Abstract
Keywords
MELATONIN No. 1
Syndrome of Inappropriate Antidiuretic Hormone
An 80-year-old Caucasian male patient developed worsening confusion, irritability, delusions, persecution, and slurred speech approximately 3 weeks after starting melatonin (1 mg daily). Concurrent medications included enalapril, atenolol, chlortalidone, gliclazide, esomeprazole, atorvastatin, dutasteride, and silodosin. No other herbal-type medications were ingested. On admission, abnormal laboratory tests included a decreased serum sodium level (110 mEq/L). Other laboratory levels were in normal. Hematological and urinary screenings for infectious etiologies were negative. Based on these results, both melatonin and chlortalidone were discontinued. Treatment was initiated with hypertonic saline (3%), haloperidol, and sodium valproate. Symptoms gradually resolved over several days and was associated with normalization of serum sodium levels. By the fourth day serum sodium levels were within normal levels. At a 2-month follow-up assessment, chlorthalidone was reinitiated with no further events noted; serum sodium and other electrolytes were within normal limits. Rechallenge with melatonin was not performed. The patient was advised to not restart melatonin therapy.
Based on the results of this case report, the author concluded that this patient experienced syndrome of inappropriate antidiuretic hormone related to melatonin therapy based on the temporal relationship between the administration of the product and the onset of symptoms.
Melatonin [Melatonin]
Famularo G (G Famularo, San Camillo Hospital, Rome, Italy) Syndrome of inappropriate antidiuretic hormone secretion in a patient treated with melatonin. Ann Pharmacother 55:131-132 (Jan) 2021
NONSTEROIDAL ANTI-INFLAMMATORY DRUGS No. 2
Risk of Pneumonia
A systematic review evaluated the role of nonsteroidal anti-inflammatory drugs on the risk of developing pneumonia complications based on data in 10 studies that met inclusion criteria. There was a total of 5 nested case-control studies, 2 population-based case-control studies, and 3 cohort studies. In total, 59 724 adults (n = 4 studies) and 1217 children (n = 5 studies) were included in the analysis. All studies demonstrated a positive association. Adults had an odds ratio/risk ratio range of 1.8 to 8.1. Children had an odds ratio/risk ratio range of 1.9 to 6.8. Limitations of the studies included moderate or serious risk of confounding bias, exposure misclassification, and protopathic biases and sparse data bias.
Based on the results of the systematic review, the authors concluded that the published studies demonstrated that the use of nonsteroidal anti-inflammatory drugs use increases the risk of pneumonia complications. However, they further suggested that the studies are subjected to several biases, and thus, the results should not be extrapolated as evidence of harm for nonsteroidal anti-inflammatory drugs. They also suggested that further study is required to explore this potential relationship.
Nonsteroidal Anti-Inflammatory Drugs [Nonsteroidal Anti-Inflammatory Drugs]
Sodhi M et al (M Etminan, Department of Ophthalmology and Visual Sciences, Faculty of Medicine, The Eye Care Center, The University of British Columbia, Room 323-2550 Willow Street, Vancouver, British Columbia, Canada V5Z 3N9; e-mail:
TRANEXAMIC ACID INJECTION No. 3
FDA Safety Alert: Medication Administration Errors
On December 3, 2020, the Food and Drug Administration (FDA) alerted health professionals regarding the risk of inadvertent intrathecal administration of tranexamic acid injection, resulting in injury, possibly fatal. Based on the case reports that were reported to the FDA, tranexamic acid injection was inadvertently administered instead of the intended intrathecal anesthetic (eg, bupvicaine injection) for neuraxial anesthesia. Tranexamic acid injection, bupivacaine injection, and other injectable products used in the perioperative setting may have a similar appearance (eg, color coding), which contribute to errors in medication administration. The FDA further stated that actions to reduce tranexamic acid injection medication errors are in place, including the revision of tranexamic acid injection container labels and carton labeling to highlight the recommended intravenous route of administration; and strengthening the warnings in the tranexamic acid prescribing information to include the risk of medication errors due to incorrect route of administration. In addition, the FDA suggests the following actions to avoid such errors, including storage of tranexamic acid injection vials separately from other drugs, adding an auxiliary warning label to note that the vial contains tranexamic acid, checking the container label to ensure the correct product is selected and administered, and utilizing barcode scanning when stocking medication cabinets and preparing or administering the product.
Tranexamic Acid Injection [Tranexamic Acid Injection]
FDA Safety Alert: FDA alerts healthcare professionals about the risk of medication errors with tranexamic acid injection resulting in inadvertent intrathecal (spinal) injection. https://www.fda.gov/drugs/drug-safety-and-availability/fda-alerts-healthcare-professionals-about-risk-medication-errors-tranexamic-acid-injection-resulting?utm_medium=email&utm_source=govdelivery (Dec 3) 2020
PREGABALIN No. 4
Poisonings
A retrospective review of patients with pregabalin poisonings over a 5-year period (2014-2019) identified 488 cases in 413 patients. More than half were male (n = 237 [57%]). The median age was 41 years. The majority of the identified cases were a result of intentional self-poisonings (n = 342 [70%]). Approximately one quarter of the cases were related to recreational exposures (n = 121 [25%]). Over the 5-year period, the recreational exposures increased (4% to 39%). The median dose of pregabalin was 1200 mg. The majority of cases that described additional data revealed that coingestion was common (n = 427 [88%]) with the most frequently cited co-ingestants included sedating agents (n = 387 [79%]). Sequelae such as coma occurred in 89 (18%) cases, requiring intubation in approximately 11% (n = 52). Other cited complications included hypotension (5%) and seizures (2%) cases. The median length of hospitalization was 16.5 hours.
Based on the results of a retrospective review of cases over a 5-year period, the authors noted that pregabalin overdose was most frequently associated with intentional poisoning but that overdoses related recreational use are increasing. Review of the clinical symptoms revealed that in these cases mild sedation and, uncommonly, seizures were observed.
