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Objectives
Define neutropenia List five medications that may cause neutropenia State three patient populations where granulocyte-
colony stimulating factor (G-CSF) therapy would be appropriate
Reiterate the recommendations presented by the British Columbia Centre for Disease Control (BCCDC) for cocaine-induced neutropenia
Patient Profile – Presentation
ID: 49 yo 1st Nations female CC: Sore, inflamed mouth, hurt to eat HPI: • 1 yr hx of neutropenia, recurrent mucositis
? 2o to laced crack-cocaine
• G-CSF therapy started
• Presented to Ft. St. James (FSJ) hospital after 1st dose w/ fever, chest pain
• Transferred to UHNBC-PG
Patient Profile – Presentation
DX: Neutropenia non-responsive to G-CSF PMH: Anemia, insomnia FH: Non-contributory SH: Hx of EtOH abuse, gas-huffing,
crack-cocaine use x ~15 years Smoking, casual use, last use 3 weeks
Allergies: codeine = itching
Patient Profile – Medications
MPTA: G-CSF 300mcg SQ daily x 1 doseIbuprofen 400mg PO tid
Vitamin B6 50mg PO daily
Vitamin B12 100mg PO daily
Calcium/Vit D 500mg/125 IU PO bid
Ferrous sulphate 300mg PO bid
Oxazepam 15mg PO hs prn
Patient Profile – Medications
UHNBC: Ceftazidime 2g IV q8h
Gentamicin 360mg IV q24h
Lansoprazole 30mg PO bid
Replavite 1 tab PO daily
Folate 5mg PO daily
Ferrous sulphate 600mg PO bid
Vitamin C 1000mg PO daily
Vitamin B12 1000mcg IM qmonthly
Patient Profile – Medications
UHNBC: Nystatin 500,000 units PO tid, swish and swallow
KCl SR 24mEq PO q4h x 3 doses then
KCl SR 8mEq PO bid
Benzydamine 5mL PO qid, swish and spit
Magic Mouthwash 10mL PO prn
Hydromorphone 2mg PO q4h prn
Dimenhydrinate 25-50mg PO q4-6h prn
Patient Profile – Review of Systems
VITALS (Oct 27)
AVSS: T=37 oC, HR=75, BP=135/75, RR= 17,SaO2=98% on RA
CNS No complaints
HEENT
RESP
Sore, inflamed mouth, pain with eating, white plaques; no cough/SOB
CVS No chest pain, iron=5 (), iron sat = 15% ()
GI
GU
Melena x 5/7, endoscopy normal; voiding per washroom, no burning/urgency/frequency (BUF)
Patient Profile – Review of Systems
LIVER
KIDNEY
SCr=46 (stable), CrCl=151; splenomegaly; LFT WNL
ENDOCRINE BG=5.3 (random)
MSK/EXTR/SKIN Slight facial edema, body aches
FLUID STATUS No complaints; K=2.8 (), Na=134 ()
Patient Profile – Neutropenia
(FSJ)
Oct 19
(PG)
Oct 27
Oct 28
Oct
29
WBC (x109) 0.7 <0.5 0.5 0.6
Hgb (g/L) 115 59 89 94
Plts (x106) 155 34 60 68
ANC (x109) -- 0.1 0.1 --
Transfused
Temp (oC) 38.9 37 37 36.5
Patient Profile – Medical Problems
Neutropenia Oral Mucositis Oral Thrush GI Bleed Anemia Pain Hypokalemia
Pharmacy Assessment – DRPs
AR is experiencing neutropenia AR is experiencing side-effects of G-CSF AR is experiencing oral mucositis pain AR is experiencing oral thrush AR is experiencing a GI bleed AR is experiencing hypokalemia AR is experiencing anemia AR is experiencing pain
Haematopoiesis – Overview
The formation of blood components from haematopoiesis stem cells found in bone marrow
All blood cells are of three lineages– Erythroid cells: red blood cells– Lymphoid cells: adaptive immune system– Myeloid cells: granulocytes, macrophages
Neutropenia – Overview
Definition: ANC less than 1.5x109/L– ANC = WBC x percent (PMNs + bands) ÷ 100
