- Email: [email protected]
Deaths associated with inappropriate intravenous colchicine administration1
The Journal of Emergency Medicine, Vol. 22, No. 4, pp. 385–387, 2002 Copyright © 2002 Elsevier Science Inc. Printed in the USA. All rights reserved 0736-4679/02 $–see front matter
PII S0736-4679(02)00430-4
Selected Topics: Toxicology
DEATHS ASSOCIATED WITH INAPPROPRIATE INTRAVENOUS COLCHICINE ADMINISTRATION Renan A. Bonnel,
PharmD, MPH,*
Maria L. Villalba, MD,† Claudia B. Karwoski, Julie Beitz, MD*
PharmD,*
and
*Office of Drug Safety, Center for Drug Evaluation and Research, US Food and Drug Administration, Rockville, Maryland, and †Division of Anti-Inflammatory, Analgesic and Ophthalmic Drug Products, Center for Drug Evaluation and Research, US Food and Drug Administration Rockville, Maryland, Reprint Address: Renan A. Bonnel, PharmD, MPH, US FDA, 5600 Fishers Lane, Rm. 15B-23, HFD-430, Rockville, MD 20857
e Abstract—Intravenous (IV) colchicine is occasionally prescribed for the treatment of acute gouty arthritis. The Food and Drug Administration (FDA) recently received a report of death in a patient that was associated with inappropriate IV dosing of colchicine. This report prompted further investigation of other deaths associated with IV colchicine use in the FDA Adverse Event Reporting System (AERS) and the medical literature. A total of 20 deaths were identified. Eight patients were females, 11 were males, and the gender was unknown in 1. In all cases, the recommended maximum cumulative dose of 2 to 4 mg during a course of therapy was exceeded. Dose reductions are recommended in patients with renal or hepatic disease and in the elderly. All reported adverse events were associated with colchicine toxicity, including thrombocytopenia, leukopenia, pancytopenia, agranulocytosis, aplastic anemia, acute renal failure, and disseminated intravascular coagulopathy. Death occurred within 1 to 40 days after drug administration. Therapeutic guidelines exist for use of IV colchicine and these guidelines should be followed to prevent serious toxicities and death. © 2002 Elsevier Science Inc.
INTRODUCTION Colchicine, an alkaloid of the Colchicum species, has anti-inflammatory action in acute attacks of gout and has a prophylactic effect against recurrent attacks. It is used “off label” for prevention of acute attacks of amyloid deposition in patients with familial Mediterranean fever (FMF), for prevention of acute attacks of pseudogout (calcium pyrophosphate deposition), and for the treatment of primary biliary cirrhosis (1–3). Emergency Department (ED) Physicians may need to administer intravenous (IV) colchicine during an acute attack or be involved in the management of the patient with colchicine toxicity presenting to the ED. IV colchicine is occasionally prescribed for the treatment of acute gouty arthritis when a rapid response is desired, when the use of the oral route is precluded, or when less toxic agents [nonsteroidal anti-inflammatory drugs (NSAIDS), corticosteroids] are contraindicated (2). The lack of early warning gastrointestinal (GI) symptoms with IV colchicine increases the risk of serious systemic toxicity. Thus, GI symptoms should not be used as an indicator of toxicity of IV colchicine. There is a limit to how much IV colchicine can be given. The USP DI® notes that the risk of colchicine-induced toxicity depends on the total IV dose given over a period of time, as well as on the size of single doses (4 – 6). This
e Keywords—intravenous; colchicine; gout
The views expressed are those of the authors and do not necessarily represent those of, nor imply endorsement from, the Food and Drug Administration or the U.S Government.
Selected Topics: Toxicology is coordinated by Kenneth Kulig,
RECEIVED: 10 April 2001; FINAL ACCEPTED: 13 November 2001
SUBMISSION RECEIVED:
MD,
22 October 2001; 385
of Denver, Colorado
386
R. A. Bonnel et al.
article highlights the problems associated with failing to follow dosing guidelines in the clinical setting and the findings associated with the toxic effects of IV colchicine.
MATERIALS AND METHODS A report of death in an elderly patient following an overdose of IV colchicine prompted the investigation of similar cases in the FDA’s Adverse Event Reports System (AERS) database and a review of the literature. AERS is a computerized database of postmarketing adverse drug event (or MedWatch) reports. We collected case reports for hands-on review based on a search of the AERS database using IV colchicine as a product and death as an outcome. Text versions of AERS data (quarterly) are available in CD-ROM format for purchase from National Technology Information System (NTIS) (www.ntis.gov).
