Abstract
The purpose of this feature is to heighten awareness of specific adverse drug reactions (ADRs), discuss methods of prevention, and promote reporting of ADRs to the FDA's medWatch program (800-FDA-1088). If you have reported an interesting preventable ADR to medWatch, please consider sharing the account with our readers. Write to Dr. Shuster at ISMP, 1800 Byberry Road, Suite 810, Huntingdon Valley, PA 19006 (call 215-947-7797; fax 215-914-1492; e-mail:
Myalgia and Elevated Creatine Kinase Associated with Rosiglitazone
A 42-year-old man with a 6-year history of diabetes was being treated with metformin, glyburide, and once-daily aspirin. Rosiglitazone (Avandia) was added to this regimen about 5 months before the patient had some routine lab work performed. At this time, the serum creatine kinase (CK) was measured to be 555 units/L (normal, 0 to 160 units/L). The patient had increased CK levels measured two more times over the next 3 weeks, and they continued to climb. By week 4, the patient was complaining of myalgia, and the CK was 1,671 units/L. He was referred to an internal medicine clinic, where a drug-induced suspicion was considered; however, the workup showed nothing, so the rosiglitazone as well as all other therapy were continued. Ten weeks later, the patient continued to complain of myalgia, and the rosiglitazone was finally stopped. All muscle symptoms resolved within 3 weeks. The CK levels fell to the mid-400 range over the same period of time.
When the patient was given rosiglitazone almost 3 years later, he developed muscle pain within 14 days, and his CK level went up to 2,195 units/L. The drug was stopped again, and the pain resolved within 2 weeks with subsequent lowering of the CK levels.
The authors point out that there are only five previously reported cases of elevated CK, myalgia, or rhabdomyolysis associated with the thiazolidinediones in the literature.
Kennie N, Antoniou T, Berger P. Elevated creatine kinase and myalgia in a patient taking rosiglitazone. Ann Pharmacother. 2007;41:521-525.
Diltiazem-Induced Eosinophilic Pleural Effusion
A 68-year-old woman came to her local emergency department (ED) with a month-long complaint of left-sided back pain, slight dyspnea, and a nonproductive cough. Her only prior medical history was hypertension of 3 to 4 years' duration. She had been on clonidine until 2 months prior to admission when diltiazem 60 mg twice daily was added.
Upon physical exam in the ED, all vital signs were normal, and the only objective finding was “dullness on percussion and diminished breath sounds at the left lung base.” The lab results revealed a normal white blood cell (WBC) count of 8.5 × 103/mm3 (4 to 10 × 103/mm3), but the eosinophil count was highly elevated to 20% (0% to 3%). The erythrocyte sedimentation rate (ESR) and C-reactive protein were also elevated. All other lab results were within normal limits. Chest radiography showed a small pleural effusion on the left side. Upon aspiration, the pleural fluid was nonhemorrhagic and was dominated by 60% eosinophils. No malignant cells were found and all stains and cultures were negative for infectious organisms.
The patient's diltiazem and clonidine were discontinued, and the patient's symptoms and labs quickly returned to normal. The patient was restarted on just clonidine and was discharged from the hospital with no sequelae. The authors' literature search did not find any other reports of pleural effusion related to diltiazem or other calcium channel blockers.
Raptis L, Pappas G, Katsanou A, Koutsouka F, Petrakis D, Akritidis N. Diltiazem-induced eosinophilic pleural effusion. Pharmacotherapy. 2007;27:600-602.
Reversible Leukoencephalopathy with Carboplatin
A 53-year-old woman was being treated for stage IV adenocarcinoma of the left lung. She underwent five cycles of gemcitabine and cisplatin every 3 weeks, where she received cisplatin on day 1 and gemcitabine on day 1 and 8. Since the cumulative dose of cisplatin reached 350 mg/m2, carboplatin was used for the sixth course of treatment. On day 7 (6 days after receiving carboplatin for the first time), the patient developed fever, severe headache, abdominal pain, and a generalized seizure. She exhibited sudden cortical blindness and was admitted to the intensive care unit. Lab testing yielded grade 4 neutropenia of 424 cells/mm3 (2,500 to 6,000 cells/mm3) and a moderate thrombocytopenia of 106 x 103/mm3 (150 to 450 × 103/mm3). A computed axial tomography (CAT) scan of the brain demonstrated “bilateral occipital white matter edema,” which was thought to be nonmetastatic disease. Regular magnetic resonance imaging (MRI) and a specific type of MRI called fluid attenuation inversion recovery were consistent with a reversible posterior leukoencephalopathy syndrome (RPLS). The patient was treated with supportive therapies, antiepileptics, and corticosteroids and improved within a few days. Within 4 weeks, a repeat MRI showed that she had made a complete recovery.
The authors discuss the fact that RPLS is a known potential complication of cisplatin therapy. Apparently, it occurs immediately at the end of therapy or shortly thereafter, usually when the cumulative dose exceeds 200 mg/m2. This patient developed the leukoencephalopathy 6 days after receiving carboplatin, a full 4 weeks after the final cisplatin dose. This may be the first such report of RPLS associated with carboplatin.
Vieillot S, Pouessel D, de Champfleur NM, Becht C, Culine S. Reversible posterior leukoencephalopathy syndrome after carboplatin therapy. Ann Oncology. 2007;18:608-609.
Renal Tubular Acidosis with Oxaliplatin
A 53-year-old man with a 3-year history of Dukes B adenocarcinoma of the transverse colon, which was treated with surgery and adjuvant 5-fluorouracil therapy, developed a single liver metastasis that was identified by MRI and positron-emitting tomography (PET scan). He was started on oxaliplatin (Eloxatin) and capecitabine (Xeloda) in 21-day cycles as neo-adjuvant therapy. On day 14 of the second cycle, the gentleman was admitted to the hospital complaining of anorexia, nausea, polyuria, and lethargy for the prior 7 days. His oral intake had been good, as he was drinking 2 to 3 L of lassi daily. (This yogurt-based beverage may be fairly acidic and is quite common throughout India). On examination, he was dehydrated, flushed, and tachypneic. An arterial blood gas revealed severe metabolic acidosis with a pH of 7.15 (7.35 to 7.45) with partial respiratory compensation. The arterial bicarbonate was very low at 7.1 mEq/L (21 to 28 mEq/L). The serum potassium was low at 3.3 mEq/L (3.5 to 5 mEq/L), and the serum chloride was elevated to 113 mEq/L (97 to 107 mEq/L). The serum phosphate was also decreased to 1.7 mg/dL (2.5 to 4.5 mg/dL). The anion gap was normal.
Laboratory evaluation of the urine indicated moderate ketonuria, while the blood glucose was 320 mg/dL (random less than 200 mg/dL). The patient was receiving metformin and simvastatin, but there was no increase in the serum lactate level (which eliminated lactic acidosis). Examination of his urinary electrolytes, along with the other lab tests, led to the diagnosis of proximal/type 2 renal tubular acidosis, based primarily on the hypokalemic, hyperchloremic metabolic acidosis.
The patient required high quantities of intravenous potassium over the next 4 days and made an excellent recovery. Sodium bicarbonate was not administered.
The authors believe that this is the first case of renal tubular acidosis associated with oxaliplatin. They state that this agent is gaining increasing use and that we must remain vigilant for this possible ADR.
Linch M, Cunningham D, Mingo O, Stiles A, Farquhar-Smith WP. Renal tubular acidosis due to oxaliplatin. Ann Oncology. 2007;18:805-806.
Oxcarbazepine and Pancytopenia
A 40-year-old woman with a history of high blood pressure and bipolar disorder presented to her local ED complaining of a pruritic rash, fever, chills, sweats, susbsternal chest pain, loose bowels, and generalized weakness. On physical exam, she was febrile at 101.6°F, and her blood pressure was 84/50 mm Hg. She exhibited a generalized maculopapular rash and expiratory wheezes were detected. The pertinent lab findings included leukopenia of 2.2 × 103 cells/mm3 and thrombocytopenia with a platelet count of 80 × 103/mm3.
The patient had been on a stable drug regimen that included sertraline, fosinopril, oral contraceptive, and clonazepam for several months. She smoked 1.5 packs of cigarettes daily and was started on oxcarbazepine (Trileptal) just 5 days before her presentation to the ED. The oxcarbazepine was dosed at 300 mg daily for 3 days and then increased to 300 mg twice daily on day 4.
The patient was presumed to have had an allergic reaction to the new medication and the oxcarbazepine was discontinued and IV corticosteroids were started. The fosinopril was halted because of persistent low blood pressure readings. Day 2 of this hospitalization showed a further drop in the WBC and platelet counts. A complete infectious workup and comprehensive metabolic tests were all normal. By hospital day 4, the lab values returned to normal.
The authors point out that oxcarbazepine is structurally related to carbamazepine, which is well known to cause blood dyscrasias. This new drug does not have previous reports of aplastic anemia or agranulocytosis. They state that they found one case report that associated oxcarbazepine with thrombocytopenia.
It is also possible that this patient suffered a case of antiepileptic hypersensitivity syndrome. The eosinophil count in this patient did reach 9.8% on the day of admission. We must be aware that oxcarbazepine may rarely exhibit hematologic ADRs.
Calamaras MR, Stowe ZN, Newport DJ. Pancytopenia associated with the introduction of ozcarbazepine. J Clin Psychopharmacol. 2007;27:217-218.
Two Cases of Acute Laryngeal Dystonia Associated with Ziprasidone
A report highlights two cases of acute laryngeal dystonia associated with the use of intramuscular (IM) ziprasidone (Geodon); the following is a description of one of those cases.
A 51-year-old man presented to an ED in a state of manic psychosis. Because of verbal aggression, irritability, and the inability to redirect the patient, it was decided that an IM dose of ziprasidone 20 mg be administered. Within the first half hour, the gentleman had difficulty speaking and swallowing. He was noted to have stridor. A laryngoscopy was quickly performed, and it revealed pooled secretions but no edema or tongue enlargement. The exam was essentially normal and within 5 minutes of receiving an IM anticholinergic agent, diphenhydramine 50 mg, all symptoms resolved. He was admitted to the psychiatric inpatient unit and was continued on oral ziprasidone that was supplemented with oral diphenhydramine. He had no further sequelae.
The other case was of a very similar nature and involved a 21-year-old man who had a similar ADR within 20 minutes of receiving the same dose of ziprasidone. Acute dystonias are considered more common in young men.
The authors offer a brief discussion of acute dystonia, which is just one type of extrapyramidal side effect (EPS). As the next report demonstrates, atypical antipsychotics can cause EPS, but certainly at a much lower incidence compared to the older, traditional antipsychotic drug classes.
Mellacheruva S, Norton JW, Schweinfurth J. Atypical antipsychotic drug-induced acute laryngeal dystonia – 2 case reports. J Clin Psychopharmacol. 2007;27:206-207.
Extrapyramidal Side Effects with Atypical Antipsychotic Drugs used in Bipolar Disorder
A recently published review looked at the English literature from 1990 through December 1, 2005 dealing with any randomized controlled trials that evaluated the incidence of EPS in bipolar patients treated with “second-generation” or “atypical” antipsychotic drugs.
For many years, the only agents used in bipolar disorder were the mood stabilizers, primarily lithium and divalproex sodium, and the typical or older antipsychotic drugs. The second-generation antipsychotic (SGA) drugs now play a very large role in the therapy of bipolar disorder and many of these newer drugs have specific indications for the maintenance therapy of bipolar disorder or even for bipolar depression.
This excellent review reminds us that bipolar patients have always been more sensitive to EPS and that the newer antipsychotic agents may cause a fair amount of EPS in this patient population. We must be aware of the possibility of EPS with the second-generation agents and must counsel our patients and inpatient staff about this possibility. One of the reviewed studies states that “in the real-world setting, more than one-half of bipolar patients may experience SGA-induced EPS.”
Gentile S. Extrapyramidal adverse events associated with atypical antipsychotic treatment of bipolar disorder. J Clin Psychopharmacol. 2007;27:35-45.