Abstract
Keywords
Medicine-Related Problems No. 239
Hospitalization
A systematic review was conducted to investigate the prevalence, causes, and risk factors and to identify the most common medication classes involved in medicine-related problems leading to hospitalization in adult patients. The hospitalization rate due to medicine-related problems (12.1%) was higher than that associated with adverse drug reactions (7%) and adverse drug events (4.6%). Retrospective studies evaluating adverse drug reactions revealed a median prevalence rate of 1.47% (interquartile range = 1% to 6.26%) with a preventability rate ranging from 30% to 62.3%. Prospective studies evaluating adverse drug reactions reported higher prevalence rates (median = 12%; interquartile range = 5.89% to 28.9%) with preventability rates up to 78%. Retrospective studies evaluating adverse drug events reported a 5% prevalence rate, and prospective studies again had a higher median prevalence rate (12.4%; interquartile range = 3.75% to 22.9%), more severe cases (up to 16%), and greater preventability (up to 60%). The reported mean prevalence rates for medicine-related problems were similar between retrospective and prospective studies (12.6% [interquartile range = 10.8% to 13.3%] and 11.6% [interquartile range = 6.4% to 24.1%], respectively). Severe cases of medicine-related problems ranged from 7.4% to 73% and had a high preventability rate (up to 78%). Risk factors that contributed to medicine-related problems included older age, polypharmacy, female gender, depression, education, cohabitation, and immobilization.
The authors concluded that hospitalization resulting from medicine-related problems represented a major concern in the studies evaluated. The main causes of hospitalization included adverse drug reactions and noncompliance. Older age and polypharmacy were highly represented among hospitalizations due to medicine-related problems.
Medication-Related Problems [Medication-Related Problems]
Al Hamid A et al (A Al Hamid, Department of Pharmacy, University of Hertfordshire, College Lane Campus, Hatfield, Hertfordshire AL 10 9AB, UK; e-mail:
Paliperidone No. 240
Pisa Syndrome (First Report*)
An 18-year-old man developed a dystonic syndrome with truncal rigidity and flexion to the right after approximately 12 months of treatment with paliperidone (12 mg daily) for schizophrenia. No concurrent medications were reported. Laboratory analyses revealed normal complete blood count, serum biochemistry, thyroid function, and chest roentgenogram. Brain magnetic resonance imaging revealed no significant findings. Treatment included discontinuation of paliperidone and led to gradual improvement of symptoms over the subsequent 7 days. Paliperidone was not restarted, and treatment for schizophrenia was continued and maintained with aripiprazole (5 mg twice daily) and trihexyphenidyl (4 mg daily).
The authors concluded that this was the first report of paliperidone-induced Pisa syndrome. Proposed mechanisms included dopaminergic–cholinergic imbalance in the brain and dysfunction of neurotransmitters such as serotonin and norepinephrine.
Paliperidone [“Invega”]
Pan PY et al (NS Tzeng, Department of Psychiatry, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan; e-mail:
Risperidone No. 241
Tardive Dyskinesia
A 35-year-old pregnant woman developed orofacial dyskinetic movements 7 days after initiating risperidone for the treatment of bipolar disorder-1. No concurrent medications were reported. Risperidone (1 mg daily) was used in the past and discontinued after 1 month due to the development of extrapyramidal symptoms. Additional prior treatments for bipolar disorder-1 included imipramine (200 mg daily), chlorpromazine (200 mg daily), haloperidol (10 mg daily), antidepressant therapy, and maintained with lithium (up to 1500 mg daily). Lithium was discontinued prior to contraception. After contraception, a manic episode with psychotic symptoms occurred for which risperidone (2 mg daily) was restarted after failure with quetiapine (up to 600 mg daily) and olanzapine (up to 20 mg daily). Tardive dyskinesia was objectively evaluated with the Abnormal Involuntary Movement Scale (total score 10) with moderate severity in perioral and facial areas. Treatment included discontinuation of risperidone and addition of lithium at the onset of the second trimester. Manic symptoms resolved and ultrasonography revealed no fetal anomalies; however, symptoms of tardive dyskinesia did not resolve. Additional treatment included administration of clonazepam (4 mg daily), which was discontinued due to sedation, and vitamin E (400 mg to 600 mg daily). Symptoms did not improve and were present until delivery occurred. After delivery, symptoms gradually improved over the subsequent 2 months, and vitamin E and lithium were increased (1200 mg and 900 mg daily, respectively). After 6 months, only mild orofacial dyskinesia remained with worsening during emotional excitement and sleep deprivation.