Pregabalin [Pregabalin]
Isoardi KZ et al (KZ Isoardi, Clinical Toxicology Unit, Princess Alexandra Hospital, Ipswich Rd, Woolloongabba, Queensland 4102, Australia; e-mail:
LEVOTHYROXINE No. 5
Nonischemic Cardiomyopathy
A 65-year-old female patient developed a 24-hour episode of chest pain approximately 1 month post-kidney transplantation. Medications at the time of event were alprazolam, colchicine, lisinopril, estradiol, omeprazole, rosuvastatin, torsemide, and levothyroxine. Prior to the transplant, the patient had a normal echocardiogram 1 year prior and a normal electrocardiogram performed 5 months prior. A repeat echocardiogram revealed diastolic dysfunction and an estimated left ventricular ejection fraction of 25% to 30%. In addition, left bundle branch block was also observed. A cardiac catheterization revealed mild coronary artery disease. Diagnosis was nonischemic cardiomyopathy. Additional symptoms included anxiety, insomnia, hair loss, and a 22-kg weight loss over a 6-month period. A thyroid panel revealed a low thyroid-stimulating hormone (0.108 µIU/mL) and high free T4 (1.66 ng/dL). The levothyroxine was decreased from 1.28 to 0.85 µg/kg/day. No other drug-induced causes were suspected. Within 6 weeks after the levothyroxine dosage reduction, the thyroid-stimulating hormone normalized (1.630 μIU/mL) and the free T4 decreased to 1.07 ng/dL. On follow-up monitoring 4 months later, a repeat echocardiogram revealed improved function and an electrocardiogram demonstrated the reversal of left bundle branch block. In addition, all clinical symptoms resolved.
The authors concluded that this case report details the occurrence of levothyroxine induced nonischemic cardiomyopathy based on the temporal relationship between the appearance and resolution of symptoms related to toxic thyroid levels. According to the Naranjo causality algorithm, this relationship of the drug to the adverse event was classified as probable.
Levothyroxine [“Synthroid”]
Girone G et al (G Girone, Yale New Haven Hospital, New Haven, CT) Levothyroxine-induced nonischemic cardiomyopathy in a kidney transplant candidate. Ann Pharmacother 54:1260-1262 (Dec) 2020
GOLDENSEAL No. 6
FDA Announcement: Bacterial Contamination
On December 4, 2020, the US Food and Drug Administration published an announcement regarding a voluntary recall regarding certain lots of Cord Care and Goldenseal Powder regarding potential bacterial contamination with Cronobacter sakazakii. The potential lots were limited to specific dates which are available in the announcement. This risk of use of such products with bacterial contamination are of particular concern in patients with immunocompromised states. Goldenseal Powder is marketed as a drying powder applied externally to skin. It is packaged in 1-oz containers and labeled with UPC 6-56490-64137-9. Affected product lots are P116-P120. These products were distributed nationwide in the United States through select practitioners. Consumers who have purchased this recalled product should discontinue use immediately and not open any sealed packages.
Goldenseal [Goldenseal]
FDA Announcement: WishGarden Herbs issues voluntary nationwide recall of Cord Care and Goldenseal Powder due to bacterial contamination. https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/wishgarden-herbs-issues-voluntary-nationwide-recall-cord-care-and-goldenseal-powder-due-bacterial?utm_medium=email&utm_source=govdelivery (Dec 4) 2020
PIPERACILLIN/TAZOBACTAM No. 7
Acute Interstitial Nephritis and Recurrent Renal Dysfunction
A 29-year-old male inpatient developed suspected acute interstitial nephritis approximately 21 days after the initiation of intravenous piperacillin-tazobactam extended infusion (3.375 g every 8 hours) for suspected infection related to a common bile duct stone. On admission, laboratory testing indicated cholestatic hepatic dysfunction and leukocytosis of unclear etiology. The serum creatinine increased from 1 mg/dL on day of admission to 2.33 mg/dL on day 23. Since acute interstitial nephritis was suspected, meropenem was substituted as the preferred antibiotic of use. Initially after the switch, the serum creatinine began to improve, but at 6 days post-switch, the laboratory value began to worsen and the patient was discharged approximately 1 month later with a serum creatinine of 2.51 mg/dL. Approximately 3 weeks post discharge, the patient was readmitted with a serum creatinine of 2.57 mg/dL and continued cholestatic hepatic dysfunction. Piperacillin-tazobactam was restarted for acute cystitis. Within 5 days after initiation of therapy, the serum creatinine increased to 3.25 mg/dL. A renal biopsy revealed eosinophils in the medullary interstitium. Despite the discontinuation of piperacillin-tazobactam, the serum creatinine continued to increase, peaking at 5.24 mg/dL. The patient had renal replacement therapy while hospitalized and after discharge.
Based on this case report, the authors concluded that this patient developed acute interstitial nephritis followed by recurrent renal dysfunction related to piperacillin/tazobactam therapy based on the temporal relationship between the administration of the drug and the appearance of symptoms. An exact mechanism of action was not proposed.
Piperacillin/Tazobactam [“Zosyn”]
Parsels S et al (KA Parsels, Upstate University Hospital, Syracuse, NY) Recurrent renal dysfunction secondary to probable piperacillin-tazobactam-induced acute interstitial nephritis. Ann Pharmacother 55:133-134 (Jan) 2021
BACLOFEN No. 8
Encephalopathy
A 75-year-old female inpatient woman was found unconscious approximately 3 hours after taking the second dose of baclofen (10 mg). The patient had been initially hospitalized with walking difficulty, decreased appetite, and mild behavioral abnormality for 2 months. Medications on admission included amlodipine (5 mg daily), metformin (1000 mg daily), aspirin (75 mg daily), clopidogrel (75 mg daily), and alprazolam (0.5 mg daily). Only alprazolam was discontinued. A physical examination on admission revealed marked spasticity in all 4 limbs, but more pronounced in the lower limbs leading to flexion deformity. The deep tendon reflexes were exaggerated. Abnormal laboratory values included hemoglobin (112 g/L), platelet count (143 × 109/L), glycosylated hemoglobin (6.4%), alkaline phosphatase (297 U/L), and serum B12 (>2000 pmol/L). An examination at this time revealed hypotension, lowered respiratory rate and dilated pupils, and sluggish reaction. An electro-encephalography revealed generalized theta slowing. Treatment included intravenous fluid (normal saline), which resulted in normalization of blood pressure and eventual resolution of sensorium. Sensorial and blood pressure symptoms recurred within 4 hours after the third dose of baclofen, which was again managed successfully with intravenous saline. Baclofen was discontinued related to suspected encephalopathy, resulting in symptomatic improvement within 12 hours, and no further events were observed. The patient was discharged without further sequelae on hospital day 8.