Drug-induced:– Decreased production or peripheral destruction
Alkylating agents, antimetabolites,anticonvulsants, antipsychotics, antibiotics, anti-inflammatory agents, anti-thyroid medications, antibiotics, levamisole
Risks: mucositis, infection, sepsis
Neutropenia – Overview
ANC ANC (10(1099/L)/L)
Risk Management
>1.5>1.5 None
1-1.51-1.5 No risk of significant infection; fever managed as outpt
0.5-10.5-1 Some risk of infection; fever can be managed as an outpt
<0.5<0.5 Significant risk of infection; fever should always be managed as inpt with IV ABX
<0.2<0.2 Very significant risk of infection; fever should always be managed on an inpt basis with IV ABX
Levamisole – Overview
Why lace cocaine with levamisole?– Stable under heated conditions– Increase dopamine and endogenous opiate levels
Previously used for colon cancer, rheumatoid arthritis and as an antihelmithic– Imidazothiazole derivative ABX
Hasn’t been available commercially since 2005 – Caused neutropenia by ?immune-mediated destruction– Still available in USA for veterinary use
Pharmacy Assessment – Goals
Stop disease process Manage patient’s symptoms Prevent disease Normalize physiological parameters Minimize side-effects of therapy
Neutropenia – Treatment Options
Alternatives for drug-induced neutropenia:– 1st line:
Discontinue offending agentSupportive care (ABX if febrile, indicated)
– 2nd line:Colony-Stimulating Factor hormone
– G-CSF (Filgrastim)– Pegylated G-CSF (Pegfilgrastim) – GM-CSF (Sargramostim)
– 3rd line:If no response to above
– IV immunoglobulin– Granulocyte infusion
G-CSF
Neutropenia – Treatment Options
G-CSF– MOA:
G-CSF is produced by monocytes
Regulates neutrophil production, progenitor differentiation
Enhances phagocytic ability
Neutropenia – Treatment Options
G-CSF (Filgrastim)– Side-effects:
>10%: fever, rash, splenomegaly, bone pain, epistaxis
1-10%: hyper/hypotension, MI/arrhythmias, chest pain, headache, N/V, peritonitis
<1%: pulmonary infiltrates, tachycardia, hematuria, wheezing, renal insufficiency, injection site reaction, ARDS, allergic reactions,
arthralgias, dyspnea, facial edema, hemoptysis
Controversy
G-CSF indications for patients with:– Febrile neutropenia due to chemotherapy– Specific chemotherapy protocols– Bone marrow transplants – Human Immunodeficiency Virus (HIV) – Chronic non-drug induced neutropenia
G-CSF use in non-febrile, otherwise healthy patients is not well established
Controversy G-CSF use for the treatment of neutropenia
– Should not be used routinely in afebrile pts – Little supporting evidence as an adjunct to ABX
therapy in febrile pts– May be considered in high risk neutropenic
febrile pts or serious infectious complications:advanced age (older than 65 years)fever at hospitalization or unstable feverprogressive infection or invasive fungal infectionspneumonia or sepsis syndromesevere (ANC less than 1) or anticipated prolonged
(greater than 10 days) neutropenia
PICO Question
P: In a 49 year old First Nations woman who chronically smokes crack-cocaine and is currently experiencing afebrile neutropenia secondary to levamisole-laced cocaine
I: is G-CSF therapy versus C: no G-CSF therapy O: effective in decreasing mortality?