The authors concluded that this case of tardive dyskinesia was induced by risperidone. The authors proposed that pregnancy heightened sensitivity to risperidone via a hyperestrogenic state and effects on the central dopaminergic system.
Risperidone [“Risperdal”]
Chatterjee B & Sharan P (B Chatterjee, Department of Psychiatry, All India Institute of Medial Sciences, New Delhi 110029, India; e-mail:
Nephrotoxic Medications No. 242
Acute Kidney Injury
In a retrospective cohort study, pediatric patients exposed to nephrotoxic medications were identified to further assess 6-month outcomes of chronic kidney disease. High nephrotoxic medication exposure was identified as receiving an intravenous aminoglycoside for at least 3 days or the simultaneous administration of at least 3 nephrotoxic medications for at least 1 day. Chronic kidney disease was defined as having markers of kidney damage or abnormal kidney function (estimated glomerular filtration rate = <60 mL/min/1.73 m2). A total of 100 patients with acute kidney injury from nephrotoxic medication exposure were identified, of which the majority had (n = 99) preevent serum creatinine data. The mean estimated glomerular filtration rate prior to acute kidney injury was 118.2 mL/min/1.73 m2. The mean age of the patients at the time of acute kidney injury was 9.3 years. The majority of patients survived to discharge (n = 92) with a mean estimated glomerular filtration rate at discharge of 105.1 mL/min/1.73 m2. At the 6-month follow-up period, 80 patients were monitored via service in one of the hospital clinics. The mean estimated glomerular filtration rate at follow-up was 113.8 mL/min/1.73 m2. Proteinuria was assessed in 35 patients, of which 68.5% (n = 24) had a urine protein to creatinine ratio > 3 mg/mg. Treatment with an antihypertensive for hypertension was documented in 29/77 patients. Approximately 33.7% of the patients had chronic kidney disease and 36.3% were considered at risk for chronic kidney disease with hypertension. Chronic kidney injury, hypertension, and proteinuria were more common in the acute kidney injury cohort study group than the control group.
The authors concluded that in this study approximately 70% of patient who developed acute kidney injury due to exposure to nephrotoxic medications had residual kidney damage when assessed 6 months after the initial event.
Nephrotoxic Medications [“Aminoglycosides,” “Acyclovir,” “Amphotericin,” “Cisplatin,” “Foscarnet”]
Menon S et al (S Menon, Center for Acute Care Nephrology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45202; e-mail:
Ceftaroline No. 243
Neutropenia With Off-Label Use
A 46-year-old male patient was rehospitalized with significant neutropenia approximately 3 weeks after treatment was switched from vancomycin to ceftaroline (600 mg every 8 hours) for the treatment of methicillin-resistant Staphylococcus aureus septic arthritis. The use of the antibiotic was determined to be off-label based on the dosage and duration of the antibiotic. Prior to the initiation of ceftaroline, the white blood cell count was 8.3 × 103 cells/mL, with 80% segmented neutrophils and 0% eosinophils. On readmission, the white blood cell count had decreased to 1.3 × 103 cells/mL, with 2.6% segmented neutrophils and 14% eosinophils. Treatment included the discontinuation of ceftaroline and initiation of daptomycin to complete the 6-week course of therapy. Nine days later, the white blood cell count was 6.5 × 103 cells/mL, with 56.6% segmented neutrophils. The patient was discharged without further event.
The authors concluded that this patient experienced profound neutropenia associated with the off-label use of ceftaroline. According to the Naranjo causality scale, this reaction was rated as probable in relation to the drug therapy.
Ceftaroline [“Teflaro”]
Yam FK & Kwan BK (FK Yam, University of California San Diego, Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, CA; e-mail:
Antithyroid Drugs No. 244
Hepatotoxicity in Hyperthyroidism Patients
The incidence and nature of hepatotoxicity was evaluated in a cohort study of 71 379 hyperthyroidism patients receiving an antithyroid agent (eg, propylthiouracil, methimazole, or carbimazole) over a 5-year study period. A total of 24 941 patients received propylthiouracil, and 46 438 received methimazole/carbimazole therapy. Hepatic outcomes were defined as cases of cholestasis, noninfectious hepatitis, acute liver failure, and liver transplant due to drug therapy. The mean age of the cohort group was 41.3 years, and the majority were female (78.5%). Median follow-up was 173 and 208 days in the propylthiouracil and methimazole/carbimazole groups, respectively. The incidence of hepatitis was the greatest in both groups with 1.19/1000 person-years in the propylthiouracil group and 3.17/1000 person-years in the methimazole/carbimazole group. Rates for acute liver failure were 0.68 and 0.32/1000 person-years, respectively. Rates for cholestasis were 0.06 and 0.24/1000 person-years, respectively. There were no cases of liver transplantation noted in the study. Factors associated with hepatotoxicity included older age (more than 65 years). For propylthiouracil use, females were associated with a 4.8-fold increase in the incidence rate of hepatitis when compared to males. Methimazole/carbimazole use was associated with a 2.89-fold increased risk of hepatitis compared with propylthiouracil use. However, there were no differences between the 2 groups for incidence of cholestasis or acute liver failure and was not related to increased risk of developing this type of hepatotoxicity.
The authors concluded that when compared to propylthiouracil use, the use of methimazole/carbimazole produced a higher risk of developing hepatitis. However, the risks for developing cholestasis and acute liver injury were similar between the therapies.
Antithyroid Drugs [“Propylthiouracil,” “Methimazole,” “Carbimazole”]
Wang MT et al (MT Wang, 9F, No. 161, Section 6, Min-Chuan East Road, Taipei 114, Taiwan; e-mail:
Levofloxacin, Simvastatin No. 245
Rhabdomyolysis
A 70-year-old male inpatient developed diffuse extremity muscle weakness approximately 8 days after starting intravenous levofloxacin therapy. Routine laboratory exams revealed elevated aspartate aminotransferase (129 U/L), alanine aminotransferase (113 U/L), and creatine kinase (2521 U/L) without myocardial injury. Levofloxacin was initiated at 500 mg daily but increased to twice daily in the hospital. Concurrent medications on admission included simvastatin (increased to 80 mg/day 20 days prior to admission), metoprolol (25 mg twice daily), aspirin (100 mg/day), digitoxin (0.07 mg/day), and furosemide (40 mg/day). Repeat testing reveled elevations in creatine kinase (31 539 U/L) and liver function tests (aspartate aminotransferase = 486 U/L; alanine aminotransferase = 182 U/L). Treatment included the discontinuation of simvastatin and levofloxacin and the initiation of intravenous crystalloid hypotonic solution (100 mL/h). Creatine kinase levels further increased to a peak of 159 450 U/L, and severe generalized weakness, including respiratory insufficiency, required intensive care unit therapy. The patient was discharged on hospital day 26 after symptoms improved. Simvastatin was restarted without further event.
The authors concluded that this patient developed severe acute rhabdomyolysis associated with an increase of levofloxacin dosage while taking simvastatin. According to the Naranjo causality assessment, this reaction was rated as probable in relation to drug therapy.
Levofloxacin [“Levaquin”]
Simvastatin [“Zocor”]
Paparoupa MM (MM Paparoupa, Department of Pulmonary Diseases, General Hospital Kassel, Kassel School of Medicine, Monchebergstraße 41-43, 53125 Kassel, Germany; e-mail:
Amphotericin B (Liposomal) No. 246
Pseudohyperphosphatemia in Pediatric Patients
A retrospective study was performed to evaluate the incidence of pseudohyperphosphatemia associated with the use of liposomal amphotericin B therapy in pediatric patients. Pseudohyperphosphatemia was defined as serum phosphorus concentrations above the age-adjusted upper limit of normal with maintenance of a normal calcium concentration. Secondary objectives evaluated the influence of dose either as low dose (≤5 mg/kg/day) or high dose (>5 mg/kg/day). A total of 140 regimens of the drug were administered to 79 patients over a 2-year study period. Of these, 68 regimens were excluded and 72 regimens in 47 patients were included in the analysis. More than half of the patients (68%) received a single regimen. The median age of the patients was 2.5 years (range = 0.02-16 years). The incidence rate of pseudohyperphosphatemia was 50% with a mean time to onset of 8.3 days after the initiation of therapy. In 40 of the cases, the event occurred within 5 days of starting therapy. When patient and therapy factors were evaluated, significant differences were observed in those patients who developed pseudohyperphosphatemia when compared to those who did not for patient mean age and weight, and mean dose when expressed in milligrams. However, when the dosage was compared as mg/kg, there was no significant differences between the 2 groups. In addition, when a multivariate generalized estimating equation was used to further evaluate which possible variables may be predictive, there was no significant association with any of the evaluated variables, including patient age and weight, duration of therapy, and the concurrent use of medications known to affect serum phosphorus.
