Brooke Bernhardt PharmD MS BCOP BCPPS Objectives Recognize medications that may cause various blood count abnormalities Identify appropriate monitoring approaches for patients on medications that may cause ID: 908397
Download Presentation The PPT/PDF document "Medications Causing Blood Count Abnormal..." is the property of its rightful owner. Permission is granted to download and print the materials on this web site for personal, non-commercial use only, and to display it on your personal computer provided you do not modify the materials and that you retain all copyright notices contained in the materials. By downloading content from our website, you accept the terms of this agreement.
Slide1
Medications Causing Blood Count Abnormalities
Brooke
Bernhardt,
Pharm.D
.,
MS
, BCOP, BCPPS
Slide2ObjectivesRecognize 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
Slide3WarningI’m a Pediatric Hematology/Oncology Pharmacist…
But this
presentation is
NOT
[just] about chemotherapy!
Slide4This presentation is about:
Idiosyncratic
reactions
not
directly related to
pharmacology
The most common drug-induced hematologic disordersAplastic anemiaAgranulocytosis Hemolytic anemiaMegaloblastic anemia
Thrombocytopenia
Slide5Audience 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?
Slide6Aplastic 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.
Slide7Drug-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
Slide8Drug-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)
Slide9Drug-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
Slide10Direct 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
.
Slide11Metabolite-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
Slide12Metabolite-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
Slide13Immune-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
Slide14Treatment of AARemove the offending agent, if knownProvide supportive care as needed
Transfusions (not growth factors)
Antimicrobial or antifungal prophylaxis (ANC <500)
Slide15Treatment 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
Slide16Drug-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
Slide17Drug-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
Slide18Drug-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)
Slide19Drug-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
Slide20Treatment of Agranulocytosis
Slide21Drug-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
Slide22Treatment of Hemolytic Anemia
Slide23Drug –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
Slide24Drug-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
Slide25Patient 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)
Slide26Patient 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
”
Slide27Patient 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
Slide28Patient 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
Slide29SummaryMedication-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
Slide30Comments/Questions?