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

Learn about drug-induced neutropenia, G-CSF therapy, levamisole, and pharmacy interventions for neutropenic patients. Understand controversies and treatment guidelines.

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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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