RESULTS A total of 20 deaths were identified from 1983 through 2000. Thirteen were from the AERS database and 7 were from the medical literature. Eight patients were females, 11 were males, and the gender was unknown in 1 patient. Two young females (21 and 31 years old) received IV colchicine for FMF. Seventeen patients (ages 50 –91 years) received the drug for the treatment of gout. In one case the age and the indication were not known. In all cases, the recommended cumulative maximum dose of 2 to 4 mg during a course of therapy was exceeded (range: 5.5–19 mg). All patients developed adverse events associated with colchicine toxicity, including thrombocytopenia (8), leukopenia (8), pancytopenia (3), agranulocytosis (2), aplastic anemia (2), acute renal failure (6), and disseminated intravascular coagulopathy (4). Death occurred within 1 to 40 days after IV colchicine administration. Sixteen (80%) of these patients experienced clinically significant bone marrow depression. Only two reports indicated empiric antibiotic treatment. Although 13 of the patients may have been at increased risk for serious toxicity, a poor outcome was temporally associated with excessive IV dose of colchicine in these cases. Possible risk factors were ages over 65 years, pre-existing medical conditions (including cardiac disease, hypertension, diabetes, and renal impairment), concomitant NSAIDs, and recent oral colchicine use. Four previously unpublished and sufficiently detailed case reports are summarized to highlight important clinical attributes.
CASE 1 An 83-year-old man was hospitalized with right hip pain and inability to walk. Colchicine was ordered as follows: 2 mg IV ⫻ 1, followed by 0.5 mg IV q2h until diarrhea. He received a total dose of 5.5 mg IV in 5 h. Concomitant medications included indomethacin 5 mg orally three times daily (received 3 doses). His past medical history was significant for chronic renal insufficiency (baseline serum creatinine 2.3 mg/dL; BUN: 48 mg/dL) and gout. He had no known drug allergies. He was discharged home. Four hours later, he was readmitted with complaints of dizziness, nausea, vomiting, diarrhea, and elevated serum creatinine (4.9 mg/dL) and BUN (78 mg/dL). The patient’s mental and respiratory status declined over the next day and he died.
CASE 2 A 65-year-old man was admitted with shortness of breath, dehydration, acute renal failure, and diabetes mellitus (DM). He received colchicine IV 2 mg q8h ⫻ 3 doses, followed by 1 mg IV q 12 ⫻ 4 and 0.5 mg IV q 12 ⫻ 1 (total dose: 10.5 mg) for hyperuricemia and gout. The patient developed thrombocytopenia with a platelet count of 37,000 (baseline platelet 200,000), leukopenia with a white blood count of 1,000 mm3/neutrophil 40% (baseline 9000 mm3/neutrophil 86%). One day after completing IV colchicine, the patient went into cardiac arrest and died. Although the cause of death was not specified, bone marrow toxicity coincided with colchicine overdose.
CASE 3 A 77-year-old man with a history of renal insufficiency, gout, and peptic ulcer disease was admitted to the hospital with nausea and diarrhea. He was on oral colchicine therapy as an outpatient. He received 4 mg of colchicine IV for 1 day followed by additional oral doses for a total of 7 mg. The patient became dehydrated and developed leukopenia, abnormal renal function, acidosis, hypocalcemia, GI hemorrhage, hypotension, adult respiratory distress syndrome, and septic shock, and he died 10 days after admission.
CASE 4 A 31-year-old woman received colchicine 1 mg IV every 6 h for 8 doses, for acute treatment of FMF. The patient was on chronic colchicine 0.6 mg orally three times
Inappropriate IV Colchicine Use
daily. Her baseline platelet count was 274,000. Within the next two days, her platelet count dropped to 167,000 and then to 17,000. Subsequently, the patient developed gastrointestinal hemorrhage, epistaxis, metabolic acidosis, and died. The total IV colchicine dose was 8 mg.
