Savvy Psychopharmacology Managing clozapine-induced neutropenia and agranulocytosis Jeremy S. Daniel, PharmD, BCPS, BCPP, and Tonya Gross, PharmD r. S, age 43, has schizophrenia and Clozapine-induced neutropenia been stable on clozapine for 6 years Clozapine was approved in 1989 for man- M after several other antipsychotic aging treatment-resistant schizophrenia regimens failed. Mr. S also has a history of after demonstrating better efficacy than hypertension, dyslipidemia, and gastroesoph- chlorpromazine.1 However, the adverse ageal reflux disorder. His medication regi- effects of neutropenia (white blood cell men includes clozapine, 400 mg/d, lisinopril, count [WBC] <3,000/μL) and agranulocyto- Vicki L. Ellingrod, 20 mg/d, atorvastatin, 40 mg/d, omeprazole, sis (ANC <500/μL3) leading to death were PharmD, FCCP 40 mg/d, and a multivitamin. During routine reported in later studies.2,3 One study in Department Editor blood monitoring, Mr. S shows a significant the United Kingdom and Ireland reported drop in absolute neutrophil count (ANC) a prevalence of 2.9% for neutropenia and (750/µL) (reference range, 1,500 to 8,000 µL). 0.8% for agranulocytosis among patients Mr. S , who is African American, has no history taking clozapine.3 Because of this risk, the of benign ethnic neutropenia (BEN) or ANC FDA mandated WBC and ANC monitor- <1,000/µL. While reviewing his chart, clini- ing before initiating clozapine and periodi- cians note that Mr. S had an ANC of 1,350/µL cally thereafter. In October 2015, the Risk 3 years earlier in 2013. Because a complete Evaluation and Mitigation Strategies pro- workup reveals no other cause for this lab gram for clozapine updated recommended abnormality, we determine that is clozapine- ANC levels and eliminated WBC monitor- induced. Mr. S’s physician asks about treat- ing. ANC monitoring frequencies are sum- ment options that would allow him to stay marized in the Table (page 52).1 on clozapine. The exact mechanism of clozapine- induced neutropenia is unknown, although Because of clozapine’s efficacy in treatment- it is possible it stems from the drug’s effect on resistant schizophrenia, many psychiatrists white blood cell precursors.2 Neutropenia aim to manage patients who develop abnor- mal laboratory values without discontinu- Practice Points ing clozapine. This article will examine the • There is lack of evidence for long-term evidence behind 2 potential management use of filgrastim for clozapine-induced Savvy Psychopharmacology strategies. neutropenia and agranulocytosis; short- is produced in partnership with the College Dr. Daniel is Assistant Professor, South Dakota State University, term treatment is recommended. of Psychiatric and Neurologic College of Pharmacy, Brookings, South Dakota, and Clinical • There is potential risk of lithium masking Pharmacist, Avera McKennan Hospital and University Health Center, Pharmacists Sioux Falls, South Dakota. Dr. Gross is PGY-2 Psychiatric Pharmacy the preliminary state of neutropenia cpnp.org Resident, Avera McKennan Hospital and University Health Center, leading to severe agranulocytosis. mhc.cpnp.org (journal) Sioux Falls, South Dakota. Disclosures • Patients who experience neutropenia with The authors report no financial relationship with any company whose clozapine are at an increased risk for a products are mentioned in this article or with manufacturers of repeat neutropenia on rechallenge. Current Psychiatry competing products. Vol. 15, No. 12 51 Savvy Psychopharmacology Table Absolute neutrophil count monitoring frequencies with clozapine ANC level Monitoring Initiation • Weekly for 6 months General population: ≥1,500/μL • Every 2 weeks from 6 to 12 months • Monthly after 12 months BEN population: ≥1,000/μL (Obtain at least 2 baseline ANC values before initiating treatment) Mild neutropenia BEN population: 1,000 to 1,499/μL • No additional monitoring needed. ANC still in normal range General population: Clinical Point • Monitor ANC 3 times weekly until ≥1,500/μL • Then can return to patient’s last ANC monitoring interval Most patients Moderate neutropeniaa BEN population: rechallenged with 500 to 999/μL • Monitor ANC 3 times weekly until ≥1,000/μL or the patient’s baseline clozapine experience • Then monitor ANC weekly for 4 weeks, then return to patient’s a more severe, faster, last ANC monitoring interval General population: and longer episode • Interrupt clozapine of neutropenia • Monitor ANC daily until ≥1,000/μL, then restart clozapine • Then monitor ANC 3 times weekly until ≥1,500/μL • Then monitor ANC weekly for 4 weeks • Then return to patient’s last ANC monitoring interval Severe neutropeniaa BEN populationb: <500/μL • Discontinue clozapine • Daily ANC until ≥500/μL • Then 3 times weekly until ANC is more than or equal to the patient’s established baseline General populationb: • Discontinue clozapine • Daily ANC until ≥1,000/μL • Then 3 times weekly until ANC ≥1,500/μL aRecommend hematology consultation bMay rechallenge if prescriber determines benefits outweigh risks ANC: absolute neutrophil count; BEN: benign ethnic neutropenia Source: Reference 1 typically appears within 3 months of clo- is viewed as a “rescue” treatment. zapine initiation; however, delayed cases Filgrastim’s mechanism of action is related have been reported. Additionally, the risk to neutrophil production and prolif- is higher in certain patient populations eration. Several articles from the 1990s Discuss this article at (African heritage, Yemenite, West Indians, reported efficacy in the short-term man- www.facebook.com/ and Arab). Patients with a lower ANC agement of low WBC or ANC. However, CurrentPsychiatry at clozapine initiation and advanced age few articles, mainly case reports, have appear to be at higher risk.2 looked at long-term use of these agents. One article examined 3 patients, average Filgrastim age 45, who developed neutropenia dur- The use of granulocyte-colony stimu- ing clozapine treatment.4 Filgrastim at an Current Psychiatry 52 December 2016 lating factor, such as filgrastim, often average dosage of 0.6 to 0.9 mg/week was Savvy Psychopharmacology used successfully. The dosage was reduced Related Resources to 0.3 mg/week in 1 patient, although • Clozapine REMS Program. www.clozapinerems.com. neutropenia returned. • Newman BM, Newman WJ. Rediscovering clozapine: Because of the lack of literature regard- adverse effects develop—what should you do now? ing long-term therapy, it is recommended Current Psychiatry. 2016;15(8):40-46,48,49. to consider short-term treatment with fil- • Whiskey E, Taylor D. Restarting clozapine after neutropenia: evaluating the possibilities and practicalities. CNS Drugs. grastim to normalize ANC after a severe 2007;21(1):25-35. drop in a symptomatic patient. Physicians Drug Brand Names also must consider the potential barriers Atorvastatin • Lipitor Lisinopril • Prinivil to filgrastim treatment including adverse Chlorpromazine • Thorazine Lithium • Eskalith, Lithobid effects, such as allergic reactions, bone pain, Clozapine • Clozaril Omeprazole • Prilosec Fligrastim • Neupogen and thrombocytopenia, and high cost. Clinical Point Adjunctive lithium There is more Lithium could cause leukocytosis, which could balance neutropenia induced by clo- possible that lithium will not protect a evidence supporting zapine. One of the largest studies evaluat- patient from clozapine-induced neutro- the efficacy ing lithium therapy with clozapine-induced penia or agranulocytosis, and can lead to of lithium neutropenia and agranulocytosis studied serious adverse events. for clozapine- 25 patients taking clozapine with a previ- When deciding whether to rechallenge a induced neutropenia ous “red result” (WBC <3,000/μL, ANC patient on clozapine who had a prior epi- <1,500/μL, or platelets <50,000/μL).3 sode of moderate or severe neutropenia or than filgrastim Lithium treatment was started before or agranulocytosis, a risk vs benefit discussion simultaneously with the reinitiation of is necessary. One study found that 20 of clozapine in most patients; the remaining 53 patients (38%) experienced a repeat patients started treatment at a later date. dyscrasia when rechallenged.5 Of these Only 1 of 25 patients experienced a repeat patients, most experienced a lower ANC “red result.” The average lithium level that presented faster and took longer to was 0.54 mEq/L. resolve.5 If a patient has experienced true It is important to remember that ini- agranulocytosis, the recommendation is to tiating adjunctive lithium carries risk. not rechallenge clozapine. Adverse effects include gastrointestinal upset, tremors, polyuria, polydipsia, and References 1. Clozapine [package insert]. North Wales, PA: TEVA nephrotoxicity. Pharmaceuticals USA; 2015. Additionally, there is risk that lithium 2. Lundblad W, Azzam PN, Gopalan P, et al. Medical management of patients on clozapine: a guide for internists. J Hosp Med. simply masks the preliminary states of 2015;8(8):537-543. neutropenia leading to a more severe 3. Kanaan RA, Kerwin RW. Lithium and clozapine rechallenge: 3 a retrospective case analysis. J Clin Psychiatry. 2006;67(5): agranulocytosis without warning. Again, 756-760. the mechanism of action of clozapine- 4. Hägg S, Rosenius S, Spigset O. Long-term combination treatment with clozapine and filgrastim in patients with induced neutropenia is thought to be clozapine-induced agranulocytosis. Int Clin Psychopharmacol. related to the drug’s effect on WBC precur- 2003;18(3):173-174. 5. Dunk LR, Annan LJ, Andrews CD. Rechallenge with clozapine sors. The mechanism of lithium-induced following leucopenia or neutropenia during previous therapy. leukocytosis is unknown, therefore it’s Br J Psychiatry. 2006;188:255-263. Current Psychiatry Vol. 15, No. 12 53.