The authors concluded that in this study, approximately half of pediatric patients receiving liposomal amphotericin B developed pseudohyperphosphatemia.
Amphotericin B, Liposomal [“AmBisome”]
Miller MM et al (MM Miller, Department of Pharmacy, Clinical and Administrative Sciences, University of Oklahoma College of Pharmacy, Oklahoma City, OK; e-mail:
Antiretrovirals No. 247
Peripheral Neuropathy in Pediatric Patients
In a cross-sectional study, the prevalence of antiretroviral associated peripheral neuropathy was assessed in 174 South African HIV-infected pediatric patients aged 5 to 15 years. Peripheral neuropathy was assessed as neuropathy symptom score of at least 5 and a neuropathy disability score of at least 3. Symptoms of peripheral neuropathy reported via neuropathy symptom score for 48 children (28%) with the most frequently observed symptoms including numbness, burning, and tingling. Neuropathy symptom score classified neuropathy was classified as mild, moderate, and severe in 56%, 29%, and 15%, of the cases, respectively. Symptoms of peripheral neuropathy reported via neuropathy disability score for 25 children (14%) with the most frequently observed symptoms including reduced temperature sensation and abnormal ankle reflexes. Cases were classified as mild and moderate in 76% and 14% of the cases, respectively. Peripheral neuropathy was established as definitive in 24% of the cases and as possible in 9.2% based on the scoring criteria. Risk factors associated with peripheral neuropathy included not taking cotrimoxazole prophylaxis (adjusted odds ratio = 2.2; 95% confidence interval = 1.1-4.8, P = .04) and didanosine use (adjusted odds ratio = 12; 95% confidence interval = 1.3-116, P = .03).
The authors concluded that this study revealed a 24% prevalence of peripheral neuropathy among HIV-infected pediatric patients receiving antiretroviral therapy.
Antiretrovirals [“Didanosine,” “Stavudine,” “Zidovudine”]
Peters RPH et al (RPH Peters, Anova Health Institute, Johannesburg and Tzaneen, 21A Peace Street, PO Box 2243, Tzaneen 0850, South Africa; e-mail:
Antiretrovirals No. 248
Alopecia in HIV-Infected Patients
A literature review to identify alopecia related to antiretroviral therapy in HIV-infected patients reveled a total of 16 articles that met inclusion criteria. Of these, 11 were case reports, 3 were case series, and 3 were observational cohort studies. A total of 46 patients with hair loss related to antiretroviral therapy were identified. The most commonly cited antiretroviral class in this review was protease inhibitors (73.9%), followed by nucleoside reverse transcriptase inhibitors (17.4%) and combination therapy (8.7%). Indinavir was the most frequently cited protease inhibitor, followed by lopinavir/ritonavir. Of the cases that reported gender information, the majority were male (75%), with a mean age of 38 years (range = 26-62 years). Median time to onset of development of alopecia after initiation of antiretroviral therapy was 2.5 months (range = 2 weeks to 2 years), but in most cases, onset was within 6 months. Total hair loss of the scalp was identified in most cases and in some cases involved hair loss on the body. Severity was ranked as severe in 10 cases. Treatment included discontinuation of the suspected causative agent in the majority of reports (67.4%) with frequent substitution to another drug. Alopecia was reversible in 26 of the cases reported. No instances of rechallenge were documented. The authors noted that the quality of evidence was variable with considerable heterogeneity among the reported cases and methods to exclude other causes.
The authors concluded that several cases of antiretroviral-associated alopecia in HIV patients have been reported with variance in the quality of data. According to this information, the authors recommend that it is important to rule out other causes of alopecia when considering this drug-induced diagnosis.
Antiretrovirals [“Indinavir,” “Lopinavir,” “Ritonavir,” “Lamivudine,” “Zidovudine”]
Woods EA & Foisy MM (MM Foisy, Northern Alberta Program, Royal Alexandria Hospital, 10240 Kingsway Ave, CSC 246, Edmonton, Alberta, Canada TSH 3V9; e-mail:
Adalimumab No. 249
Urticarial Reaction, Angioedema
A 37-year-old female patient developed localized injection site erythema and edema within 12 days after starting subcutaneous adalimumab (40 mg every 2 weeks) for the treatment of rheumatoid arthritis. Concurrent therapy was not specified. Symptoms progressed to generalized urticaria and bilateral eyelid angioedema, which was treated with parenteral corticosteroids and antihistamines. The patient underwent a desensitization protocol with an initial subcutaneous dose of 0.003 mg, increased to 40.333 mg. Premedications included oral dexamethasone (20 mg) and parenteral dexchlorpheniramine (5 mg) 1 hour before administration of adalimumab. Two weeks later, rechallenge with a full-dose adalimumab regimen was tolerated without further event. The patient went on to receive the remainder of therapy without further event.
The authors concluded that this patient represented a successful desensitization to adalimumab after experiencing significant allergic reactions on initial dosing.
Adalimumab [“Humira”]
Fernandez DG et al (DG Fernández, Hospital Universitario Puerta del Mar UGC Neumología–Alergia Avda, Ana de Viya, 2111009 Cádiz, Spain; e-mail:
Adverse Drug Events No. 250
Detection in Pediatric Oncology and Hematology Patients
The effectiveness of an electronic trigger tool to detect adverse drug events was investigated in an electronic chart review of pediatric oncology and hematology patients over a 4-year period. An adverse drug event was defined as an unintended injury or complication arising from the use of a drug and required additional monitoring, hospitalization, or treatment, or death. The inpatient and specialty pharmacies in the pediatric hospital dispenses approximately 70 000 doses/month. The potential adverse drug events identified by the trigger tool were evaluated by a pharmacist and a physician, and if consensus was achieved, further assessment was performed. A total of 706 triggers were detected in 390 patients during the study period. The mean age of the patients was 11 years and approximately 55% were male. The most common diagnoses were leukemia (54%) and some form of solid tumor (24%). The medication triggers examined included hyaluronidase, flumazenil, naloxone, sodium polystyrene sulfonate, protamine, and vitamin K. The 2 evaluators determined that 114 triggers detected 33 unique adverse drug events. The mean time required to determine whether a trigger was associated with an adverse drug events was 2.55 minutes. Of the 33 adverse drug events, the majority (82%) were classified as causing temporary harm (score E) according to the National Coordinating Council for Medication Error Reporting and Prevention criteria. Only 4 events were categorized as National Coordinating Council for Medication Error Reporting and Prevention category F (temporary harm requiring initial or prolonged hospitalization). One each were classified as National Coordinating Council for Medication Error Reporting and Prevention category G (permanent harm) and category H (intervention to sustain life). None of the adverse drug events reviewed resulted in fatalities. In general, the sodium polystyrene sulfonate trigger was responsible for detecting the most adverse drug events with hyperkalemia being the most frequently cited adverse drug event. The most frequently cited drug in these reports was cyclosporine. Vitamin K and protamine triggers did not detect any adverse drug events. Of the 33 identified adverse drug events, 15 occurred in the prescribing phase of medication delivery.
The authors concluded that based on the results of this study, the medication triggers identified some adverse drug events but typically had low positive predictive values. They suggested that in order for mediation trigger tools to be efficient, they may need to be refined to accommodate practices in hematology and oncology pediatric patients.