DISCUSSION Guidelines for the use of IV colchicine published in the literature have been included in the USP DI® Drug Information for the Health Care Professionals since 1994, and are included in the product labeling (3–5,7). For adults with normal renal or liver function, no colchicine should be given by any route within 7 days of receiving the maximum recommended cumulative dose of 4 mg IV for a treatment course (3,4,8,9). Many clinicians misinterpret total treatment course doses for total daily doses (10). If IV colchicine needs to be given as a substitute for oral doses, such as postoperatively, the dose should be no greater than 50% of the oral dose (4). For adults with abnormal renal function and the elderly, even with apparent normal organ function, the maximum cumulative dose should be reduced. Some authors recommend the use of a maximum of 2 mg for the whole course for these individuals (4,5,7). A retrospective study, involving hospitalized patients receiving IV colchicine, reported that there were prescribing errors in 26% (5 in 19 patients) of records reviewed (11). Another retrospective study indicated a 2% incidence of death as a result of inappropriate use of IV colchicine (7). Our evaluation of deaths with IV colchicine indicates that warnings, precautions, contraindications, and dosage guidelines in the product labeling were not followed or incorrectly interpreted, resulting in colchicine overdose and death in 20 patients. Older age, concomitant use of oral colchicine or NSAIDs, and multiple pre-existing medical conditions such as renal failure, were identified in nearly 60% of the cases and might have contributed to the fatal outcome. Although colchicine has been on the market for many years, therapeutic dosage guidelines should be followed to prevent serious toxicities and death. Although information varied between reports, most reports suggested colchicine toxicity was not acutely recognized nor specifically treated. The signs and symptoms of colchicine toxicity in-
387
clude a sensation of suffocation and tightness in the chest, difficulty in swallowing, abdominal pain, nausea, vomiting, diarrhea, severe generalized myalgia, arthralgia, cyanosis, dilated pupils, bone marrow depression, severe shock, hematuria, oliguria, ascending paralysis, delirium, and convulsions (10). The patient’s past history of oral colchicine use before an acute attack, age, renal, and liver function should guide physicians to determine the appropriate IV dose of colchicine and may prevent severe toxicity. Prompt recognition and treatment of clinically significant bone marrow depression secondary to colchicine toxicity may reduce the risk of death (12,13). Certified Regional Poison Control Centers that are listed in the Physicians’ Desk Reference (PDR) provide up-to-date information about the treatment of colchicine overdose.
REFERENCES 1. Simons RJ, Kingma DW. Fatal colchicine toxicity. Am J Med 1989;86(Mar):356 –7. 2. Emerson B, Klippel JH, Dieppe P, eds. The management of gout. Rheumatology, 2nd edn. Philadelphia: Mosby; 1998;15.1–15.8. 3. Insel P. Analgesic-antipyretic and antiinflammatory agents and drugs employed in the treatment of gout. In Hardman JG, Limbard LE, Molinoff PB, Ruddon RW, Goodman LS, Gilman A, eds. The pharmaceutical basis of therapeutics, 9th edn. New York: McGrawHill; 1996:647–9. 4. Wallace SL, Singer JZ. Review: systemic toxicity associated with the intravenous administration of colchicine-guidelines for use. J Rheumatol 1988;15(3):495–9. 5. USP DI ® Volume I- Drug Information for the Health Care Professional. Colchicine Monograph, 20th edn. Colorado: Micromedex Inc.; 2000:963– 8. 6. Cohen MR. Prevention of colchicine overdose. Hosp Pharm 1998; 33;529 –30. 7. Roberts WN, Liang MH, Stern S. Colchicine in acute gout: reassessment of risks and benefits. JAMA 1987;257(Apr 10);1920 –2. 8. Davis JS. Safety and effectiveness of colchicine by intravenous administration in the treatment of gout. J Clin Pharmacol & J New Drugs 1969;9(6):410 –2 9. Mengert T, Eisenberg M, Copass M, eds. Emergency medical therapy. Rheumatologic emergencies, 4th edn. Philadelphia: W.B. Saunders; 1996. 10. Cain H. Flint’s emergency treatment and management. Philadelphia: W. B. Saunders; 1980. 11. Evans TI, Wheeler MT, Small RE, Breitbach SA, Sanders KM, Roberts WN. A comprehensive investigation of patient intravenous colchicine use shows more education is needed. J Rheumatol 1996;Jan 23(1):143– 8. 12. Dixon A, Wall G. Probable colchicine-induced neutropenia not related to intentional overdose. Ann Pharmacother 2001;35:192–5. 13. Katz R, Chuang LC, Sutton JD. Use of granulocyte colony-stimulating factor in the treatment of pancytopenia secondary to colchicine overdose. Ann Pharmacother 1992;26:1087– 8.
PII S0736-4679(02)00430-4
Selected Topics: Toxicology
DEATHS ASSOCIATED WITH INAPPROPRIATE INTRAVENOUS COLCHICINE ADMINISTRATION Renan A. Bonnel,
PharmD, MPH,*
Maria L. Villalba, MD,† Claudia B. Karwoski, Julie Beitz, MD*
PharmD,*
and
*Office of Drug Safety, Center for Drug Evaluation and Research, US Food and Drug Administration, Rockville, Maryland, and †Division of Anti-Inflammatory, Analgesic and Ophthalmic Drug Products, Center for Drug Evaluation and Research, US Food and Drug Administration Rockville, Maryland, Reprint Address: Renan A. Bonnel, PharmD, MPH, US FDA, 5600 Fishers Lane, Rm. 15B-23, HFD-430, Rockville, MD 20857
e Abstract—Intravenous (IV) colchicine is occasionally prescribed for the treatment of acute gouty arthritis. The Food and Drug Administration (FDA) recently received a report of death in a patient that was associated with inappropriate IV dosing of colchicine. This report prompted further investigation of other deaths associated with IV colchicine use in the FDA Adverse Event Reporting System (AERS) and the medical literature. A total of 20 deaths were identified. Eight patients were females, 11 were males, and the gender was unknown in 1. In all cases, the recommended maximum cumulative dose of 2 to 4 mg during a course of therapy was exceeded. Dose reductions are recommended in patients with renal or hepatic disease and in the elderly. All reported adverse events were associated with colchicine toxicity, including thrombocytopenia, leukopenia, pancytopenia, agranulocytosis, aplastic anemia, acute renal failure, and disseminated intravascular coagulopathy. Death occurred within 1 to 40 days after drug administration. Therapeutic guidelines exist for use of IV colchicine and these guidelines should be followed to prevent serious toxicities and death. © 2002 Elsevier Science Inc.
INTRODUCTION Colchicine, an alkaloid of the Colchicum species, has anti-inflammatory action in acute attacks of gout and has a prophylactic effect against recurrent attacks. It is used “off label” for prevention of acute attacks of amyloid deposition in patients with familial Mediterranean fever (FMF), for prevention of acute attacks of pseudogout (calcium pyrophosphate deposition), and for the treatment of primary biliary cirrhosis (1–3). Emergency Department (ED) Physicians may need to administer intravenous (IV) colchicine during an acute attack or be involved in the management of the patient with colchicine toxicity presenting to the ED. IV colchicine is occasionally prescribed for the treatment of acute gouty arthritis when a rapid response is desired, when the use of the oral route is precluded, or when less toxic agents [nonsteroidal anti-inflammatory drugs (NSAIDS), corticosteroids] are contraindicated (2). The lack of early warning gastrointestinal (GI) symptoms with IV colchicine increases the risk of serious systemic toxicity. Thus, GI symptoms should not be used as an indicator of toxicity of IV colchicine. There is a limit to how much IV colchicine can be given. The USP DI® notes that the risk of colchicine-induced toxicity depends on the total IV dose given over a period of time, as well as on the size of single doses (4 – 6). This
e Keywords—intravenous; colchicine; gout
The views expressed are those of the authors and do not necessarily represent those of, nor imply endorsement from, the Food and Drug Administration or the U.S Government.
Selected Topics: Toxicology is coordinated by Kenneth Kulig,
RECEIVED: 10 April 2001; FINAL ACCEPTED: 13 November 2001
SUBMISSION RECEIVED:
MD,
22 October 2001; 385
of Denver, Colorado
386
R. A. Bonnel et al.
article highlights the problems associated with failing to follow dosing guidelines in the clinical setting and the findings associated with the toxic effects of IV colchicine.
MATERIALS AND METHODS A report of death in an elderly patient following an overdose of IV colchicine prompted the investigation of similar cases in the FDA’s Adverse Event Reports System (AERS) database and a review of the literature. AERS is a computerized database of postmarketing adverse drug event (or MedWatch) reports. We collected case reports for hands-on review based on a search of the AERS database using IV colchicine as a product and death as an outcome. Text versions of AERS data (quarterly) are available in CD-ROM format for purchase from National Technology Information System (NTIS) (www.ntis.gov).
