment and monitor ANC more

frequently

Patients

should promptly report any symptoms which may indicate

infection

Withhold other

medications which may also be associated with

neutropenia

Do

not resume or

rechallenge

unless the potential benefits outweigh potential

risks

Neutropenia

and agranulocytosis were generally reversible upon

discontinuation

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Patient Education Report any new or unexpected symptoms that may be related to abnormal hematopoiesis or changes in blood counts, such as:

Bruising

Bleeding

Fever

Mouth ulcers

Non-healing wounds

FatiguePallor Shortness of breath

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SummaryMedication-induced hematologic disorders are typically rare and often result from either direct drug toxicity or immune-mediated reaction

The most important treatment approach is removal of the offending agent

Supportive care may be necessary for some abnormalities

Re-challenge with the causative agent should NOT be considered

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Comments/Questions?