Journal of Clinical Pharmacy and Therapeutics, 2014, 39, 328–330
doi: 10.1111/jcpt.12144
Case Report
Rhabdomyolysis associated with initiation of febuxostat therapy for hyperuricaemia in a patient with chronic kidney disease Y. Kang* MD, M. J. Kim* MD, H. N. Jang* MD, E. J. Bae* MD, S. Yun* MD, H. S. Cho* MD, S.-H. Chang*† MD and D. J. Park*† MD *Department of Internal Medicine,
and †Institute of Health Science, Gyeongsang National University Hospital, Jinju, South Korea
Received 23 January 2014, Accepted 27 January 2014
Keywords: chronic kidney disease, febuxostat, rhabdomyolysis
Febuxostat is a new non-purine selective inhibitor of xanthine oxidase for the treatment of hyperuricaemia in patients with gout.5 Febuxostat, approved in 2009, by the US FDA for the treatment of hyperuricaemia in patients with gout, is now recommended as the first-line pharmacological urate-lowering therapy for gout in the American College of Rheumatology guidelines.6 In clinical trials, 80 mg/day febuxostat was superior to the conventional dose of allopurinol (300 mg/day) in lowering the level of uric acid.1 There is no requirement for renal dosage-adjustment of febuxostat in patients with mild-to-moderate renal impairment.7 The most commonly reported adverse effects (AEs) of febuxostat are nausea, diarrhoea, arthralgia, headache, increased hepatic serum enzyme levels and rash.1,7 We know of no previous report of febuxostatassociated rhabdomyolysis. Here, we describe a case of rhabdomyolysis following the administration of febuxostat for hyperuricaemia in a patient with chronic kidney disease (CKD).
SUMMARY What is known and objective: Febuxostat is now recommended as the first-line pharmacological urate-lowering therapy for gout in the American College of Rheumatology guidelines. There is no case of rhabdomyolysis associated with febuxostat among reported side effects of the drug. Our objective is to report on a case of rhabdomyolysis associated with initiation of febuxostat in a patient with chronic kidney disease (CKD). Case summary: A 73-year-old male patient visited our emergency room due to progressive weakness in both lower extremities starting 3 days earlier. Ten days before presentation, his primary physician had changed his prescription from allopurinol to febuxostat (80 mg) because of poor control of uric acid levels. There was tenderness in both thighs. Initial creatinine kinase (CK) was 7652 U/L (0–170 U/L), and a bone scan using 99m Tc-HDP revealed strong uptake in soft tissues in both thighs and buttocks. Electromyography (EMG) and nerve conduction velocity (NCV) showed abnormal spontaneous activities (ASA), suggesting myopathy, not nerve damage. On day 7 of admission, after conservative management and febuxostat withdrawal, he could walk on the ward. He is being followed in our clinic as an outpatient with no sequelae. What is new and conclusion: This report is first case of rhabdomyolysis associated with initiation of febuxostat. Febuxostat should be withdrawn when rhabdomyolysis is confirmed.
DETAILS OF THE CASE A 73-year-old male patient with stage 3 CKD visited our emergency room due to progressive weakness in both lower extremities starting 3 days earlier. He could barely move his legs and could not walk by himself. He had suffered from chronic tophaceous gout for 40 years. His medical history included hyperlipidaemia, stable angina pectoris and hypertension. He had been taking allopurinol (200 mg/day), colchicine (06 mg/ day), rosuvastatin (10 mg/day), aspirin (100 mg/day), losartan (50 mg/day) and diltiazem (180 mg/day) for several years without changes. Ten days before the present admission, his primary physician had changed the prescription from allopurinol to febuxostat (80 mg/day) because of poor control of serum uric acid. He denied intake of other drugs except those listed above. He also denied smoking and analcohol consumption and was unemployed. He did not present with any upper respiratory symptoms or signs including cough, sore throat, fever or rhinorrhoea. He also had no history of excessive physical activity. Upon physical examination in the emergency room, his blood pressure was 140/70 mmHg, his pulse rate was 70 beats/min, his breathing rate was 20/min, and his body temperature was 362°C. His conjunctivae were not anaemic and sclerae were not icteric. There was no palpable lymphadenopathy on a neck examination. No skin lesion was found anywhere on his body. Pretibial pitting oedema was not detected. There were several tophi on several joints of both hands and feet. Tenderness in both thighs was detected. His muscle power in both lower extremities decreased to grade III/V, whereas it was normal in both upper extremities.