Adverse Drug Events [Adverse Drug Events]
Call RJ et al (JM Hoffman, St Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38103; e-mail:
Varicella Zoster Immune Globulin No. 251
Medication Error Related to Dilution Problems
A recent report highlighted problems with the dilution of the varicella zoster immune globulin product that led to a medication administration error. In the United States, the product is approved for intramuscular use requiring 1.25 mL of diluent. In Canada, it is approved for intravenous or intramuscular use, requiring 2.5 mL and 1.25 mL of diluent, respectively. In the case reported, the labeling specified international units abbreviated as “IU,” which may have been misinterpreted as “IV” and led to dilution with more volume but resulted in 3 intramuscular injections being administered to a 5-year-old patient.
Varicella Zoster Immune Globulin [“VARIZIG”]
Smetzer J et al [J Smetzer, Institute for Safe Medication Practices, 200 Lakeside Drive, Suite 200, Horsham, PA 19044; e-mail:
Statins No. 252
Predictors of Increases in Creatine Phosphokinase Concentrations
In a cohort study evaluating 641 703 UK adult patients receiving statins, the prevalence of rhabdomyolysis was evaluated as well as factors related to increases in creatine phosphokinase concentrations. Creatine phosphokinase values were classified according to the upper limit of normal. Upper limit of normal was defined as 19 U/L for men and 170 U/L for women. Predictors for creatine phosphokinase concentration or rhabdomyolysis were analyzed using logistic regression and compared to case–controls. The mean duration of follow-up was 4.1 years, and the total follow-up was 2.6 million person-years. Simvastatin was the most frequently prescribed statin (66.3%), followed by atorvastatin (24.4%), pravastatin (4.9%), rosuvastatin (3.6%), fluvastatin (0.6%), and cerivastatin (0.1%). The majority of patients (81.4%) with a documented creatine phosphokinase measurement during therapy were found to be in normal range. Approximately 0.7% and 0.1% had creatine phosphokinase concentrations at least 4 times the upper limit of normal and at least 10 times the upper limit of normal, respectively. A total of 59 patients had documented rhabdomyolysis with an incidence rate of 1.8/100 000 person-years and 2.6/100 000 person-years in women and men, respectively. Risk factors associated with increased odds of creatine phosphokinase at least 4 times above upper limit of normal included physician-recorded myalgia (adjusted odds ratio = 1.73) and concomitant prescribing of CYP3A4 interacting drugs (adjusted odds ratio = 1.28). Factors associated with increased risk of rhabdomyolysis include concomitant prescribing of CYP3A4 interacting drugs (adjusted odds ratio = 3.71) and those patients who received more than 50 recent non–statin prescriptions (adjusted odds ratio = 13.52).
The authors concluded that the overall use of statins was associated with a low risk of increases in creatine phosphokinase and rhabdomyolysis.
Statins [“Atorvastatin,” “Pravastatin,” “Rosuvastatin,” “Fluvastatin”, “Cerivastatin”]
Van StSaa TP et al (TP van Staa, London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, UK; e-mail:
Oxaliplatin No. 253
Anaphylaxis After Skin Testing
A 45-year-old female patient developed generalized pruritus, lacrimation, rhinorrhea, dyspnea, and hypotension within minutes of starting the seventh infusion of oxaliplatin in the treatment of metastatic colorectal cancer. Each cycle consisted of oxaliplatin, 5-fluorouracil, and leucovorin every 3 weeks. Treatment included the discontinuation of the infusion and supportive therapy (nonspecified). Follow-up prick skin testing was with a concentration of 5 mg/mL for the prick test and 0.05 mg/mL and 0.5 mg/mL for the intradermal test. Though the prick test with the lower dose was negative, within 15 minutes after testing with the 0.5 mg/mL dose, the patient experienced itching of the eyes and nose, palpebral swelling, generalized pruritus (especially on the palms, soles, and genitals), chest erythema, and restlessness. Treatment included the administration of intramuscular epinephrine and intravenous dexchlorpheniramine and hydrocortisone, resulting in immediate recovery. The patient underwent a successful 12-step desensitization program without further event.
The authors concluded that this patient experienced anaphylaxis as a result of oxaliplatin prick testing.
Oxaliplatin [“Eloxatin”]
Martin-Lazaro J et al (J Martin-Lazaro, Unidad de Alergología Centro Médico El Carmen Avda, Habana 50 32003 Ourense, Spain; e-mail: