Jennifer Day
NHA Resident
March 26, 2010

Overview
 Objectives
 Patient Profile
 Controversy
 Pharmacy Intervention
 Monitoring
 Outcome

Objectives
 Define neutropenia
 List five medications that may cause neutropenia
 State three patient populations where granulocytecolony 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 1 st Nations female


CC: Sore, inflamed mouth, hurt to eat
HPI : • 1 yr hx of neutropenia, recurrent mucositis
? 2 o to laced crack-cocaine
• G-CSF therapy started
• Presented to Ft. St. James (FSJ) hospital after 1 st dose w/ fever, chest pain
• Transferred to UHNBC-PG

Patient Profile – Presentation
 DX:
 SH:
Neutropenia non-responsive to G-CSF
 PMH: Anemia, insomnia
 FH: Non-contributory
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 dose
Ibuprofen 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)
CNS
HEENT
RESP
CVS
GI
GU
AVSS: T=37 o C, HR=75, BP=135/75, RR= 17,
SaO
2
=98% on RA
No complaints
Sore, inflamed mouth, pain with eating, white plaques; no cough/SOB
No chest pain, iron=5 (  ), iron sat = 15% (  )
Melena x 5/7, endoscopy normal; voiding per washroom, no burning/urgency/frequency (BUF)

Patient Profile – Review of Systems
LIVER
KIDNEY
ENDOCRINE
SCr=46 (stable), CrCl=151; splenomegaly;
LFT WNL
BG=5.3 (random)
MSK/EXTR/SKIN Slight facial edema, body aches
FLUID STATUS No complaints; K=2.8 (  ), Na=134 (  )

Patient Profile – Neutropenia
WBC
(x10 9 )
Hgb
(g/L)
Plts
(x10 6 )
ANC
(x10 9 )
Temp
( o C)
(FSJ)
Oct
19
0.7
115
155
--
38.9
(PG)
Oct
27
<0.5
59
34
0.1
Transfused
37
Oct
28
0.5
89
60
0.1
37 36.5
Oct
29
0.6
94
68
--

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
(10 9 /L)
Risk Management
>1.5
None
1-1.5
No risk of significant infection; fever managed as outpt
0.5-1 Some risk of infection; fever can be managed as an outpt
<0.5
Significant risk of infection; fever should always be managed as inpt with IV ABX
<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 agent
 Supportive 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

Neutropenia – Treatment Options
 G-CSF
– MOA:
 G-CSF is produced by monocytes
 Regulates neutrophil production, progenitor differentiation
 Enhances phagocytic ability
G-CSF

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 fever
 progressive infection or invasive fungal infections
 pneumonia or sepsis syndrome
 severe (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: hospitalize
 Infectious 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 stopped
 Monitored for sign of infection
 Recovered 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
Temp < 38 o C
Frequency Who?
Twice daily Nurse, Pt CNS
HEENT
RESP
CVS
DERM
MSK
Mucositis, cough, SOB,

RR,

O
2
Sat

HR,

BP
Daily
Daily
MD, Nurse,
Pharm
Nurse
GI/GU Burning, urgency, frequency
KIDNEY SCr, urine output
Daily
HEME CBC (Neuts >1.5x10
9 /L) Daily
Nurse, Pt
Weekly/Daily MD, Pharm
MD, Pharm
Chills, night sweats, facial edema
Daily Nurse, Pt

Monitoring Plan – Toxicity
CNS
Parameter Frequency Who?
Temp < 38 o C, headache Twice daily
HEENT
RESP
CVS
Epistaxis, peritonitis, dyspnea, wheezing
Daily

HR,

BP, chest pain Daily
GI/GU Splenomegaly, N/V, hematuria
KIDNEY
LIVER
Renal insufficiency

Alk Phos
HEME CBC (WBC >10)
DERM
MSK
Rash, bone pain, injection site rxn
Daily
Weekly
Daily
Daily
Nurse, Pt
MD, Nurse,
Pharm
Nurse, Pt
Nurse, Pt,
MD
MD, Pharm
MD, Pharm
Nurse, Pt

Course in Hospital
WBC
(x10 9 )
Hgb
(g/L)
Plts
(x10 6 )
Neuts
(x10 9 )
G-CSF
Temp
( o C)
Oct
27
Oct
28
Oct
29
Oct
30
Oct
31
Nov
1
Nov
2
Nov
3
Nov
4
Nov
5
Nov
6
<0.5
0.5
0.6
0.8
0.7
0.6
0.5
0.6
0.8
1.4
1.6
59 89 94 114 113 103 105 101 99 100 102
34 60 68 102 79 86 81 96 98 87 89
0.1
0.1
-0.0
0.2
0.1
0.2
0.1
-0.5
0.6
        
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 x10 9 /L
– G-CSF dose given (18 doses total)
– Pt stable, afebrile, no signs of further infection
– Transferred back to FSJ
– Lost to follow-up

Addendum

References








Up to date
Cps
Toronto’s notes
Micromedex
Lexi drugs
Asco guidelines
Harm reduction article
Reporting form article

Questions?