WHAT IS KNOWN AND OBJECTIVE The natural course of gout is variable, from asymptomatic hyperuricaemia to acute gouty attack, intercritical gout and advanced gout presenting with tophi, urolithiasis, chronic erosive arthritis and gouty nephropathy.1 Above all, it is known that control of hyperuricaemia, by drugs and/or life-style modification, is important for preventing advanced or acute gout attacks.1,2 Allopurinol, a non-selective xanthine oxidase inhibitor with a purine-like structure, is prescribed widely for the management of hyperuricaemia despite the occurrence of allopurinol hypersensitivity syndrome, occurring in ~2% of patients. This complication, associated with a 20% mortality rate, has been tolerated because of the absence of other pharmacological options.3,4 Correspondence: Dong Jun Park, MD, Department of Internal MedicineSchool of Medicine Gyeongsang University, 816 Beongil 15 Jinju-daero, Jinju, Gyeongnam, South Korea. Tel.: 055-750-8739; fax: 055-758-9122; e-mail: [email protected]
© 2014 John Wiley & Sons Ltd
328
Y. Kang et al.
Febuxostat-associated rhabdomyolysis
Fig. 1. The change of serum creatinine kinase (CK) after admission, D1 means on the day of admission. However, sensory function was intact. Deep tendon reflexes were normal. Neither ankle clonus nor the Babinski sign was detected in either leg. His laboratory results were haematocrit 36% (39–52%), haemoglobin 120 g/dL (13–17 g/dL), white blood cell count of 17 520/ mm3 (4000–10 000/mm3, neutrophils: 796%, lymphoid cells: 107%, monocytes: 94%) and platelets 232 000/mm3 (130 000– 400 000/mm3). Liver function tests were as follows: alkaline phosphatase 46 U/L (35–130 U/L), aspartate aminotransferase 278 U/L (0–37 U/L) and alanine aminotransferase 285 U/L (0–41 U/L). His initial blood urea nitrogen (BUN) was 508 mg/ dL (6–20 mg/dL), and serum creatinine level was 254 mg/dL (06–12 mg/dL). Initial creatinine kinase (CK) and lactate dehydrogenase (LDH) were 7652 U/L (0–170 U/L) and 711 U/L (135– 225 U/L) and decreased to 302 and 353 U/L, respectively, on day 21 after admission (Fig. 1). Urinalysis with micro showed blood (++), pro ( ) and RBC 1–4/HPF. The urine was positive for myoglobin. Electromyography (EMG) and nerve conduction velocity (NCV) showed abnormal spontaneous activities (ASA), suggesting myopathy, not nerve damage. This result was compatible with his muscular symptoms. A bone scan using 99mTc-HDP revealed that there were multiple, diffuse uptakes in the soft tissues of both thighs, both arms, the upper back and buttocks, consistent with rhabdomyolysis (Fig. 2). We considered that febuxostat was the cause of his muscular symptom, withdrew the febuxostat immediately and started conservative management, including saline hydration and furosemide injection. On day 7 of admission, his serum creatinine level returned to baseline (165 mg/dL) and he could walk on the ward. He was discharged on day 14 after admission. Although rosuvastatin was maintained during his hospital stay and he started colchicine (06 mg) again and allopurinol (150 mg/day) 1 month after discharge, his muscular symptoms did not recur. He is being followed in our clinic as an outpatient with no recurrence of rhabdomyolysis at 1 year, maintaining his previous medications, as described above. Febuxostat is generally well tolerated, with adverse effects similar to those of the placebo and allopurinol. In a multicenter, controlled trial, the most common treatment-related AEs were liver enzyme elevations (66% and 46% for 40 and 80 mg/d, respectively), nausea (11% and 13% for 40 and 80 mg/d, respectively), arthralgia (11% and 07% for 40 and 80 mg/d, respectively) and rash (05% and 16% for 40 and 80 mg/d, respectively).1 A meta-analysis also revealed that febuxostat was well tolerated, and AEs included diarrhoea, headache and
Fig. 2. Bone scan using 20 m Ci of Tc-99 m HDP to show hot uptake in soft tissue of both thigh and buttocks compatible rhabdomyolysis. musculoskeletal and joint-related symptoms.8 This tolerability and similar AEs were also described in gout patients older than 65 years of age; the most frequently reported AEs were diarrhoea, upper respiratory tract infection and musculoskeletal and connective tissue signs and symptoms.9 Although musculoskeletal AEs were reported, those were not severe enough to restrict patient movement, unlike our patient. Also, there has been no report of elevated muscle enzymes. Febuxostat can be taken regardless of food intake or antacids. It is mostly metabolized in the liver, with ~45% excreted in the stool, and the remaining 49% (
doi: 10.1111/jcpt.12144
Case Report
Rhabdomyolysis associated with initiation of febuxostat therapy for hyperuricaemia in a patient with chronic kidney disease Y. Kang* MD, M. J. Kim* MD, H. N. Jang* MD, E. J. Bae* MD, S. Yun* MD, H. S. Cho* MD, S.-H. Chang*† MD and D. J. Park*† MD *Department of Internal Medicine,
and †Institute of Health Science, Gyeongsang National University Hospital, Jinju, South Korea
Received 23 January 2014, Accepted 27 January 2014
Keywords: chronic kidney disease, febuxostat, rhabdomyolysis
Febuxostat is a new non-purine selective inhibitor of xanthine oxidase for the treatment of hyperuricaemia in patients with gout.5 Febuxostat, approved in 2009, by the US FDA for the treatment of hyperuricaemia in patients with gout, is now recommended as the first-line pharmacological urate-lowering therapy for gout in the American College of Rheumatology guidelines.6 In clinical trials, 80 mg/day febuxostat was superior to the conventional dose of allopurinol (300 mg/day) in lowering the level of uric acid.1 There is no requirement for renal dosage-adjustment of febuxostat in patients with mild-to-moderate renal impairment.7 The most commonly reported adverse effects (AEs) of febuxostat are nausea, diarrhoea, arthralgia, headache, increased hepatic serum enzyme levels and rash.1,7 We know of no previous report of febuxostatassociated rhabdomyolysis. Here, we describe a case of rhabdomyolysis following the administration of febuxostat for hyperuricaemia in a patient with chronic kidney disease (CKD).
SUMMARY What is known and objective: Febuxostat is now recommended as the first-line pharmacological urate-lowering therapy for gout in the American College of Rheumatology guidelines. There is no case of rhabdomyolysis associated with febuxostat among reported side effects of the drug. Our objective is to report on a case of rhabdomyolysis associated with initiation of febuxostat in a patient with chronic kidney disease (CKD). Case summary: A 73-year-old male patient visited our emergency room due to progressive weakness in both lower extremities starting 3 days earlier. Ten days before presentation, his primary physician had changed his prescription from allopurinol to febuxostat (80 mg) because of poor control of uric acid levels. There was tenderness in both thighs. Initial creatinine kinase (CK) was 7652 U/L (0–170 U/L), and a bone scan using 99m Tc-HDP revealed strong uptake in soft tissues in both thighs and buttocks. Electromyography (EMG) and nerve conduction velocity (NCV) showed abnormal spontaneous activities (ASA), suggesting myopathy, not nerve damage. On day 7 of admission, after conservative management and febuxostat withdrawal, he could walk on the ward. He is being followed in our clinic as an outpatient with no sequelae. What is new and conclusion: This report is first case of rhabdomyolysis associated with initiation of febuxostat. Febuxostat should be withdrawn when rhabdomyolysis is confirmed.
DETAILS OF THE CASE A 73-year-old male patient with stage 3 CKD visited our emergency room due to progressive weakness in both lower extremities starting 3 days earlier. He could barely move his legs and could not walk by himself. He had suffered from chronic tophaceous gout for 40 years. His medical history included hyperlipidaemia, stable angina pectoris and hypertension. He had been taking allopurinol (200 mg/day), colchicine (06 mg/ day), rosuvastatin (10 mg/day), aspirin (100 mg/day), losartan (50 mg/day) and diltiazem (180 mg/day) for several years without changes. Ten days before the present admission, his primary physician had changed the prescription from allopurinol to febuxostat (80 mg/day) because of poor control of serum uric acid. He denied intake of other drugs except those listed above. He also denied smoking and analcohol consumption and was unemployed. He did not present with any upper respiratory symptoms or signs including cough, sore throat, fever or rhinorrhoea. He also had no history of excessive physical activity. Upon physical examination in the emergency room, his blood pressure was 140/70 mmHg, his pulse rate was 70 beats/min, his breathing rate was 20/min, and his body temperature was 362°C. His conjunctivae were not anaemic and sclerae were not icteric. There was no palpable lymphadenopathy on a neck examination. No skin lesion was found anywhere on his body. Pretibial pitting oedema was not detected. There were several tophi on several joints of both hands and feet. Tenderness in both thighs was detected. His muscle power in both lower extremities decreased to grade III/V, whereas it was normal in both upper extremities.
