Hypokalemia secondary to capecitabine: A hidden toxicity?

Background: Hyopkalemia is a listed toxicity in the capecitabine (Xeloda®;Roche, Nutley, NJ) package insert. However, the incidence and severity of this toxicity is not known. Methods: We performed a retrospective evaluation of hypokalemia in 77 patients, who received capecitabine for gastrointestinal malignancies between April 2002 and November 2004. Hypokalemia was defined as K⁺ level <3.2 mEq/L. Patients with documented ≥grade 2 vomiting or diarrhea, diuretics, hypomagnesemia, hypokalemia, renal insufficiency, endocrine dysfunction (thyroid, adrenal, diabetic) were excluded. Hypokalemic patients were graded as: mild (grade 1: 3.0-3.2 mEq/L), moderate (grade 3: 2.5-2.9 mEq/L) and severe (grade 4: <2.5 mEq/L). We also reviewed the literature. Results: Fifty-four patients met the above criteria. The most common cause of exclusion was ≥ grade 2 diarrhea (23 patients; 3 0%). Overall, hypokalemia was encountered in 11 patients (20.4%). Among hypokalemic patients, 8 patients (73%) presented with mild/grade 1 hypokalemia (3.0-3.2 mEq/L), 2 patients (18.18%) with moderate/grade 3 hypokalemia (2.5-2.9 mEq/L) and 1 patient (9.09%) with severe/grade 4 hypokalemia (<2.5 mEq/L) 8 (73%). Dose of capecitabine ranged between 1000-2000 mg/ m². Hypokalemia occurred after an average of 83.7 days of capecitabine administration. No cardiac or neuromuscular complications were noticed. Replacement of K⁺ was required in 6 patients (2 intravenous and 4 oral), while 2 patients (3.7%) required oral supplements >4 weeks. No patient had to stop capecitabine due to hypokalemia. One patient had persistent hypokalemia even after stopping capecitabine. Normalization of K⁺ levels was achieved in 91% of patients. Four patients were on K⁺ sparing diuretics for ascites and never presented with hypokalemia. Mean urine K⁺ was 28 mEq/L. Only 5.5% patients had ≥grade 3 hypokalemia in our study compared with 2% and 14% in two other studies. Conclusions: Although diarrhea being the most common cause of hypokalemia in patients on capecitabine, we postulate that hypokalemia may also be related to the effect of capecitabine on renal tubules suggested by the urine K⁺ in some patients. Due to potential complications, hypokalemia inpatients on capecitabine deserves special diagnostic and therapeutic attention.