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RA’s Nasty Neutropenia: To stimulate or not to stimulate

RA’s Nasty Neutropenia: To stimulate or not to stimulate. 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

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RA’s Nasty Neutropenia: To stimulate or not to stimulate

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

  2. Overview • Objectives • Patient Profile • Controversy • Pharmacy Intervention • Monitoring • Outcome

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. Patient Profile – Review of Systems

  10. Patient Profile – Review of Systems

  11. Patient Profile – Neutropenia

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

  13. 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

  14. 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

  15. 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

  16. Neutropenia – Overview

  17. 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

  18. Pharmacy Assessment – Goals • Stop disease process • Manage patient’s symptoms • Prevent disease • Normalize physiological parameters • Minimize side-effects of therapy

  19. 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

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

  21. 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

  22. 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

  23. 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

  24. 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?

  25. Search Strategy • Databases: • PubMed, Embase, Google Scholar • Search terms: • Cocaine-induced • Levamisole • Neutropenia • G-CSF • Results: anger and frustration

  26. 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”

  27. 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

  28. 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

  29. Bottom Line • Should we use G-CSF in this pt population? • May be considered in high risk neutropenic febrilepts 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

  30. Pros Not contraindicated Possibility of effect Weighing the Options • Cons • No evidence • Not clearly indicated • Hasn’t worked in past • Experiencing side-effects • Expensive • ? Mortality benefits

  31. 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

  32. 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

  33. Monitoring Plan – Efficacy

  34. Monitoring Plan – Toxicity

  35. Course in Hospital

  36. 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

  37. Addendum

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

  39. Questions?

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