Search Strategy
Databases:– PubMed, Embase, Google Scholar
Search terms:– Cocaine-induced– Levamisole – Neutropenia– G-CSF
Results: anger and frustration
Literature Review – Evidence
Levamisole tainted cocaine causing severe neutropenia in Alberta and British Columbia, Harm Reduction Journal; 2009– Retrospective, 42 cases – 93% used crack-cocaine; 72% smoked– Conclusions:
If fever or infection present empiric IV ABX and supportive care are recommended
“Treatment with G-CSF should be considered”
Literature Review – Evidence
Agranulocytosis associated with levamisole in cocaine, BCCDC update: April 2009– Developed standard case report form– Diagnostic tests: CBC & diff, urine for drugs– Management:
If ANC <1.0, febrile with active infection: hospitalizeInfectious work-up, broad spectrum ABX“G-CSF should not be started until consultation
with haematologist”– Recovery in 7-10 days
Literature Review – Evidence
Neutropenia during treatment of rheumatoid arthritis (RA) with levamisole, Annals of Rheumatic Diseases, 1978– 60 pts with RA treated with levamisole– 35% showed persistent decrease of neutrophils– 10% developed severe neutropenia (ANC <1.0)– Management:
Therapy stoppedMonitored for sign of infectionRecovered within 10 days
Bottom Line
Should we use G-CSF in this pt population?– May be considered in high risk neutropenic
febrile pts or those at risk of serious infectious complications
– No evidence for decreased mortality or increased benefit over appropriate ABX for febrile neutropenia
– Consider cost vs. benefits– BCCDC advises against routine use– More studies and clear guidelines needed
Weighing the Options
Pros– Not contraindicated– Possibility of effect
Cons– No evidence – Not clearly indicated– Hasn’t worked in past– Experiencing side-effects– Expensive– ? Mortality benefits
Pharmacy Recommendations
Discontinue G-CSF in this pt– Experiencing side-effects– No evidence, no effect
Report case to BCCDC, counsel pt on risks Continue to monitor temperature, signs of systemic
infection Increase nystatin 500,000 units PO qid, swish and
swallow Change Magic Mouthwash 5mL PO qid ac meals Increase benzydamine 15mL PO qid, swish and spit
Outcome
G-CSF 300 mcg SQ daily Oct 29-Nov 5 Bone marrow biopsy active Awaiting HIV serology tests D/C ABX, lansoprazole Pt able to eat regular meals with minimal pain and
discomfort Oral thrush resolved
Monitoring Plan – Efficacy
Parameter Frequency Who?
CNS Temp < 38 oC Twice daily Nurse, Pt
HEENT
RESP
Mucositis, cough, SOB, RR, O2Sat
Daily MD, Nurse,
Pharm
CVS HR, BP Daily Nurse
GI/GU Burning, urgency, frequency
Daily Nurse, Pt
KIDNEY SCr, urine output Weekly/Daily MD, Pharm
HEME CBC (Neuts >1.5x109/L) Daily MD, Pharm
DERM
MSK
Chills, night sweats, facial edema
Daily Nurse, Pt
Monitoring Plan – Toxicity
Parameter Frequency Who?CNS Temp < 38 oC, headache Twice daily Nurse, Pt
HEENT
RESP
Epistaxis, peritonitis, dyspnea, wheezing
Daily MD, Nurse,
Pharm
CVS HR, BP, chest pain Daily Nurse, Pt
GI/GU Splenomegaly, N/V, hematuria
Daily Nurse, Pt, MD
KIDNEY
LIVER
Renal insufficiency
Alk Phos
Weekly MD, Pharm
HEME CBC (WBC >10) Daily MD, Pharm
DERM
MSK
Rash, bone pain, injection site rxn
Daily Nurse, Pt
Course in HospitalOct 27
Oct 28
Oct
29
Oct
30
Oct
31
Nov
1
Nov
2
Nov
3
Nov
4
Nov
5
Nov
6
WBC (x109)
<0.5 0.5 0.6 0.8 0.7 0.6 0.5 0.6 0.8 1.4 1.6
Hgb (g/L)
59 89 94 114 113 103 105 101 99 100 102
Plts (x106)
34 60 68 102 79 86 81 96 98 87 89
Neuts (x109)
0.1 0.1 -- 0.0 0.2 0.1 0.2 0.1 -- 0.5 0.6
G-CSF
Temp (oC)
37 36.5 37 37 36 36.5 36 36.5 38.5 38.5 37.3
Outcome
Saturday, Nov 7, 2009– ANC = 1.2 x109/L– G-CSF dose given (18 doses total)– Pt stable, afebrile, no signs of further infection– Transferred back to FSJ– Lost to follow-up
References
Up to date Cps Toronto’s notes Micromedex Lexi drugs Asco guidelines Harm reduction article Reporting form article
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