RAs Nasty Neutropenia To stimulate or not to

RA’s Nasty Neutropenia: To stimulate or not to stimulate Jennifer Day NHA Resident March 26, 2010

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

Objectives l l 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 l l l 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 l l l DX: PMH: FH: SH: Neutropenia non-responsive to G-CSF Anemia, insomnia Non-contributory Hx of Et. OH abuse, gas-huffing, crack-cocaine use x ~15 years l Smoking, casual use, last use 3 weeks Allergies: codeine = itching

Patient Profile – Medications l MPTA: G-CSF 300 mcg SQ daily x 1 dose Ibuprofen 400 mg PO tid Vitamin B 6 50 mg PO daily Vitamin B 12 100 mg PO daily Calcium/Vit D 500 mg/125 IU PO bid Ferrous sulphate 300 mg PO bid Oxazepam 15 mg PO hs prn

Patient Profile – Medications l UHNBC: Ceftazidime 2 g IV q 8 h Gentamicin 360 mg IV q 24 h Lansoprazole 30 mg PO bid Replavite 1 tab PO daily Folate 5 mg PO daily Ferrous sulphate 600 mg PO bid Vitamin C 1000 mg PO daily Vitamin B 12 1000 mcg IM qmonthly

Patient Profile – Medications UHNBC: Nystatin 500, 000 units PO tid, swish and swallow KCl SR 24 m. Eq PO q 4 h x 3 doses then KCl SR 8 m. Eq PO bid Benzydamine 5 m. L PO qid, swish and spit Magic Mouthwash 10 m. L PO prn Hydromorphone 2 mg PO q 4 h prn Dimenhydrinate 25 -50 mg PO q 4 -6 h prn l

Patient Profile – Review of Systems VITALS (Oct 27) CNS AVSS: T=37 o. C, HR=75, BP=135/75, RR= 17, Sa. O 2=98% on RA HEENT RESP CVS Sore, inflamed mouth, pain with eating, white plaques; no cough/SOB GI GU Melena x 5/7, endoscopy normal; voiding per washroom, no burning/urgency/frequency (BUF) No complaints No chest pain, iron=5 ( ), iron sat = 15% ( )

Patient Profile – Review of Systems LIVER KIDNEY SCr=46 (stable), Cr. Cl=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 WBC (x 10 ) Hgb (g/L) 9 Plts (x 106) ANC (x 109) (FSJ) Oct 19 (PG) Oct 27 Oct 28 Oct 29 0. 7 <0. 5 0. 6 115 59 89 94 155 34 60 68 -- 0. 1 -- 37 36. 5 Transfused Temp (o. C) 38. 9 37

Patient Profile – Medical Problems l l l l Neutropenia Oral Mucositis Oral Thrush GI Bleed Anemia Pain Hypokalemia

Pharmacy Assessment – DRPs l l l l 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 l l 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 l l l Definition: ANC less than 1. 5 x 109/L – ANC = WBC x percent (PMNs + bands) ÷ 100 Drug-induced: – Decreased production or peripheral destruction l Alkylating agents, antimetabolites, anticonvulsants, antipsychotics, antibiotics, anti -inflammatory agents, anti-thyroid medications, antibiotics, levamisole Risks: mucositis, infection, sepsis

Neutropenia – Overview ANC Risk Management (109/L) >1. 5 1 -1. 5 None 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 l Why lace cocaine with levamisole? – – l Previously used for colon cancer, rheumatoid arthritis and as an antihelmithic – l Stable under heated conditions Increase dopamine and endogenous opiate levels 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 l l l Stop disease process Manage patient’s symptoms Prevent disease Normalize physiological parameters Minimize side-effects of therapy

Neutropenia – Treatment Options l Alternatives for drug-induced neutropenia: – 1 st line: l Discontinue offending agent l Supportive care (ABX if febrile, indicated) – 2 nd line: l Colony-Stimulating Factor hormone G-CSF (Filgrastim) – Pegylated G-CSF (Pegfilgrastim) – GM-CSF (Sargramostim) – 3 rd line: l If no response to above – IV immunoglobulin – Granulocyte infusion –

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

Neutropenia – Treatment Options l G-CSF (Filgrastim) – Side-effects: l >10%: fever, rash, splenomegaly, bone pain, epistaxis l 1 -10%: hyper/hypotension, MI/arrhythmias, chest pain, headache, N/V, peritonitis l <1%: pulmonary infiltrates, tachycardia, hematuria, wheezing, renal insufficiency, injection site reaction, ARDS, allergic reactions, arthralgias, dyspnea, facial edema, hemoptysis

Controversy l l 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 l 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: l advanced age (older than 65 years) l fever at hospitalization or unstable fever l progressive infection or invasive fungal infections l pneumonia or sepsis syndrome l severe (ANC less than 1) or anticipated prolonged (greater than 10 days) neutropenia

PICO Question l l 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 l l l Databases: – Pub. Med, Embase, Google Scholar Search terms: – Cocaine-induced – Levamisole – Neutropenia – G-CSF Results: anger and frustration

Literature Review – Evidence l 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: l If fever or infection present empiric IV ABX and supportive care recommended l “Treatment with G-CSF should be considered”

Literature Review – Evidence l Agranulocytosis associated with levamisole in cocaine, BCCDC update: April 2009 – Developed standard case report form – Diagnostic tests: CBC & diff, urine for drugs – Management: l If ANC <1. 0, febrile with active infection: hospitalize l Infectious work-up, broad spectrum ABX l “G-CSF should not be started until consultation with haematologist” – Recovery in 7 -10 days

Literature Review – Evidence l 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: l Therapy stopped l Monitored for sign of infection l Recovered within 10 days

Bottom Line l 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 l Pros – Not contraindicated – Possibility of effect l Cons – No evidence – Not clearly indicated – Hasn’t worked in past – Experiencing side-effects – Expensive – ? Mortality benefits

Pharmacy Recommendations l Discontinue G-CSF in this pt – – l l l 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 5 m. L PO qid ac meals Increase benzydamine 15 m. L PO qid, swish and spit

Outcome l l l 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 o. C Twice daily Nurse, Pt HEENT RESP Mucositis, cough, SOB, RR, O 2 Sat Daily MD, Nurse, Pharm CVS HR, BP Daily Nurse GI/GU Burning, urgency, frequency Daily Nurse, Pt Weekly/Daily MD, Pharm KIDNEY SCr, urine output HEME CBC (Neuts >1. 5 x 109/L) Daily MD, Pharm DERM MSK Chills, night sweats, facial edema Daily Nurse, Pt

Monitoring Plan – Toxicity Parameter Frequency Who? CNS Temp < 38 o. C, 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 Weekly MD, Pharm CBC (WBC >10) Daily MD, Pharm Rash, bone pain, injection site rxn Daily Nurse, Pt KIDNEY Renal insufficiency Alk Phos LIVER HEME DERM MSK

Course in Hospital WBC Oct 27 Oct 28 Oct 29 Oct 30 Oct 31 Nov 2 Nov 3 Nov 4 Nov 5 Nov 6 <0. 5 0. 6 0. 8 0. 7 0. 6 0. 5 0. 6 0. 8 1. 4 1. 6 59 89 94 113 105 101 99 100 102 34 60 68 102 79 86 81 96 98 87 89 0. 1 -- 0. 0 0. 2 0. 1 -- 0. 5 0. 6 37 37 36 36. 5 38. 5 37. 3 (x 109) Hgb (g/L) Plts (x 106) Neuts (x 109) G-CSF Temp (o. C) 37 36. 5

Outcome l Saturday, Nov 7, 2009 – ANC = 1. 2 x 109/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 l l l l Up to date Cps Toronto’s notes Micromedex Lexi drugs Asco guidelines Harm reduction article Reporting form article

Questions?