The authors concluded that this patient developed encephalopathy related to baclofen based on the temporal relationship between the administration of the drug and the appearance and resolution of symptoms.
Baclofen [Baclofen]
Sachan A et al (UK Misra, Neurology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh 226014, India; e-mail:
ERTAPENEM No. 9
Neurotoxicity
A retrospective study evaluated the incidence of ertapenem associated neurotoxicity in 99 adult patients with chronic kidney disease stage 5 utilizing dialysis who also received the drug as 0.5 g intravenous daily. Of this group, approximately 10% developed neurotoxicity, all of which were male (mean age: 74 years). Analysis revealed that associated risk factors with increased risk of seizures included male sex (17%; P = .014), dementia (27%; P = .012), and concurrent use of β-lactams, aminoglycosides, or fluoroquinolones (19.6%; P = .042).
Based on the results of this retrospective review, the authors concluded that the currently approved ertapenem dose is associated with the risk of developing neurotoxicity in patients with chronic kidney disease stage 5 utilizing dialysis. They suggested that alternate dosing in this population should be further investigated.
Ertapenem [Ertapenem]
El Nekidy WS et al (WS El Nekidy, Department of Pharmacy Services, Cleveland Clinic Abu Dhabi, PO Box 112412, Abu Dhabi, UAE; e-mail:
RIFAMPICIN No. 10
Lichenoid Drug Eruption
A 45-year-male patient developed a pruritic generalized skin eruption approximately 2 weeks after starting isoniazid and rifampicin for the treatment of sputum-positive pulmonary tuberculosis. A physical examination revealed multiple, violaceous, discrete, and coalescing papules and plaques distributed almost symmetrically over the scalp, face, trunk, and extremities. No concurrent medications were noted in the report. Abnormal laboratory values indicated eosinophilia. A histopathological examination demonstrated hyperkeratosis with focal parakeratosis, basal cell degeneration with upper dermal band-like infiltrates consistent with lichenoid drug eruption. Both drugs were discontinued and treatment with topical steroids and oral antihistamines (both nonspecified) were initiated. Within 2 weeks, all skin lesions resolved. Isoniazid and rifampicin were restarted at reduced doses. However, once the rifampicin dose was increased to 450 mg, similar skin lesions recurred. The dose was further increased to 600 mg and the lesions were managed with treatment using topical steroids.
Based on the results of this case report, the authors concluded that this patient developed a lichenoid drug eruption related to rifampicin based on the temporal relationship between the administration of the drug and the appearance and resolution of symptoms. According to the Naranjo probability causality scale, this relationship was classified as probable.
Rifampicin [Rifampicin]
Bhanja DB et al (DB Bhanja, Department of Dermatology, Venereology, and Leprosy, RG Kar Medical College and Hospital, Kolkata, West Bengal, India; e-mail:
LIDOCAINE GEL No. 11
FDA Announcement: Recall of Bacterially Contaminated Product
On December 2, 2020, the US Food and Drug Administration announced that Mesquite, TX MPM Medical voluntarily recalled one lot of nonprescription lidocaine gel 2% to the consumer based on reports of bacterial contamination with Burkholderia cepecia. The announcement stated that topical application of bacterially contaminated product may result in local skin infections, particularly in immune-compromised patients. The announcement further noted that to date the manufacturer has not received any reports of adverse events related to this recall. MPM Medical is also notifying distributors and customers by first class mail, electronic mail, and phone call and is arranging for return of all recalled product. Patients and health care facilities in possession of this product, which is being recalled, are advised to stop using and dispensing the product.
Lidocaine Gel [“Regenecare HA Hydrogel”]
FDA Announcement: MPM Medical LLC issues voluntary nationwide recall of Regenecare HA Hydrogel due to Burkholderia cepecia contamination. https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/mpm-medical-llc-issues-voluntary-nationwide-recall-regenecare-ha-hydrogel-due-burkholderia-cepecia?utm_medium=email&utm_source=govdelivery (Dec 2) 2020
MEDICATIONS No. 12
Vitiligo
The occurrence of drug-induced vitiligo occurrence as reported in VigiBase, the World Health Organization pharmacovigilance database, was evaluated in 741 reported cases. The mean age of the identified patients was 49 ± 20 years. Results demonstrated an association between vitiligo and pembrolizumab (reporting odds ratio = 116.9, 95% confidence interval = 94.8-144.3), nivolumab (reporting odds ratio = 22.6, 95% confidence interval = 15.8-32.4), ipilimumab (reporting odds ratio = 41.7, 95% confidence interval = 25.0-69.7), imiquimod (reporting odds ratio = 152.8, 95% confidence interval = 103.0-226.7), adalimumab (reporting odds ratio = 3.8, 95% confidence interval = 2.5-5.8), infliximab (reporting odds ratio = 2.6, 95% confidence interval = 1.65-4.01), alemtuzumab (reporting odds ratio = 27.8, 95% confidence interval = 17.6-43.9), and ustekinumab (reporting odds ratio = 9.3, 95% confidence interval = 5.6-15.6).
Based on the results of this evaluation in a moderate size sample of case reports in the World Health Organization pharmacovigilance database suggested potential associations between vitiligo and immune checkpoint inhibitors, imiquimod, tumor necrosis factor-α inhibitors, and interferons. New signals were demonstrated with alemtuzumab and interleukin inhibitors.
Medications [Alemtuzumab, Adalimumab, Ipilimumab, Nivolumab, Ustekinumab]
Anthony N et al (M Briet, Service de Pharmacologie-Toxicologie et Pharmacovigilance, Centre hospital-Universitaire d’Angers, 4 rue larrey, 49100 Angers, France; e-mail:
PIPERACILLIN/TAZOBACTAM, TEICOPLANIN No. 13
Nephrotoxicity With Combined Therapy Compared to Monotherapy
In a single-center retrospective cohort study, the incidence of nephrotoxicity was evaluated with the combined use of piperacillin/tazobactam with teicoplanin compared to monotherapy with either agent in 4202 adult patients. The incidence of acute kidney injury, the primary outcome, was assessed at 48 to 72 hours after the initiation of antibiotic therapy. Change in serum creatinine was measured as a secondary outcome. Approximately three quarters of the patients (n = 3188; 75.9%) received piperacillin/tazobactam, 18.8% (n = 791) received teicoplanin, and 223 (5.3%) received monotherapy. The incidence of acute kidney injury was 5.4%, 3.4%, and 11.7% for piperacillin/tazobactam, teicoplanin, and combined therapy, respectively (P < .001). Mean serum creatinine was slightly higher in the piperacillin/tazobactam and teicoplanin group therapy compared with baseline (1.61% [95% confidence interval = 2.25 to 5.70]).
Based on the results of this study, the authors suggested that combined piperacillin/tazobactam and teicoplanin is associated with a higher prevalence acute kidney injury compared with monotherapy. However, they also noted that the overall reduction in decline in renal function may not be clinically relevant.
Piperacillin/Tazobactam [“Zosyn”]
Teicoplanin [“Teicoplanin”]
Workum JD et al (J Workum, Radboud University Medical Center, Department of Intensive Care Medicine, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands; e-mail:
REMDESIVIR No. 14
Acute Hepatotoxicity
Two cases of acute liver failure associated with remdesivir therapy are described in COVID patients.
Patient 1. A 68-year-old female inpatient developed elevated liver function tests within 24 hours after the initiation of intravenous remdesivir (200 mg loading dose followed by 100 mg daily for 4 days) for the treatment of severe COVID-19 pneumonia. Concurrent therapy included amiodarone infusion and high flow nasal cannula oxygen. Prior to remdesivir therapy, liver function tests were within normal limits. Over the next 24 hours, aspartate transaminase and alanine transaminase were greater than 5000 units/L with an elevated total bilirubin (3.1 mg/dL). Both remdesivir and amiodarone were discontinued. Treatment with acetylcysteine infusion was initiated as 150 mg/kg over 1 hour, 50 mg/kg over 4 hours, and 100 mg/kg over 16 hours. By the end of the 21-hour acetylcysteine protocol, aspartate transaminase and alanine transaminase had decreased to 1348 and 1861 units/L, respectively, with further decreases noted by day 14 (235 and 966 U/L, respectively). Total bilirubin decreased to 2.1 mg/dL. The patient’s condition eventually improved with subsequent discharge to home health care.
Patient 2. An 80-year-old female inpatient developed elevated liver function tests approximately 5 days after starting intravenous remdesivir (200 mg loading dose followed by 100 mg daily for 4 days). Concurrent therapy included oral dexamethasone (6 mg every day), convalescent plasma (single dose), and high flow nasal cannula oxygen. While receiving remdesivir, transaminases levels were within normal limits, but began increasing on day 5 of therapy. The patient’s condition worsened, and on hospital day 12, intravenous tocilizumab (640 mg single dose) was administered for suspected cytokine storm. On day 14, aspartate transaminase and alanine transaminase were elevated (2178 and 1510 units/L, respectively) as was alkaline phosphatase (109 units/L). Remdesivir-induced acute liver failure was suspected. Treatment was initiated with continuous acetylcysteine infusion (150 mg/kg over 1 hour, 50 mg/kg over 4 hours, and 100 mg/kg over 16 hours). Approximately 12 hours after finishing the 21-hour acetylcysteine protocol, aspartate transaminase/alanine transaminase, and alkaline phosphatase decreased. On hospital day 17, the patient’s condition worsened, experiencing cardiac rest, and eventually died.
The authors concluded that these patients developed acute liver failure related to remdesivir therapy based on the temporal relationship between the administration of the drug and the appearance and resolution of elevations in liver function tests.
Remdesivir [“Veklury”]
Carothers C et al (C Carothers, Department of Pharmacy, Orlando Regional Medical Center, 52 West Underwood Street, Orlando, FL 32806-2093; e-mail:
SILDENAFIL, TRAZODONE No. 15
FDA Safety Announcement: Recall
On December 9, 2020, one lot of sildenafil 100 mg tablets and one lot of trazodone 100 mg tablets was recalled by the manufacturer (AvKARE) to the consumer level related to a product mix-up of the listed 2 separate products inadvertently packaged together during bottling at a third party facility.
Sildenafil [Sildenafil]
Trazodone [Trazodone]
FDA Announcement: AvKARE issues voluntary nationwide recall of sildenafil 100 mg tablets and trazodone 100 mg tablets due to product mix-up. https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/avkare-issues-voluntary-nationwide-recall-sildenafil-100mg-tablets-and-trazodone-100mg-tablets-due?utm_medium=email&utm_source=govdelivery (Dec 9) 2020
BUPROPION No. 16
Risk of Seizures
A retrospective study evaluated the incidence of late-onset seizures associated with acute bupropion overdoses in 437 patients in California and Arizona over an 8-year time period. Approximately one fourth (27.9%; n = 122) of the patients experienced postingestion seizures, but only 8 patients (1.8%) had late-onset seizures (greater than 8 hours) after arriving at the hospital. Common features observed on medical evaluation included tachycardia and altered mental status. Of patients with tachycardia on hospital arrival, the odds of having a seizure was 6.7 (95% confidence interval = 3.7-10.9). The odds of a developing a late-onset seizure, defined as more than 8 hours after arrival, was 5.24 (95% confidence interval = 1.2=23.5). Altered mental status on arrival was considered a risk factor for the development of seizures (odds ratio = 3.93; 95% confidence interval = 2.21-7.0).
Based on this retrospective review of bupropion overdoses, the authors concluded that seizures are relatively common events associated with the event. Potential risk factors included tachycardia or altered mental status.
Bupropion [Bupropion]
Offerman S et al (M Levine, Department of Emergency Medicine, University of California, Los Angeles, CA; e-mail:
BREXPIPRAZOLE No. 17
Toxicity After Inadvertent Ingestion in Pediatric Patient
A 16-month-old male patient was hospitalized with drowsiness and ataxia approximately 18 hours after inadvertently ingesting brexpiprazole (up to 10 tablets of 3 mg each) the night before evaluation. The ingestion was only discovered the next morning. No other co-ingestants were identified. Abnormal laboratory values included hypoglycemia, which was treated with dextrose. Approximately 24 hours after exposure, the patient developed tremors, myoclonic jerks, agitation, and restlessness, which persisted over the next 24 hours. Treatment was initiated with lorazepam and the patient was discharged at 72 hours post-ingestion without further event. At 48 hours post-ingestion, the serum brexpiprazole concentration was 31 ng/mL. Drug screening for other agents were negative with the exception of lorazepam that had been prescribed.
The authors concluded that this patient developed typical symptoms of atypical antipsychotic toxicity, including lethargy, ataxia, tremor, and hypoglycemia. They suggested that the prolonged duration of effects was possibly related to the long half-life of brexpiprazole.
Brexpiprazole [“Rexulti”]
Rodriguez S & Moss MJ (MJ Moss, Utah Poison Control Center, College of Pharmacy, University of Utah, Salt Lake City, Utah; Division of Emergency Medicine, University of Utah, Salt Lake City, Utah; e-mail:
BUPROPION No. 18
Serotonin Syndrome After Overdose
A retrospective study evaluated the incidence of serotonin syndrome (using Hunter criteria) in 96 adult patients with bupropion toxicity related to overdoses at a toxicology referral center from 2015 to 2017. Patients who overdosed on other serotonergic medications were excluded. Of the 96 patients, 18 patients ingested bupropion in the absence of other serotonergic drugs. The incidence of serotonin toxicity was 33% in this population. The most frequently cited other symptoms included tachycardia (100%), hyperreflexia (56%), tremor (39%), seizure (39%), encephalopathy/agitation (50%), and clonus (33%). An analysis of the case data suggested that serotonin toxicity was more likely after an intentional suicidal ingestion when compared to accidental ingestion or after recreational drug use. In patients diagnosed with serotonin syndrome, the median bupropion dose was 2.25 g.
Based on this small retrospective study, the authors suggested that the incidence of bupropion induced serotonin toxicity is higher than reported. However, they noted that this study was limited by the retrospective study design and a small sample population.
Bupropion [Bupropion]
Sidlak AM et al (AM Sidlak, Division of Medical Toxicology, Department of Emergency Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA; e-mail:
DIPEPTIDYL PEPTIDASE-4 INHIBITORS No. 19
Bullous Pemphigoid
A systematic review and meta-analysis evaluating the potential association between dipeptidyl peptidase-4 inhibitors for diabetes and the onset of bullous pemphigoid included 5 retrospective studies with cases and controls. The meta-analysis revealed significant association between dipeptidyl peptidase-4 inhibitors use and bullous pemphigoid (odds ratio = 2.13; 95% confidence interval = 1.59-2.86, P < .00001). Heterogeneity of the studies was considered moderate. Vildagliptin had the strongest risk (odds ratio = 5.08; 95% confidence interval = 1.70-15.19, P = .004) when compared to linagliptin (odds ratio = 2.87; 95% confidence interval = 1.06-7.79, P = .04). There was no association observed for sitagliptin (odds ratio = 1.29; 95% confidence interval = 0.79-2.08, P = .31). Subgroup analysis found that these associations were not affected by gender and were significant in both males and females.
The authors concluded that this meta-analysis suggests a significant association between the use of dipeptidyl peptidase-4 inhibitors and the onset of bullous pemphigoid, with vildagliptin carrying the greatest odds of developing the event. The authors also recognized that there were several limitations to the meta-analysis including that the studies were retrospective. The authors also noted that clinicians should be aware of this potential complication associated with the use of these drugs.
Dipeptidyl Peptidase-4 Inhibitors [Vildagliptin, Linagliptin, Sitagliptin]
Phan K et al (K Phan, Department of Dermatology, Liverpool Hospital, Sydney, New South Wales, Australia) Dipeptidyl peptidase-4 inhibitors and bullous pemphigoid: a systematic review and adjusted meta-analysis. Australas J Dermatol 61:e15-e21 (Feb) 2020
MEDICATIONS No. 20
QT Prolongation
A prospective multicenter cohort US study using data from the ToxIC Registry between 2015 and 2018 evaluated patients with acute drug overdose to identify predictors of adverse cardiovascular events, specifically severe QT prolongation. The primary outcome was severe QT prolongation, defined as 500 milliseconds. Mean difference in QTc was also calculated for specific drugs. Of the 25 303 adult patients screened, 6473 met inclusion criteria. Severe QT prolongation occurred in 13% (n = 825) of the patients. Drugs associated with an increased adjusted odds of severe QT prolongation included sotalol, sodium channel blockers (amitriptyline, diphenhydramine, doxepin, imipramine, nortriptyline), antidepressants (bupropion, citalopram, escitalopram, trazodone), antipsychotics (haloperidol, quetiapine), and ondansetron.
Based on the results of this large US cohort study regarding severe QT prolongation with acute drug overdose, the authors identified a group of drugs that appeared to be associated with increased risk of event. Based on these data, they suggested that clinicians caring for patients with acute drug overdoses with these drugs should consider cardiac monitoring for the occurrence of severe QT prolongation.
Medications [Medications]
Campleman SL et al (AF Manini, One Gustave Levy Place, Box 1620, New York, 10029, NY; e-mail:
DIPEPTIDYL PEPTIDASE-4 INHIBITORS No. 21
Bullous Pemphigoid
A systematic review and meta-analysis evaluating the potential association between dipeptidyl peptidase-4 inhibitors for diabetes and the onset of bullous pemphigoid included data from 138 randomized controlled trials identified (61 514 patients in dipeptidyl peptidase-4 inhibitors and 59 661 patients in the control group). All trials included type 2 diabetics with a duration of at least 24 weeks, and compared dipeptidyl peptidase-4 inhibitors with placebo or active drugs. A total of 6 trials reported at least one case of pemphigoid (17 and 1 cases in dipeptidyl peptidase-4 inhibitors and control groups, respectively). Dipeptidyl peptidase-4 inhibitors were associated with an increased risk of pemphigoid A separate analysis for trials with linagliptin showed a significant increase of bullous pemphigoid with the active drug (MH-OR 4.69 [1.09, 20.22]; P = .04).
Based on the data from this meta-analysis of randomized controlled trials, the authors confirmed an association between dipeptidyl peptidase-4 inhibitors and bullous pemphigoid. In this analysis, linagliptin showed an increased risk when compared to active drug. Data on vildagliptin was insufficient to make a determination. Further study is suggested.
Dipeptidyl Peptidase-4 Inhibitors [Vildagliptin, Linagliptin, Sitagliptin, Omarigliptin, Saxagliptin, Alogliptin, Trelagliptin, Anagliptin, Gemigliptin, Evogliptin, Teneligliptin]
Silverii GA et al (M Monami, Diabetology Unit, Careggi Hospital and University of Florence, Florence, Italy; e-mail:
DIPEPTIDYL PEPTIDASE-4 INHIBITORS No. 22
Bullous Pemphigoid
A retrospective review included 70 patients histologically diagnosed with bullous pemphigoid between October 2015 and October 2018. Of these patients, half were diabetic and the vast majority (88.57%) were treated with a dipeptidyl peptidase-4 inhibitor when diagnosed with bullous pemphigoid. The most commonly documented dipeptidyl peptidase-4 inhibitors included linagliptin (18.6%) and vildagliptin (17.1%). The median onset between the initiation of therapy and the development of the complication was 27.5 months for all treatments, 16 months for linagliptin, and 39 months for vildagliptin. The majority of patients (87%) required the discontinuation of dipeptidyl peptidase-4 inhibitor therapy. Almost all (96%) of these patients experienced a complete resolution of symptoms.
Based on the data collected from this retrospective review, the authors suggested that the majority of patients diagnosed with bullous pemphigoid in their setting had received dipeptidyl peptidase-4 inhibitor therapy. In addition, they noted that the duration between initiation of therapy and the onset of the complication was shortest with linagliptin when compared to other gliptins.
Dipeptidyl Peptidase-4 Inhibitors [Linagliptin, Vildagliptin]
Magdaleno-Tapial J et al (J Magdaleno-Tapial, Servicio de Dermatología, Hospital General Universitario de Valencia, Valencia, España; e-mail:
FLUOROQUINOLONES No. 23
Mitral and Aortic Regurgitation
A disproportionality analysis including 102 events of fluoroquinolone-related valvular regurgitation reported to the US Food and Drug Administration Adverse Events Reporting System and a case-control study including a random sample of 9 053 240 patients from the US PharMetrics Plus Database were performed to examine if fluoroquinolones increased the risk of aortic and mitral regurgitation. A total of 6099 reports of valvular regurgitation events related to other medications were reported to the US Food and Drug Administration Adverse Events Reporting System for a reporting odds ratio of fluoroquinolone events of 1.45 (95% confidence interval = 1.20-1.77). In the case-control study, a total of 12 502 cases and 125 020 controls were included. The average age was 58.1 ± 12.7 years. The reported fluoroquinolones in the exposed cases included ciprofloxacin (48.5%), levofloxacin (44.2%), moxifloxacin (7%), and gemifloxacin (0.3%). Cases had a higher prevalence of atrial fibrillation (17.3% vs 2.6%) and coronary artery disease (31.4% vs 8.3%). The adjusted rate ratio for current users of fluoroquinolones compared to current amoxicillin users was 2.40 (95% confidence interval = 1.82-3.16). The adjusted rate ratio for recent fluoroquinolone users compared to recent amoxicillin users was 1.47 (95% confidence interval = 1.03-2.09), and the adjusted rate ratio for past fluoroquinolone users compared past amoxicillin users was 1.06 (95% confidence interval = 0.91-1.21). The adjusted rate ratio for current users of fluoroquinolones compared to current users of azithromycin was 1.75 (95% confidence interval = 1.34-2.29), and when recent users of fluoroquinolones were compared to recent users of azithromycin, the rate ratio was 1.37 (95% confidence interval = 0.95-1.98).
The authors concluded that results of this study suggested that the risk of mitral and aortic regurgitation was increased with current and recent use of fluoroquinolones. Proposed mechanisms included fluoroquinolone-induced damage to connective tissue and collagen in the aortic and mitral valves.
Fluoroquinolones [“Avelox,” “Cipro,” “Factive,” Gemifloxacin,” “Levaquin,” “Maxaquin,” “Noroxin”]
Etminan M et al (M Etminan, The University of British Columbia, The Eye Care Center, Room 323-2550 Willow St, Vancouver, British Columbia, Canada V5Z 3N9; e-mail:
OXYCODONE No. 24
Drug Interaction: Adverse Effects
A retrospective cohort study including 111 hospitalized Korean Veterans over the age of 65 that received oxycodone was performed to evaluate oxycodone-related adverse drug reactions and drug-drug interactions. Mean patient age was 70.4 ± 5.4 years. Indications for oxycodone use included cancer pain (n = 44), back pain (n = 21), neuropathy (n = 17), postsurgical pain (n = 4), dyspnea (n = 1), traumatic pain (n = 1), and other pains (n = 23). Concomitant medications included tramadol or fentanyl patch (n = 55), benzodiazepines (n = 34), GABA analogs (n = 60), cytochrome (CYP) P450 2D6 inhibitors (n = 16), and CYP3A4 inhibitors (n = 17). The frequency of oxycodone-induced adverse drug reactions was 32.4% (n = 36) and included gastrointestinal problems (n = 21), dizziness and drowsiness (n = 8), urinary retention (n = 4), skin rash (n = 3), and others (n = 11). The adjusted odds ratio of experiencing an adverse drug reaction was 20.4 (95% confidence interval = 2.22-186.7; P < .05) and 25.4 (95% confidence interval = 2.86-224.76; P < .05) among patients using CYP2D6 and CYP3A4 inhibitors, respectively. In patients using both CYP2D6 and 3A4 inhibitors, the adjusted odds ratio was 48.6 (95% confidence interval = 5.75-410.60; P < .01), and the attributable risk was 97.9%.
The authors concluded that results of this study suggested that the use of oxycodone and CYP2D6 and CYP3A4 inhibitors were associated with increased risk of adverse drug reactions, and the combination may need to be avoided. The proposed mechanism was CYP inhibition of oxycodone metabolism.
Oxycodone [“Oxaydo,” “Oxycontin,” “Roxicodone,” “Xtampza ER”]
Kim JH et al (HS Gwak, College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, 2 Ewhayeodae-gil Seodaemun-gu, Seoul 03760, Korea; e-mail:
DEXMEDETOMIDINE No. 25
FDA Announcement: Recall Due to Contamination
On November 19, 2020, the Food and Drug Administration published an announcement regarding a recall of a single lot of dexmedetomidine HCl in 0.9% sodium chloride injection (200 µg/50 mL) manufactured by Fresenius Kabi Inc, due to a trace amount of lidocaine present in the lot. This recall is being performed to the user level. To date, no adverse drug experience reports have been received for the recalled lot. Administration of dexmedetomidine HCl containing trace amounts of lidocaine to a patient with lidocaine allergy could result in a potentially life-threatening allergic reaction.
Dexmedetomidine [Dexmedetomidine]
FDA Announcement: Fresenius Kabi issues voluntary nationwide recall of a single lot of dexmedetomidine hydrochloride injection due to cross-contamination of lidocaine. https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/fresenius-kabi-issues-voluntary-nationwide-recall-single-lot-dexmedetomidine-hydrochloride-injection?utm_medium=email&utm_source=govdelivery (Nov 19) 2020
ASPIRIN No. 26
Acute Focal Neurological Deficit Related to Salicylate Toxicity
A 61-year-old female developed left-sided hemiparesis, blurred vision, shortness of breath, tinnitus, delirium, and possible hallucinations while taking aspirin (650 mg every 2 hours while awake) for 3 weeks for persistent chest discomfort. Past medical history included essential hypertension, generalized anxiety disorder, ischemic stroke, and seizure disorder. She had not taken any prescribed medications including diazepam, phenobarbital, antiplatelet, and anticoagulant medicine, for at least 1 week prior to symptom onset. Initial neurologic examination revealed slow movement and hyperreflexia in the left extremities. Bilateral horizontal nystagmus was present, and a Kussmaul breathing pattern was noted. Cardiac examination revealed no abnormal results. A brain magnetic resonance imaging revealed changes from the previous stroke and no acute cerebral infarction. Significant laboratory findings included an increased serum anion gap (20), hypokalemia (2.7 mEq/L), and reduced bicarbonate level (12 mEq/L). Blood gas evaluation revealed alkalosis (pH 7.46, pCO2 21 mm Hg, pO2 32, and bicarbonate 15 mmol/L). A diagnosis of mixed acid-base disorder with a wide anion gap metabolic acidosis and respiratory alkalosis was made. Initial serum salicylate level was elevated (78.1 mg/dL). Treatment included oral activated charcoal, intravenous administration of crystalloid with dextrose, potassium, and sodium bicarbonate (1000 mL bolus followed by continuous infusion). Salicylate levels declined to normal within 25 hours (16.5 mg/dL), and the metabolic acidosis, respiratory alkalosis, delirium, and hemiparesis had resolved completely by 48 hours after presentation.
The authors concluded that the acute focal neurologic deficit described in this case was related to salicylate toxicity. Proposed mechanisms included exacerbation of existing neurologic deficit.
Aspirin [Acetylsalicylic Acid]
Delaney TM et al (JF Schiffermiller, Department of Internal Medicine, Section of Hospital Medicine, University of Nebraska Medical Center, Omaha, NE; e-mail:
POSACONAZOLE No. 27
Pseudohyperaldosteronism
A retrospective review evaluated the management of 20 consecutive adult patients diagnosed with posaconazole-induced pseudohyperaldosteronism. The majority of patients (85%) required therapeutic modification, including posaconazole dose reduction (n = 11) or discontinuation (n = 3). Other interventions included a switch to an alternative antifungal (n = 2) to the addition of spironolactone (n = 1). Clinical improvement (decrease in systolic blood pressure and increase in serum potassium) was observed approximately half of the patients (52.9%). Mean decreases in systolic blood pressure (7.1 mm Hg) and mean increases in serum potassium (0.22 mmol/L) were observed following therapeutic interventions.
Based on this small retrospective review, the authors noted that there is no single therapeutic approach to the management of posaconazole-induced pseudohyperaldosteronism. They suggested that posaconazole dose reduction and repeat assessment of clinical and laboratory parameters is helpful but switching to an alternative antifungal may be required.
Posaconazole [Posaconazole]
Davis MR et al (NR Davis, Department of Pharmacy, University of California Los Angeles Ronald Reagan Medical Center, Los Angeles, CA, USA) Management of posaconazole-induced pseudohyperaldosteronism. J Antimicrob Chemother 75:3688-3693 (Dec) 2020
POSACONAZOLE No. 28
Pseudohyperaldosteronism
A female patient in her 60s developed shortness of breath on exertion, orthopnea, and bilateral pitting pedal edema approximately 4 months after starting oral posaconazole (300 mg extended release once daily) for the management of refractory histoplasmosis. Previous therapy included itraconazole and voriconazole, which were discontinued due to adverse events (hives and alopecia, respectively).
Computed tomography revealed a large bilateral pleural effusions. A transthoracic echocardiogram revealed grade II diastolic dysfunction with normal ejection fraction, dilated right ventricle and atrium, and severe functional mitral regurgitation with normal valve morphology. The corrected QT interval was prolonged (520 ms). Treatment included the initiation of Intravenous furosemide and holding the posaconazole therapy. Abnormal laboratory values revealed hypokalemia (2.9 mEq/L) and mild alkalosis (bicarbonate: 30 mEq/L). A repeat posaconazole trough was 6.1 g/mL. Hypertension was difficult to control and was treated with several antihypertensive drugs (furosemide, lisinopril, spironolactone, and hydralazine) and aggressive potassium supplementation. Hyperaldosteronism was ruled out with normal renin, early morning cortisol, and aldosterone levels. Symptomatic improvement occurred with blood pressure control and diuresis. Therapy was switched to fluconazole without further event.
The authors concluded that this patient developed systemic hypertension, hypokalemia, and edema related to posaconazole therapy based on the temporal relationship between the administration of the drug and the appearance and resolution of symptoms.
Posaconazole [Posaconazole]
Kuriakose K et al (K Kuriakose, Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN; e-mail:
USTEKINUMAB No. 29
Fixed Drug Reaction
A 36-year-old male patient developed a single, itchy, and painful lesion on the right calf approximately 2 days after receiving the second dose of ustekinumab for the management of moderate chronic plaque psoriasis without psoriatic arthritis. No other medications were noted in the report. The initial dose was 90-mg subcutaneous followed by a similar dose at 4 weeks and 12 weeks. A similar lesion recurred in the same site 2 days after the third injection. On dermal examination, a solitary, well-demarcated, rounded, erythematous plaque with a dusky purple center surrounded by an erythematous rim was observed on the right calf. Other areas and mucous membrane examination results were normal. Histologic examination revealed vacuolar degeneration at the dermoepidermal junction, necrotic keratinocytes scattered in the epidermis, papillary dermal edema, dermal melanophages, and a dermal perivascular inflammatory infiltrate composed of lymphocytes and eosinophils. Treatment included clobetasol propionate 0.05% ointment twice a day and the discontinuation of ustekinumab. Improvement occurred after 10 days.
The authors concluded that this patient developed a fixed drug eruption related to ustekinumab therapy based on the temporal relationship between the administration of the drug and the appearance and resolution of symptoms.
Ustekinumab [Ustekinumab]
Hafez DM et al (DM Hafez, Asir Central Hospital, Abha 62523, Saudi Arabia; e-mail:
TAMOXIFEN No. 30
Baboon Syndrome (First Report*)
A 44-year-old female patient developed a pruritic papulovesicular eruption on her body accompanied by facial erythema of 6 months duration. Medications included tamoxifen (10 mg twice daily) over the last 8 years. Previous therapy included Taxotere and Microrelin for 4 years and 3 months, respectively. On physical examination, there was no evidence of ocular or mucosal involvement. A skin biopsy revealed extensive hyperorthokeratosis, minimal parakeratosis, hypergranulosis, and lichenoid interface dermatitis in the irregularly acanthotic epidermis. The clinical manifestations and the pathological findings were congruent with a diagnosis of baboon syndrome related to tamoxifen therapy. Treatment included the discontinuation of the drug and initiation of oral and topical steroids, which resulted in great improvement within days of therapy initiation.
The authors concluded that this patient developed a baboon syndrome related to tamoxifen therapy based on the temporal relationship between the administration of the drug and the appearance and resolution of symptoms. They noted that this is the first published case report associated with tamoxifen.
Tamoxifen [Tamoxifen]
Mofarrah R et al (R Mofarrah, Department of Dermatology, Faculty of Medicine, Islamic Azad University of Medical Sciences, Sari, Iran; e-mail:
CLADRIBINE No. 31
Severe Systemic Rash
A 49-year-old male patient developed a pruritic skin rash on the chest on the last day of treatment with cladribine (6 mg on day 1 to day 7 cycle) for the management of hairy cell leukemia. Additional symptoms included a high fever (over 39 °C) and shivering with the rash spreading throughout the body in the afternoon. Abnormal laboratory values included C-reactive protein and procalcitonin (30 mg/L and 0.35 ng/mL, respectively). Treatment included the use of antihistamines (nonspecified), steroids, and antibiotics (for suspected secondary infection). During the first 2 days of treatment, the fever and rash persisted. However, on the third day, the temperature normalized, but no significant decrease was observed in the systemic rash. Immunoglobulin therapy (15 g/day) was initiated for 3 days along with oral ebastine and sodium thiosulfate. The rash began to improve within 5 days and resolved 10 days later. The patient was eventually discharged without further event.
The authors concluded that this patient developed a severe systemic rash related to cladribine therapy based on the temporal relationship between the administration of the drug and the appearance and resolution of symptoms.
Cladribine [Cladribine]
Dong H et al (D Wu, Department of Hematology, First Affiliated Hospital of Zhejiang Chinese Medical University, 54 Youdian Road, Hangzhou, Zhejiang 31006, People’s Republic of China; e-mail: