Two probable cases of serious drug interaction between clarithromycin and colchicine.

Abstract: Although colchicine is a commonly used medication in patients with gouty arthritis and various multisystem disorders, its safety margin in therapeutic use is not well understood. This report describes two fatal cases of agranulocytosis presumed to result from a drug interaction involving colchicine and clarithromycin.

Key Words: colchicine, clarithromycin, drug-drug interactions

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Colchicine is a medication used in various medical conditions, but its safety margin in therapeutic use is not well understood. There have been case reports in the literature describing serious drug interactions with inhibitors of cytochrome P450, such as macrolide antibiotics. We hereby describe two fatal cases of agranulocytosis presumed to result from a drug interaction involving colchicine and clarithromycin.

Case Reports

Patients 1

A 68-year-old male presented with acute gouty arthritis and community-acquired pneumonia 1 month after completion of empirical antituberculous treatment for a clinical diagnosis of pulmonary tuberculosis. Admission temperature was 39.4[degrees]C. Tophi were present over both big toes, with marked tenderness and inflammation over both knees, ankles, and elbow joints. Chest examination revealed crepitations over the right lower zone posteriorly. Laboratory investigations showed a polymorphonuclear (PMN) predominant leukocytosis (total white cell count, 18.3 X [10.sup.9]/L; PMN, 16.6 X [10.sup.9]/L) and an increased erythrocyte sedimentation rate of 120 mm/h. Renal function was normal, but the liver function tests were mildly abnormal (alanine aminotransferase, 77 IU/L; aspartate aminotransferase, 100 IU/L). Chest radiography showed right middle and left lower zone consolidations. Ultrasonography of the abdomen showed multiple gallstones only. Blood, sputum, and urine cultures were negative, as were serodiagnostic studies for Mycoplasma, Chlamydia, and Legionella. He was given intravenous 4.5 g piperacillin-tazobactam every 6 hours and 500 mg oral clarithromycin twice daily on the day of admission. Fever persisted despite broad-spectrum antimicrobial coverage. Oral colchicine (0.5 mg) every 6 hours was started on day 2 for the acute gouty arthritis. The patient was not given colchicine before admission. Fever and joint symptoms gradually improved after 48 hours of colchicine therapy. The dose of colchicine was decreased to 0.5 mg every 8 hours due to the occurrence of diarrhea on day 5. Total white cell count also decreased from 24.3 (on day 2) to 8.1 (on day 6). However, the parenchymal liver enzymes remained abnormal. Intravenous piperacillin-tazobactam was stopped on day 9. Concomitant clarithromycin and colchicine therapy was prescribed from day 2 to 11 of hospitalization. On day 12, he had sudden deterioration, with recurrence of fever, chills, and rigors, severe paralytic ileus, and systemic hypotension requiring mechanical ventilation and inotropic support. The peripheral blood count showed pancytopenia (total white cell count, 0.70 X [10.sup.9]/L; PMN, 0.29 X [10.sup.9]/L; hemoglobin, 8.7 d/dL; platelets, 95) and acute renal and hepatic failure (urea, 25.2 mmol/L; creatinine, 305 [micro]mol/L; alanine aminotransferase, 643 IU/L; aspartate aminotransferase, 3,165 IU/L). Examination did not reveal any evidence of septic foci or recurrent gouty arthritis. Serial chest radiographs did not show any interval changes. Repeated septic workup was negative. Despite supportive treatment, he died on day 13. Bone marrow agranulocytosis, massive hepatic necrosis and old changes of pulmonary tuberculosis were found at postmortem examination.

Patient 2

A 55-year-old female with a history of gout and end stage renal failure due to diabetes on continuous ambulatory peritoneal dialysis, presented with mental confusion, vomiting and diarrhea, associated with acute gout attack of the right metacarpophalangeal joint 2 days before admission. She was afebrile. Physical examination did not reveal meningitic signs but showed bilateral lung basal crepitations. Preliminary investigation revealed low hemoglobin of 5.1 g/dL, elevated urea (13.8 mmol/L) and creatinine (484 [micro]mol/L) compatible with chronic renal failure. She had mild derangement of liver function tests with alanine aminotransferase of 37 U/L (normal range: 5-31 U/L) and aspartate aminotransferase of 44 U/L (normal range: 12 to 28 U/L). Otherwise, she had normal white cell count (6.6 X [10.sup.9]/L), neutrophil (4.6 X [10.sup.9]/L) and platelet count (195 X [10.sup.9]/L). Her urate level (353 [micro]mol/L) was within the normal limits. Chest x-ray demonstrated bilateral lower zone haziness compatible with pneumonia. The patient was treated with oral colchicine 0.5 mg three times daily and oral clarithromycin 250 mg twice daily for acute gout and community acquired pneumonia respectively. Patient was not put on colchicine before admission. After 5 doses of colchicine and 3 doses of clarithromycin, she had marked reduction of white cell count (0.54 X [10.sup.9]/L), neutrophil (0.25 X [10.sup.9]/L) and platelet count (53 X [10.sup.9]/L). Bone marrow examination revealed moderate to marked marrow hypocellularity. She developed neutropenic fever, and IV piperacillin-tazobactum 4.5 g every 12 hours was commenced. Repeated septic workup was negative. Despite supportive treatment, she died 12 days after admission.

Discussion

Colchicine has a very narrow therapeutic index. (1) Previous case reports have documented the potential complications of colchicine overdose. (2-3) Although the exact mechanism for toxicity was not completely understood, the interference of mitochondrial microtubule in metabolically active cells in different systems may be the culprit. (4) However, adverse drug reactions may be self-limiting if patients are closely monitored. Therefore, it is one of the most commonly used agents in the treatment of acute gouty arthritis and pseudogout. (5)

Fatal cases of colchicine-induced marrow toxicity in patients with hepatic or renal impairment have been well reported in the literature following a total dosage of as low as 12 mg. (6-8) However, potentiation of colchicine-induced marrow suppression by clarithromycin has to be alerted. Since clarithromycin inhibits the isoenzyme CYP3A4 of cytochrome P450 system, the major enzyme responsible for colchicine demethylation, (9) concomitant use of clarithromycin may potentiate the accumulation of colchicine leading to marrow suppression, (10) especially in patients with renal failure. (11) Similar observations were reported following a 14-day course of erythromycin given to a female patient who was receiving long-term colchicine therapy for familial Mediterranean fever and amyloidosis. (12) A serum colchicine level of 22 ng/mL (typically 1 to 2.5 ng/mL) was documented in her case, suggesting a drug interaction between colchicine and macrolides. To our knowledge, this is the first report of a possible adverse drug interaction between clarithromycin and colchicine. Because both of these are commonly prescribed medications, awareness of their possible interaction and close monitoring is indicated.

Conclusion

Clinicians should be aware of the possibility of colchicine toxicity in patients with underlying renal or hepatic impairment. Colchicine toxicity can manifest as pancytopenia secondary to bone marrow failure. There may be increased potential for colchicine toxicity when the drug is coadministered with a macrolide such as clarithromycin.

References

1. Levy M, Spino M, Read SE. Colchicine: a state-of-the-art review. Pharmacotherapy 1991;11:196-211.

2. Hood RL. Colchicine poisoning. J Emerg Med 1994;12:171-7.

3. Stanley MW, Taurog JD, Snover DC. Fatal colchicine toxicity: report of a case. Clin Exp Rheumatol 1984;2:167-171.

4. Critchley JA, Critchley LA, Yeung EA, et al. Granulocyte-colony stimulating factor in the treatment of colchicine poisoning. Hum Exp Toxicol 1997;16:229-232.

5. Emmerson BT. The management of gout. N Engl J Med 1996;334:445-451.

6. Liu YK, Hymowitz R, Carroll MG. Marrow aplasia induced by colchicine: a case report. Arthritis Rheum 1978;21:731-735.

7. Neuss MN, McCallum RM, Brenckman WD, et al. Long-term colchicine administration leading to colchicine toxicity and death. Arthritis Rheum 1986;29:448-449.

8. Finklestein M, Goldman L, Grace ND, et al. Granulocytopenia complicating colchicine therapy for primary biliary cirrhosis. Gastroenterology 1987;93:1231-1235.

9. Tateishi T, Soucek P, Caraco Y, et al. Colchicine biotransformation by human liver microsomes: identification of CYP3A4 as the major isoform responsible for colchicine demethylation. Biochem Pharmacol 1997;53:111-116.

10. Anonymous. Severe colchicine-macrolide interactions. Prescrire Int 2003;12:18-19.

11. Dogukan A, Oymak FS, Taskapan H, et al. Acute fatal colchicine intoxication in a patient on continuous ambulatory peritoneal dialysis (CAPD): possible role of clarithromycin administration. Clin Nephrol 2001;55:181-182.

12. Caraco Y, Putterman C, Rahamimov R, et al. Acute colchicine intoxication: possible role of erythromycin administration. J Rheumatol 1992;19:494-496.

Vincent C. C. Cheng, MRC PATH, P. L. Ho, MRC PATH, and K. Y. Yuen, MD

From the Centre of Infection, The University of Hong Kong, Hong Kong Special Administrative Region, China.

Reprint requests to Prof. K. Y. Yuen, University of Pathology Building, Queen Mary Hospital, Pokfulam Road, Hong Kong, Hong Kong Special Administrative Region, China. Email: [e-mail]

Accepted January 20, 2005.

RELATED ARTICLE: Key Points

* Clinician should be aware of the possibility of colchicine toxicity in patients with underlying renal or hepatic impairment.

* Colchicine toxicity can manifest as pancytopenia secondary to bone marrow failure.

* There may be increased potential for colchicine toxicity when the drug is coadministered with a macrolide such as clarithromycin.