RESULTS A total of 20 deaths were identified from 1983 through 2000. Thirteen were from the AERS database and 7 were from the medical literature. Eight patients were females, 11 were males, and the gender was unknown in 1 patient. Two young females (21 and 31 years old) received IV colchicine for FMF. Seventeen patients (ages 50 –91 years) received the drug for the treatment of gout. In one case the age and the indication were not known. In all cases, the recommended cumulative maximum dose of 2 to 4 mg during a course of therapy was exceeded (range: 5.5–19 mg). All patients developed adverse events associated with colchicine toxicity, including thrombocytopenia (8), leukopenia (8), pancytopenia (3), agranulocytosis (2), aplastic anemia (2), acute renal failure (6), and disseminated intravascular coagulopathy (4). Death occurred within 1 to 40 days after IV colchicine administration. Sixteen (80%) of these patients experienced clinically significant bone marrow depression. Only two reports indicated empiric antibiotic treatment. Although 13 of the patients may have been at increased risk for serious toxicity, a poor outcome was temporally associated with excessive IV dose of colchicine in these cases. Possible risk factors were ages over 65 years, pre-existing medical conditions (including cardiac disease, hypertension, diabetes, and renal impairment), concomitant NSAIDs, and recent oral colchicine use. Four previously unpublished and sufficiently detailed case reports are summarized to highlight important clinical attributes.
CASE 1 An 83-year-old man was hospitalized with right hip pain and inability to walk. Colchicine was ordered as follows: 2 mg IV ⫻ 1, followed by 0.5 mg IV q2h until diarrhea. He received a total dose of 5.5 mg IV in 5 h. Concomitant medications included indomethacin 5 mg orally three times daily (received 3 doses). His past medical history was significant for chronic renal insufficiency (baseline serum creatinine 2.3 mg/dL; BUN: 48 mg/dL) and gout. He had no known drug allergies. He was discharged home. Four hours later, he was readmitted with complaints of dizziness, nausea, vomiting, diarrhea, and elevated serum creatinine (4.9 mg/dL) and BUN (78 mg/dL). The patient’s mental and respiratory status declined over the next day and he died.
CASE 2 A 65-year-old man was admitted with shortness of breath, dehydration, acute renal failure, and diabetes mellitus (DM). He received colchicine IV 2 mg q8h ⫻ 3 doses, followed by 1 mg IV q 12 ⫻ 4 and 0.5 mg IV q 12 ⫻ 1 (total dose: 10.5 mg) for hyperuricemia and gout. The patient developed thrombocytopenia with a platelet count of 37,000 (baseline platelet 200,000), leukopenia with a white blood count of 1,000 mm3/neutrophil 40% (baseline 9000 mm3/neutrophil 86%). One day after completing IV colchicine, the patient went into cardiac arrest and died. Although the cause of death was not specified, bone marrow toxicity coincided with colchicine overdose.
CASE 3 A 77-year-old man with a history of renal insufficiency, gout, and peptic ulcer disease was admitted to the hospital with nausea and diarrhea. He was on oral colchicine therapy as an outpatient. He received 4 mg of colchicine IV for 1 day followed by additional oral doses for a total of 7 mg. The patient became dehydrated and developed leukopenia, abnormal renal function, acidosis, hypocalcemia, GI hemorrhage, hypotension, adult respiratory distress syndrome, and septic shock, and he died 10 days after admission.
CASE 4 A 31-year-old woman received colchicine 1 mg IV every 6 h for 8 doses, for acute treatment of FMF. The patient was on chronic colchicine 0.6 mg orally three times
Inappropriate IV Colchicine Use
daily. Her baseline platelet count was 274,000. Within the next two days, her platelet count dropped to 167,000 and then to 17,000. Subsequently, the patient developed gastrointestinal hemorrhage, epistaxis, metabolic acidosis, and died. The total IV colchicine dose was 8 mg.
DISCUSSION Guidelines for the use of IV colchicine published in the literature have been included in the USP DI® Drug Information for the Health Care Professionals since 1994, and are included in the product labeling (3–5,7). For adults with normal renal or liver function, no colchicine should be given by any route within 7 days of receiving the maximum recommended cumulative dose of 4 mg IV for a treatment course (3,4,8,9). Many clinicians misinterpret total treatment course doses for total daily doses (10). If IV colchicine needs to be given as a substitute for oral doses, such as postoperatively, the dose should be no greater than 50% of the oral dose (4). For adults with abnormal renal function and the elderly, even with apparent normal organ function, the maximum cumulative dose should be reduced. Some authors recommend the use of a maximum of 2 mg for the whole course for these individuals (4,5,7). A retrospective study, involving hospitalized patients receiving IV colchicine, reported that there were prescribing errors in 26% (5 in 19 patients) of records reviewed (11). Another retrospective study indicated a 2% incidence of death as a result of inappropriate use of IV colchicine (7). Our evaluation of deaths with IV colchicine indicates that warnings, precautions, contraindications, and dosage guidelines in the product labeling were not followed or incorrectly interpreted, resulting in colchicine overdose and death in 20 patients. Older age, concomitant use of oral colchicine or NSAIDs, and multiple pre-existing medical conditions such as renal failure, were identified in nearly 60% of the cases and might have contributed to the fatal outcome. Although colchicine has been on the market for many years, therapeutic dosage guidelines should be followed to prevent serious toxicities and death. Although information varied between reports, most reports suggested colchicine toxicity was not acutely recognized nor specifically treated. The signs and symptoms of colchicine toxicity in-
387
clude a sensation of suffocation and tightness in the chest, difficulty in swallowing, abdominal pain, nausea, vomiting, diarrhea, severe generalized myalgia, arthralgia, cyanosis, dilated pupils, bone marrow depression, severe shock, hematuria, oliguria, ascending paralysis, delirium, and convulsions (10). The patient’s past history of oral colchicine use before an acute attack, age, renal, and liver function should guide physicians to determine the appropriate IV dose of colchicine and may prevent severe toxicity. Prompt recognition and treatment of clinically significant bone marrow depression secondary to colchicine toxicity may reduce the risk of death (12,13). Certified Regional Poison Control Centers that are listed in the Physicians’ Desk Reference (PDR) provide up-to-date information about the treatment of colchicine overdose.
REFERENCES 1. Simons RJ, Kingma DW. Fatal colchicine toxicity. Am J Med 1989;86(Mar):356 –7. 2. Emerson B, Klippel JH, Dieppe P, eds. The management of gout. Rheumatology, 2nd edn. Philadelphia: Mosby; 1998;15.1–15.8. 3. Insel P. Analgesic-antipyretic and antiinflammatory agents and drugs employed in the treatment of gout. In Hardman JG, Limbard LE, Molinoff PB, Ruddon RW, Goodman LS, Gilman A, eds. The pharmaceutical basis of therapeutics, 9th edn. New York: McGrawHill; 1996:647–9. 4. Wallace SL, Singer JZ. Review: systemic toxicity associated with the intravenous administration of colchicine-guidelines for use. J Rheumatol 1988;15(3):495–9. 5. USP DI ® Volume I- Drug Information for the Health Care Professional. Colchicine Monograph, 20th edn. Colorado: Micromedex Inc.; 2000:963– 8. 6. Cohen MR. Prevention of colchicine overdose. Hosp Pharm 1998; 33;529 –30. 7. Roberts WN, Liang MH, Stern S. Colchicine in acute gout: reassessment of risks and benefits. JAMA 1987;257(Apr 10);1920 –2. 8. Davis JS. Safety and effectiveness of colchicine by intravenous administration in the treatment of gout. J Clin Pharmacol & J New Drugs 1969;9(6):410 –2 9. Mengert T, Eisenberg M, Copass M, eds. Emergency medical therapy. Rheumatologic emergencies, 4th edn. Philadelphia: W.B. Saunders; 1996. 10. Cain H. Flint’s emergency treatment and management. Philadelphia: W. B. Saunders; 1980. 11. Evans TI, Wheeler MT, Small RE, Breitbach SA, Sanders KM, Roberts WN. A comprehensive investigation of patient intravenous colchicine use shows more education is needed. J Rheumatol 1996;Jan 23(1):143– 8. 12. Dixon A, Wall G. Probable colchicine-induced neutropenia not related to intentional overdose. Ann Pharmacother 2001;35:192–5. 13. Katz R, Chuang LC, Sutton JD. Use of granulocyte colony-stimulating factor in the treatment of pancytopenia secondary to colchicine overdose. Ann Pharmacother 1992;26:1087– 8.