WHAT IS KNOWN AND OBJECTIVE The natural course of gout is variable, from asymptomatic hyperuricaemia to acute gouty attack, intercritical gout and advanced gout presenting with tophi, urolithiasis, chronic erosive arthritis and gouty nephropathy.1 Above all, it is known that control of hyperuricaemia, by drugs and/or life-style modification, is important for preventing advanced or acute gout attacks.1,2 Allopurinol, a non-selective xanthine oxidase inhibitor with a purine-like structure, is prescribed widely for the management of hyperuricaemia despite the occurrence of allopurinol hypersensitivity syndrome, occurring in ~2% of patients. This complication, associated with a 20% mortality rate, has been tolerated because of the absence of other pharmacological options.3,4 Correspondence: Dong Jun Park, MD, Department of Internal MedicineSchool of Medicine Gyeongsang University, 816 Beongil 15 Jinju-daero, Jinju, Gyeongnam, South Korea. Tel.: 055-750-8739; fax: 055-758-9122; e-mail: [email protected]
© 2014 John Wiley & Sons Ltd
328
Y. Kang et al.
Febuxostat-associated rhabdomyolysis
Fig. 1. The change of serum creatinine kinase (CK) after admission, D1 means on the day of admission. However, sensory function was intact. Deep tendon reflexes were normal. Neither ankle clonus nor the Babinski sign was detected in either leg. His laboratory results were haematocrit 36% (39–52%), haemoglobin 120 g/dL (13–17 g/dL), white blood cell count of 17 520/ mm3 (4000–10 000/mm3, neutrophils: 796%, lymphoid cells: 107%, monocytes: 94%) and platelets 232 000/mm3 (130 000– 400 000/mm3). Liver function tests were as follows: alkaline phosphatase 46 U/L (35–130 U/L), aspartate aminotransferase 278 U/L (0–37 U/L) and alanine aminotransferase 285 U/L (0–41 U/L). His initial blood urea nitrogen (BUN) was 508 mg/ dL (6–20 mg/dL), and serum creatinine level was 254 mg/dL (06–12 mg/dL). Initial creatinine kinase (CK) and lactate dehydrogenase (LDH) were 7652 U/L (0–170 U/L) and 711 U/L (135– 225 U/L) and decreased to 302 and 353 U/L, respectively, on day 21 after admission (Fig. 1). Urinalysis with micro showed blood (++), pro ( ) and RBC 1–4/HPF. The urine was positive for myoglobin. Electromyography (EMG) and nerve conduction velocity (NCV) showed abnormal spontaneous activities (ASA), suggesting myopathy, not nerve damage. This result was compatible with his muscular symptoms. A bone scan using 99mTc-HDP revealed that there were multiple, diffuse uptakes in the soft tissues of both thighs, both arms, the upper back and buttocks, consistent with rhabdomyolysis (Fig. 2). We considered that febuxostat was the cause of his muscular symptom, withdrew the febuxostat immediately and started conservative management, including saline hydration and furosemide injection. On day 7 of admission, his serum creatinine level returned to baseline (165 mg/dL) and he could walk on the ward. He was discharged on day 14 after admission. Although rosuvastatin was maintained during his hospital stay and he started colchicine (06 mg) again and allopurinol (150 mg/day) 1 month after discharge, his muscular symptoms did not recur. He is being followed in our clinic as an outpatient with no recurrence of rhabdomyolysis at 1 year, maintaining his previous medications, as described above. Febuxostat is generally well tolerated, with adverse effects similar to those of the placebo and allopurinol. In a multicenter, controlled trial, the most common treatment-related AEs were liver enzyme elevations (66% and 46% for 40 and 80 mg/d, respectively), nausea (11% and 13% for 40 and 80 mg/d, respectively), arthralgia (11% and 07% for 40 and 80 mg/d, respectively) and rash (05% and 16% for 40 and 80 mg/d, respectively).1 A meta-analysis also revealed that febuxostat was well tolerated, and AEs included diarrhoea, headache and
Fig. 2. Bone scan using 20 m Ci of Tc-99 m HDP to show hot uptake in soft tissue of both thigh and buttocks compatible rhabdomyolysis. musculoskeletal and joint-related symptoms.8 This tolerability and similar AEs were also described in gout patients older than 65 years of age; the most frequently reported AEs were diarrhoea, upper respiratory tract infection and musculoskeletal and connective tissue signs and symptoms.9 Although musculoskeletal AEs were reported, those were not severe enough to restrict patient movement, unlike our patient. Also, there has been no report of elevated muscle enzymes. Febuxostat can be taken regardless of food intake or antacids. It is mostly metabolized in the liver, with ~45% excreted in the stool, and the remaining 49% (
