Abstract
Keywords
ATORVASTATIN No. 90
Toxic Epidermal Necrolysis
A 68-year-old woman developed a diffuse rash and a fever approximately 1 month after starting atorvastatin (20 mg nightly) following mitral valve replacement. Concurrent medications included digoxin (0.125 mg daily), furosemide (20 mg twice daily), potassium chloride (1 g twice daily), and warfarin (0.625 mg nightly). Laboratory findings included albumin (34.6 g/L), γ-glutamyl transpeptidase (45 units/L), glucose (13.24 mmol/L), creatine kinase MB subtype (18.0 units/L), creatine kinase (20 units/L), lactic dehydrogenase (398 units/L), sodium (135.9 mmol/L), leukocyte count (5.19 × 109/L), hemoglobin (98.0 g/L), platelet count (267 g/L), procalcitonin (0.130 ng/mL), and fibrinogen (4.35 g/L). Treatment included discontinuation of all drugs used prior to admission and administration of loratadine (10 mg daily), cetirizine (10 mg daily), vitamin C (100 mg 3 times daily), methylprednisolone (120 mg every 12 hours), intravenous omeprazole (40 mg every 12 hours), calamine, and ethacridine. A large number of blisters covering greater than 30% of the body appeared the next day, accompanied by fever. Additional treatment included administration of intravenous human immunoglobulin. The facial skin began to peel, and the trunk blisters ruptured. Mupirocin was applied topically. A new red patchy rash appeared on the lower extremities. On day 17, the face of the skin and trunk was mostly healed. After 60 days, the skin had regrown. HLA allele detection revealed the HLA-A*2:07, HLA-A*11:01, HLA-B*15:02, HLA-B*40:01, HLA-C*3:04, and HLA-C*08:01 alleles.
The authors concluded that this case described toxic epidermal necrolysis associated with atorvastatin. They proposed that the mutant HLA genotypes carried may have a correlation with Stevens-Johnson syndrome and toxic epidermal necrolysis.
Atorvastatin [“Lipitor”]
Lv M et al (J Zhang, Department of Pharmacy, Fujian Medical University Union Hospital, #29 Xinquan Rd, Fuzhou 350001, China; e-mail:
CYCLOSPORINE, FOOD No. 91
Drug Interaction: Reduced Cyclosporine Concentrations
In a prospective, monocentric study, the pharmacokinetic parameters of cyclosporine was evaluated in 24 kidney grafted patients after a meal and without a meal (fasting). Blood concentrations were evaluated at trough, and 0.5, 1, 2, 3, and 4 hours after administration. Food intake significantly increased volume of distribution and decreased elimination of cyclosporine. Olive oil intake suggested that lipid intake was the main factor of pharmacokinetic variability due to food, resulting in a decrease in area under the concentration curve of 14.6%.
Based on this pharmacokinetic study, the authors concluded that food, and especially lipid intake (as olive oil), is associated with a decreased exposure of cyclosporine. The authors also noted that such an interaction could potentially lead to a decrease in treatment efficacy and that timing of administration in relation to food intake should be considered.
Cyclosporine [“Neoral”]
Food [Olive Oil]
Bennani Rtel M et al (D Ternant, Laboratoire de Biotechnologie, Environnement, Agroalimentaire et Santé, Faculté Des Sciences Dhar El Mahraz, Université Sidi Mohammed Ben Abdellah, Fès, Morocco; e-mail:
CISPLATIN No. 92
Nephrotoxicity
A retrospective, observational study, including 186 adult patients receiving cisplatin in outpatient infusion centers, was performed to evaluate risk factors for cisplatin-induced nephrotoxicity and develop a risk prediction score for the development of nephrotoxicity. The risk prediction score included age, cisplatin dose, hypertension, and serum albumin. The most common cancer types included head and neck (37.1%), lung (29.0%), and bladder (10.8%). Comorbid conditions included hypertension (59.1%), diabetes mellitus (17.2%), and preexisting kidney dysfunction (11.9%). Concurrent nephrotoxic agents included angiotensin converting enzyme inhibitors/angiotensin receptor blockers (34.4%), nonsteroidal anti-inflammatory drugs (19.9%), anticancer agents (18.3%), and loop diuretics (7.5%). Participants were classified as low (46.2%), moderate (41.9%), or high (11.9%) risk of developing cisplatin-induced nephrotoxicity. Cisplatin-induced nephrotoxicity occurred in 23.7% of participants. It occurred during cycle 1 (36.4%), cycle 2 (20.4%), cycle 3 (27.3%), and cycles 4 and beyond (15.9%). The majority of cases were stage I (70.5%), and less occurred in stage II (20.5%) and stage III (9.0%). Premature discontinuation due to cisplatin-induced nephrotoxicity occurred in 6.5% of participants. Participants who developed nephrotoxicity had a higher mean prediction score than those that did not (4.0 ± 2.0 vs 2.9 ± 2.1, P = .004). Each 1-point increase in the risk prediction score increased the odds of nephrotoxicity by 26.5% (odds ratio = 1.27; 95% confidence interval = 1.02-1.57; P = .034). Participants with diabetes mellitus had an increased risk of cisplatin-induced nephrotoxicity (odds ratio = 3.66; 95% confidence interval = 1.43-9.33; P = .007), while receipt of 1 liter or more of 0.9% sodium chloride decreased the odds by 25% (odds ratio = 0.25; 95% confidence interval = 0.09-0.67; P = .006).
The authors concluded that the use of the risk prediction model successfully predicted the risk of cisplatin-induced nephrotoxicity in this study. Proposed mechanisms for cisplatin-induced nephrotoxicity included renal elimination of cisplatin resulting in accumulation on renal tubular cells and tubular cell injury, death, inflammation, renal vasculature injury, and renal ischemia.
Cisplatin [“Platinol”]
Burns CV et al (S Edwin, Department of Pharmacy, Ascension St. John Hospital, 22101 Moross Rd, Detroit, MI 48236; e-mail:
IVERMECTIN No. 93
FDA Announcement: Warning Against Use for COVID-19 Infection
On March 5, 2021, the US Food and Drug Administration (FDA) published an announcement alerting consumers and health professionals regarding safety issues with the use of veterinary-grade ivermectin in humans. This use has been based on new interest in the drug being used to treat COVID-19 infection. The announcement also notes that the FDA has received multiple reports of patients who have required medical support and been hospitalized after self-medicating with ivermectin intended for horses. The announcement noted that the FDA has not approved ivermectin for use in treating or preventing COVID-19 in humans and that the drug is not an antiviral agent. Taking large doses of this drug is dangerous and is associated with toxicity.
Ivermectin [Ivermectin]
FDA Safety Announcement: Why you should not use ivermectin to treat or prevent COVID-19. https://www.fda.gov/consumers/consumer-updates/why-you-should-not-use-ivermectin-treat-or-prevent-covid-19?utm_medium=email&utm_source=govdelivery (Mar 5) 2021
GEMCITABINE No. 94
Drug-Induced Livery Injury
A 73-year-old male developed jaundice, itching, acholic feces, and hyperchromic urine approximately 21 days after starting neoadjuvant chemotherapy including gemcitabine (1000 mg/m2 on days 1 and 8) and carboplatin (5 area under the curve on day 1) every 21 days for urothelial carcinoma (stage pT2N0M0, G3). Concurrent medications included pantoprazole (40 mg daily), tamsulosin (400 µg daily), and timolol (1 drop intraocular twice daily). Consumption of alcohol, psychotropic drugs, and herbal products was denied. One week prior, an episode of diarrhea following consumption of cooked fish had occurred. Significant findings on physical examination included cutaneous jaundice. Significant laboratory findings included normocytic normochromic anemia (113 g/L), high hyperbilirubinemia (6.37 mg/dL) with a prevalence of conjugated bilirubin (5.96 mg/dL), hypertransaminasemia (aspartate transaminase 82 units/L and alanine transaminase 158 units/L), elevated cholestasis enzymes (alkaline phosphatase 407 units/L and γ-glutamyl transpeptidase 186 units/L), and elevated ammonia level (134.54 µg/dL). Evaluation for viral and autoimmune hepatitis was negative. Additional evaluations for etiology revealed no abnormalities. An abdominal computed tomography scan and magnetic cholangiopancreatography revealed a hepatic hemangioma. Treatment included administration of levocetirizine and dexamethasone. Approximately 1 week later, symptoms and laboratory findings had improved. Additional treatment included discontinuation of gemcitabine, and a liver biopsy suggested drug injury characterized by mild-to-moderate portal hepatitis, eosinophilia, bile duct injury, and mild perisinusoidal fibrosis. One month later no symptoms remained, liver laboratory values were normalized, and an abdomen computed tomography revealed no abnormalities.
The authors concluded that the liver injury described in this case had a high probability of being a drug-induced liver injury as evaluated by the Roussel Uclaf Causality Assessment Method (score 10) related to gemcitabine. Proposed mechanisms for drug-induced livery injury included cell membrane destruction and cell death, development of an immunological reaction, inhibition of cellular metabolism pathways, abnormal bile glow, apoptosis, and inhibition of mitochondrial function.
Gemcitabine [“Gemza,” “Infugem”]
Mascherona I et al (I Mascherona, Ospedale La Caritá, Medicina Interna, Locarno, Switzerland; e-mail:
ALCOHOL 70% No. 95
FDA Announcement: Recall Due to Methanol Contamination
On January 4, 2021, the US Food and Drug Administration (FDA) announced that Essaar Inc voluntarily recalled a specific lot (200528303) of Soho Fresh 70% Rubbing Alcohol related to an FDA analysis of the product that identified contamination with methanol. The announcement noted that substantial methanol exposure is associated with symptoms including nausea, vomiting, headache, blurred vision, permanent blindness, seizures, coma, permanent damage to the nervous system, or death. Although the product is intended only for topical use, young children may accidently ingest these products. To date, Essar Inc has not received any reports of adverse events related to this recall.
Alcohol 70% [Rubbing Alcohol]
FDA Announcement: Essaar Inc. issues voluntary nationwide recall of rubbing alcohol contaminated with methanol. https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/essaar-inc-issues-voluntary-nationwide-recall-rubbing-alcohol-contaminated-methanol (Jan 4) 2021
COVID VACCINE No. 96
Delayed Large Local Reactions
In a letter to the editor, a case series describes reports of 12 patients with delayed large local reactions to the mRNA-1273 vaccine. There was a median onset on day 8 (range = 4-11 days) after the administration of the first vaccine dose. All reactions occurred near the injection site after complete resolution of the initial local and systemic symptoms associated with vaccination. In addition, some patients experienced systemic adverse effects. Treatment included ice, antihistamines, and topical or oral glucocorticoids. One patient received oral antibiotics for presumed cellulitis. The symptoms in these patients resolved within a median of 6 days after onset (range = 2-11 days). A skin biopsy in another patient (not included in the case series) with a similar delayed large local reaction revealed superficial perivascular and perifollicular lymphocytic infiltrates with rare eosinophils and scattered mast cells. Three patients had a recurrence of similar symptoms on receiving the second vaccination dose, with a shorter onset (within 1 to 3 days).
Based on this small case series, the authors cautioned clinicians to be aware of the possibility of delayed large local reactions suggestive of delayed-type or T-cell-mediated hypersensitivity.
COVID Vaccine [“mRNA-1273 Vaccine”]
Blumenthal KG et al (K Blumenthal, Massachusetts General Hospital, Boston, MA; e-mail:
IBUPROFEN No. 97
Increased Risk of Acute Kidney Injury in Hospitalized Pediatric Patients
A large, multicenter retrospective cohort study evaluated the association between the use of ibuprofen and the risk of hospital-acquired acute kidney injury in pediatric inpatients in China. Acute kidney injury was defined as an increase in serum creatinine level of 26.5 µmol/L or higher within 48 hours or by 50% or more over the baseline value, according to the Kidney Disease: Improving Global Outcomes guidelines. In the 50 420 children (mean age = 5.0 years), approximately 11% (n = 5526) used ibuprofen and 6.9% (n = 3476) developed acute kidney injury during hospitalization. After adjusting for cofounders, ibuprofen use was associated with a statistically significantly increased risk of hospital-acquired acute kidney injury (hazard ratio = 1.23; 95% confidence interval = 1.14-1.34). Risk factors associated with acute kidney injury included children with chronic kidney disease, those that required intensive care, or those that were older (greater than 10 years). In addition, a dose-response analysis suggested that the association of ibuprofen with the risk of hospital-acquired acute kidney injury was dose-dependent.
Based on this large, multicenter retrospective cohort study in Chinese pediatric inpatients, the authors suggested that ibuprofen was widely used and associated with an increased risk of hospital-acquired acute kidney injury. They also noted that clinicians should consider these data when selecting ibuprofen for use and that close monitoring of kidney function in children may be needed.
Ibuprofen [Ibuprofen]
Su L et al (X Xu, Division of Nephrology, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 1838 N Guangzhou Ave, Guangzhou 510515, China; e-mail:
CANNABIS No. 98
Pediatric Exposures in France
A retrospective observational study utilizing data from French poison centers between January 2010 and December 2017 evaluated 965 cases of cannabis exposures in children (less than 10 years). The median age of the patients evaluated was 15 months (range = 6 months to 10 years). The most frequently cited form of cannabis ingested was resin (75%). During the study period, symptoms included coma (4.5%) and respiratory depression (4.6%). A total of 11.7% were admitted to pediatric intensive care. No fatalities were documented in the study. The mean number of annual cases increased between 2010 and 2014 and 167 between 2015 and 2017 (93 vs 167). In addition, the length of hospitalization was significantly higher for the latter time period (P < .0001). When adjustments were made for the sex, age, and weight of the children, the severity of the poisonings was significantly greater (as measured by Poisoning Severity Scales) in the latter period of the study (P < .001).
Based on this retrospective observational study, the authors concluded that a significant increase occurred in the number of pediatric exposures to cannabis. In addition, there was also an increase in the severity of poisonings between 2010 and 2017.
Cannabis [Cannabis]
Chartier C et al (M Deguigne, Centre Antipoison-Toxicovigilance Grand Ouest, CHU Angers, 4 rue Larrey, Angers Cedex 09, 49933, France; e-mail:
HAND SANITIZERS (ALCOHOL BASED) No. 99
Poisoning Exposures in Small Children
A retrospective review of data from the American Association of Poison Control Centers’ National Poison Data System from January to April 2020 identified 4451 exposures of alcohol-based hand sanitizers in children up to 5 years (range = 5 days to 5 years; median = 1.9 years). The National Poison Data System database received a 35.8% increase in cases over the 4-month study period. This may have been reflective of the demand for use of such products during the initial phases of the COVID-19 pandemic. The most common ingredient in alcohol-based hand sanitizers’ exposures included ethanol (98.7%). Isopropanol accounted for less than 2% of the cases (1.3%). The vast majority of the cases were unintentional (99.8%) and occurred in the home (96.1%). Exposures were via ingestion (94%) or ocular route (5.5%). Only 5 children were hospitalized. The most commonly documented related effects were gastrointestinal, ocular, or central nervous system related. No deaths were documented.
Based on this retrospective analysis of pediatric exposures to alcohol-based hand sanitizers early in the COVID-19 pandemic, the authors concluded that these products pose a particular risk to small children and should be monitored in the household for preventive storage measures.
Hand Sanitizers [Hand Sanitizers]
McCulley L et al (L McCulley, Division of Pharmacovigilance, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD; e-mail:
CANNABIS No. 100
Poisoning Cases in Older US Adults
A retrospective review of data from the American Association of Poison Control Centers’ National Poison Data System between January 2009 and December 2019 evaluated 5201 cases of cannabis poisoning in US adults aged at least 50 years. Analysis of the data revealed that cannabis-related cases involving older adults increased 18-fold between 2009 and 2019 (61 vs 1074). Plant forms were less commonly cited as exposure product in the latter part of the study period when compared with other preparations. In addition, synthetic cannabinoids/e-cigarettes had 2.19 times greater odds of appearing in 2014-2015 (95% confidence interval = 1.64-2.93) but lower odds of appearing in 2016-2017 (relative risk reduction = 0.67, 95% confidence interval = 0.50-0.89). Use of synthetic cannabinoids/e-cigarettes were positively associated with being male, intentional misuse/abuse, and chronic use.
Based on the results of this retrospective analysis of cannabis poison cases in the United States, cannabis cases involving older adults were relatively few. The involvement of nonplant forms of cannabis increased rapidly in more recent years while cases of synthetic cannabinoids decreased.
Cannabis [Cannabis]
Choi NG et al (NG Choi, Steve Hicks School of Social Work, The University of Texas at Austin, Austin, TX; e-mail:
METHADONE No. 101
QTc Prolongation in Maintenance Therapy Program
In a prospective study, the incidence of QT interval prolongation associated with maintenance methadone therapy was evaluated in 93 patients in an urban opioid treatment program. All patients underwent a 12-lead electrocardiogram prior to initiating methadone and repeated during steady-state maintenance methadone therapy. QT (QTc) prolongation was defined as ≥470 ms in men or ≥480 ms in women and/or ≥60 ms lengthening from pretreatment value. The mean age of the patients was 36 years. The majority of the patients were female (73%). QTc prolongation occurred in 15.1% (n = 14) of the patients. Factors that were associated with the development of QTc prolongation included being older and having a longer pre-methadone QTc compared with those who did not have QTc prolongation (429 ± 11 vs 420 ± 20 ms, respectively, P = .02). Serum (S)-methadone concentrations were higher in patients with QTc prolongation compared with patients without prolongation (199 ± 81 vs 128 ± 68 ng/mL, respectively, P = .01).
In this prospective study, approximately 15% of patients taking maintenance methadone therapy developed QT interval prolongation.
Methadone [Methadone]
Titus-Lay EN et al (JE Tisdale, College of Pharmacy, Purdue University, Indianapolis, Indiana; School of Medicine, Indiana University, Indianapolis, Indiana; e-mail:
COCAINE No. 102
Health Consequences Associated With Use in France
A retrospective review evaluated the health consequences of cocaine using data from the French Addictovigilance Network, OPPIDUM (Observation of Illegal Drugs and Misuse of Psychotropic Medications), and DRAMES (Deaths Related to the Abuse of Licit and Illicit Psychoactive Substances) from 2010 to 2016. A total of 1265 spontaneous reports linked to cocaine use were evaluated. The majority of reports involved men (75%) with a median age of 35.0 years (IQ25-75 = 28 to 42 years). The most frequently cited routes of administration included intranasal (52%), intravenous (32%), and inhalation (24%). Cocaine was consumed with other psychoactive substances and alcohol in approximately half of the cases reviewed (47% and 60%, respectively). The main health complications cited were psychiatric, neurological, or cardiovascular in nature (29% vs 24% vs 23%). The DRAMES survey indicated that cocaine-related deaths increased by threefold from 2014 to 2016.
Based on the review of data in 3 large French databases, the authors concluded that cocaine use in France has increased, including severe complications and deaths associated with its use.
Cocaine [Cocaine]
Eiden C et al (C Eiden, Département de Pharmacologie Médicale et Toxicologie, Centre d’Addictovigilance, CHU Montpellier, Univ Montpellier, Avenue du Doyen Gaston Giraud, Montpellier 34295, France; e-mail:
ITRACONAZOLE, EFAVIRENZ No. 103
Drug Interaction: Reduced Itraconazole and Hydroxyitraconazole Exposure
An open-label, single-arm, sequential pharmacokinetic study assessed the drug-drug interaction between itraconazole/hydroxyitraconazole (and efavirenz in 10 adult HIV patients diagnosed with talaromycosis. Itraconazole was administered as 100 mg capsules at a dose of 200 mg 3 times/day for the first 3 days, followed by 200 mg twice daily. Steady-state pharmacokinetic assessments (pre-dose and at 1, 3, 4, 5, 6, 8 and 12 hours post-dose) were performed for itraconazole/hydroxyitraconazole on day 14 of therapy without and with efavirenz use. After completion of the pharmacokinetic sampling, an efavirenz-based regimen was initiated, and an identical set of intensive pharmacokinetic blood samples were drawn 2 weeks later. Mid-dose efavirenz concentrations were assessed 7 and 14 days after initiation. The majority of patients were male (70%) with a median age of 29.5 years (range = 22-64 years). The mean CD4 cell count was 18.0 cells/mm3. Mean itraconazole and hydroxyitraconazole AUC0-12 without efavirenz were 9097 ng/h/mL and 11 705 ng/h/mL, respectively. Intrasubject comparison revealed that both itraconazole and hydroxyitraconazole exposures (AUC0-12) were significantly reduced with concomitant efavirenz use (lowered by 86% and 84%, respectively). Concurrent efavirenz administration also reduced itraconazole trough concentrations below the recommended therapeutic levels (0.5 ng/mL).
Based on the results of this pharmacokinetic study, the authors concluded that the concomitant administration of itraconazole capsule with efavirenz significantly reduced itraconazole and hydroxyitraconazole exposures. They also suggested that the clinical impact of this drug-drug interaction needs to be studied further.
Itraconazole [“Itracon”]
Efavirenz [“Efavirenz”]
Kaewpoowat Q et al (Q Kaewpoowat, Department of Medicine, Faculty of Medicine, Chiang Mai University, Thailand; e-mail:
CETIRIZINE No. 104
Psychosis
A young male adult (in his 20s) with no psychiatric history was hospitalized with episodes of unusual aggressive behavior, agitation, paranoia, short-term memory loss, and auditory and visual hallucinations. The psychiatric symptoms began approximately 2 days after starting oral cetirizine (20 mg daily) for the management of a pruritic rash. No concurrent medications were taken. A dermatological examination revealed resolving red-purple papules and nodules on the anterior and posterior trunk. Abnormal laboratory values revealed slight lymphopenia, mild aminitis, and elevated ferritin. Toxicology screening was positive for tetrahydrocannabinol only. The possibility of cannabis-induced psychosis was considered but the patient had been chronic user without prior event. Treatment was initiated with sertraline (50 mg daily) and aripiprazole (5 mg daily). The patient was discharged after 5 days of hospitalization without further event on follow-up postdischarge.
The authors suggested that this patient developed psychosis related to cetirizine use based on the temporal relationship between the administration of drug and the appearance and resolution of symptoms.
Cetirizine [“Zyrtec”]
Croitoru D et al (D Croitoru, University of Toronto, Toronto, Ontario, Canada; e-mail:
ANTICONVULSANTS No. 105
Decreased Risk of Developing Chronic Obstructive Pulmonary Disease
A matched case-control study evaluated the association between enzyme-inducing anticonvulsants and the potential risk of developing chronic obstructive pulmonary disease or lung cancer in smokers. A total of 5952 incident chronic obstructive pulmonary disease and 1373 incident lung cancer cases were identified and matched to 59 328 and 13 681 controls, respectively. Compared with never use, ever use of enzyme-inducing anticonvulsants was associated with slightly decreased risk estimates of chronic obstructive pulmonary disease (adjusted odds ratio = 0.85; 95% confidence interval = 0.81-0.89) and lung cancer (adjusted odds ratio = 0.82; 95% confidence interval = 0.73-0.92). These risk estimates were attenuated in heavy smokers.
Based on this matched case-control study in smokers, slightly decreased risk estimates of chronic obstructive pulmonary disease and lung cancer were observed among smokers taking enzyme-inducing anticonvulsants.
Anticonvulsants [Anticonvulsants]
Leuppi-Taegtmeyer AB et al (CR Meier, Basel Pharmacoepidemiology Unit, Hospital Pharmacy, University Hospital Basel, Spitalstrasse 26, CH-4031 Basel, Switzerland; e-mail:
EPIDERMAL GROWTH FACTOR RECEPTOR TYROSINE KINASE INHIBITORS No. 106
Hepatotoxicity
A network meta-analysis evaluated the risk of hepatotoxicity associated with different epidermal growth factor receptor tyrosine kinase inhibitors in patients with non–small cell lung cancer. The 5 epidermal growth factor receptor tyrosine kinase inhibitors included in the analysis were gefitinib, erlotinib, afatinib, dacomitinib, icotinib, and osimertinib. The meta-analysis included a total of 12 randomized controlled trials enrolling 6280 patients with non–small cell lung cancer who were receiving epidermal growth factor receptor tyrosine kinase inhibitors. A random-effects pairwise meta-analysis and network meta-analysis were performed. Gefitinib was associated with a significant increased risk for all-grades alanine transaminase elevation compared to placebo (risk ratio = 2.96; 95% confidence interval = 1.75-5.00), erlotinib (risk ratio = 1.39; 95% confidence interval = 1.16-1.67), afatinib (risk ratio = 2.21; 95% confidence interval = 1.37-3.58), and dacomitinib (risk ratio = 2.03; 95% confidence interval = 1.48-2.77). When considering all-grades aspartate transaminase elevation, gefitinib and erlotinib demonstrated a significantly increased risk for hepatotoxicity compared to afatinib, dacomitinib, and placebo (erlotinib vs afatinib: risk ratio = 1.85; 95% confidence interval = 1.05-3.24; erlotinib vs dacomitinib: risk ratio = 1.68; 95% confidence interval = 1.19-2.36; erlotinib vs placebo: risk ratio = 3.38; 95% confidence interval = 1.69-6.73; gefitinib vs afatinib: risk ratio = 2.23; 95% confidence interval = 1.32-3.79; gefitinib vs dacomitinib: risk ratio = 2.03; 95% confidence interval = 1.51-2.73; gefitinib vs placebo: risk ratio = 4.08; 95% confidence interval = 2.11-7.91). No statistically significant differences were identified among 5 agents analyzed in terms of all-grades TB elevation and high-grade aspartate transaminase elevation.
Based on this network meta-analysis, the authors suggested that gefitinib and erlotinib may be associated with a significantly increased risk for hepatotoxicity in non–small cell lung cancer patients. The mechanism behind hepatotoxicity caused by epidermal growth factor receptor tyrosine kinase inhibitors is currently unclear The authors also acknowledged several limitations to the analysis, including that the elevation of liver enzymes was not definitively associated with epidermal growth factor receptor tyrosine kinase inhibitors, that there were a small number of studies available, that other indicators of hepatotoxicity were not available, and that this meta-analysis demonstrated publication bias. Based on these limitations, the authors noted that further studies are required to confirm these results.
Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors [Gefitinib, Erlotinib, Afatinib, Dacomitinib, Icotinib, Osimertinib]
Wu Z et al (X Xie, Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University, Beijing, China; e-mail:
LINEZOLID No. 107
Thrombocytopenia, Hyponatremia
A retrospective, single-center observational cohort study evaluated the possible relationship between linezolid-induced hyponatremia and thrombocytopenia and identified risk factors associated with hyponatremia and/or thrombocytopenia. Hyponatremia was defined as a sodium level lower than 134 mEq/L and more than 5% decrease from baseline after initiation of the drug. Thrombocytopenia was defined as more than 30% decrease in platelet count compared with baseline levels. The definition of acute kidney injury was 0.5 mg/dL or more than 50% increase in serum creatinine level compared with baseline levels. A total of 63 adult inpatients who received intravenous linezolid for more than 7 consecutive days were enrolled in the study. The median administration period for the drug was 12 days. Thrombocytopenia and hyponatremia occurred in 39.7% and 17.5% of the patients, respectively. A total of 7 of the 11 patients with hyponatremia also developed concurrent thrombocytopenia. Although both serum sodium level and platelet counts declined in most patients who developed hyponatremia, no significant association between thrombocytopenia and hyponatremia was detected. Risk factors identified for thrombocytopenia included creatinine clearance and administration period. Risk factors identified for hyponatremia included serum albumin. Risk factors for developing both events included the administration period and serum albumin.
Based on the results of this study, the authors concluded that thrombocytopenia and hyponatremia may occur in patients receiving linezolid. However, there was no significant relationship between linezolid-induced thrombocytopenia and hyponatremia events together. Although potential risk factors were identified, the authors suggested that further study is needed to validate these results.
Linezolid [Linezolid]
Tanaka R et al (R Tanaka, Department of Clinical Pharmacy, Oita University Hospital, Yufushi, Oita 879-5593, Japan; e-mail:
ADVERSE DRUG REACTION REPORTING No. 108
Adverse Drug Reaction Reporting Program in Saudi Arabia Tertiary Care Healthcare System
A retrospective analysis was performed of all adverse drug reactions submitted by health care providers in a tertiary Saudi Arabian health care system between January 2016 and December 2019. A total of 1156 adverse drug reaction reports were submitted and reviewed. The most frequently cited drug classes included antimicrobials (56.8%), analgesics (11.4%), diagnostic agents (5.1%), gastrointestinal agents (4.1%), and serums-toxoids-vaccines (3.1%). The vast majority of reactions involved immune system disorders (87.8%). Approximately 11.4% and 24.2% were classified as definitely and possibly preventable, respectively. Although the rate of adverse drug reaction reporting was noted to increase over the evaluation time period, there was a lack of reporting by physicians as a group.
Based on this retrospective study, the authors concluded that almost one third of the reported adverse drug reactions were considered to be preventable or possibly preventable in their review of the reporting program in a tertiary healthcare system.
Adverse Drug Reaction Reporting [Adverse Drug Reaction Reporting]
Abu Esba LC et al (LC Abu Esba, King Abdulaziz Medical City, King Saud Bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Centre, PO Box 22490, Riyadh 11426, Saudi Arabia; e-mail:
POLY-ADP-RIBOSE POLYMERASE INHIBITORS No. 109
Incidence and Risk of Gastrointestinal Adverse Events in Cancer Patients
A meta-analysis included 29 phase II and III randomized controlled trials, enrolling 9529 cancer patients, to evaluate the incidence and the relative risk of gastrointestinal events in cancer patients receiving poly-ADP-ribose polymerase inhibitors (eg, olaparib, rucaparib, niraparib, talazoparib, veliparib). Two investigators independently performed data extraction, and discrepancies were resolved by consensus. If heterogeneity existed, data were analyzed using a random-effects model. In the absence of heterogeneity, a fixed-effects model was used. Heterogeneity was high (I2 = 87%). No significant publication bias was noted. The use of poly-ADP-ribose polymerase inhibitors significantly increased the risk of developing all-grade nausea (risk ratio = 1.46; 95% confidence interval = 1.29-1.66; P < .00001), vomiting (risk ratio = 1.39; 95% confidence interval = 1.17-1.64; P = .0001), diarrhea (risk ratio = 1.14; 95% confidence interval = 1.06-1.23; P = .0003), and decreased appetite (risk ratio = 1.24; 95% confidence interval = 1.14-1.36; P < .00001), but not for constipation. The use of poly-ADP-ribose polymerase inhibitors also significantly increased the risk of high-grade nausea, vomiting, and decreased appetite. Veliparib was associated with a relatively lower risk of all-grade nausea and vomiting. Patients with ovarian cancer tended to have a higher risk of all-grade nausea and vomiting than those with non–ovarian cancer. The risk of all-grade nausea and vomiting was higher with longer poly-ADP-ribose polymerase inhibitors treatment durations.
Based on the results of this meta-analysis, the authors concluded that poly-ADP-ribose polymerase inhibitors were associated with a significant increased risk of gastrointestinal events. Noted limitations included a high heterogeneity and that the included studies investigated primarily olaparib and veliparib, with only one randomized controlled trial concerning rucaparib and one concerning talazoparib. Thus, these drugs might be under represented.
Poly-ADP-Ribose Polymerase Inhibitors [Olaparib, Rucaparib, Niraparib, Talazoparib, Veliparib]
Sun W et al (J Li, College of Pharmacy, Southwest Minzu University, No. 16 South 4th Section, 1st Ring Road, Chengdu 610041, Sichuan, China; e-mail:
FLAXSEED OIL No. 110
Gynecomastia (First Report*)
A 70-year-old male patient developed left breast swelling and pain approximately 3 months after starting the ingestion of flaxseed oil daily for the management of hyperlipidemia. Concurrent medications included atorvastatin (10 mg daily). A physical examination revealed a mass in his left breast. A breast biopsy was compatible with gynecomastia, showing ductal hyperplasia without evidence of malignancy. It was recommended that both atorvastatin and flaxseed oil be discontinued but the patient stopped the use of the flaxseed oil. Three months later, the patient was free of breast pain and swelling without any palpable mass.
The authors suggested that this patient developed gynecomastia related to flaxseed use based on the temporal relationship between the administration of the product and the appearance and resolution of symptoms. They also noted that this was the first case report of its kind. A possible mechanism of action suggests that phytoestrogens may play a role in growing breast tissue rather than suppressing it in this case. Statins are also noted to reduce testosterone levels, presumably leading to a synergistic effect in inducing gynecomastia.
Flaxseed Oil [Flaxseed Oil]
Takenaka T et al (T Takenaka, Department of Medicine and Surgery, Kokusai Iryo Fukushi Daigaku Daigakuin—Tokyo Aoyama Campus, Minato-ku, Tokyo, Japan; e-mail:
COUGH/COLD MEDICATIONS No. 111
Adverse Events in Children
In a retrospective review, data were collected from 2009 to 2016 regarding exposures to over-the-counter cough and cold products in children less than 12 years old. A total of 4756 cases were determined at least potentially related to at least one index cough and cold ingredient. Accidental unsupervised ingestions were the most common case type cited (65.9%). Almost half of the adverse event cases involved children 2 to less than 4 years old (45.4%). Health care facility admissions related to cough and cold exposures increased significantly from 2009 to 2016 (32.4% vs 43.4%; P < .01), and most commonly related to exposures to diphenhydramine (67.3%) and/or dextromethorphan (30.5%). were involved in the majority of health care facility admissions. Critical care admissions related to cough/cold medications also increased during the same time period (15.4% vs 20.6%; P = .01).
Based on the results of this retrospective study, the authors noted that the number of cases resulting in health care facility admissions related to cough/cold medications exposures in children increased from 2009 to 2016. Ingredients that were most commonly documented were diphenhydramine and dextromethorphan-containing products.
Cough/Cold Medications [Diphenhydramine, Dextromethorphan]
Wang GS et al (KM Reynolds, Rocky Mountain Poison and Drug Safety, 777 Bannock St. MC 0180, Denver 80204, CO; e-mail:
ADVERSE DRUG REACTION REPORTING No. 112
Use of ICD Codes for Adverse Drug Reaction Identification
This retrospective study evaluated the utilization of the International Statistical Classification of Diseases and Related Health Problems (ICD) system for the identification of adverse drug events in hospital claims data of hospitalized patients in a single center from July 2016 and June 30, 2018. An adverse drug event was defined as actual if an ICD-10-CM T code was present among the primary or secondary diagnosis codes. A total of 1384 inpatients were identified using the ICD code method during the study period. Code T36 (poisoning by, adverse effect of, or underdosing of systemic antibiotics) was the most frequently cited code (56.6%), followed by T42 (17.7%; poisoning by, adverse effect of, or underdosing of antiepileptic, sedative-hypnotic or antiparkinsonism drug). A total of 789 clinically significant adverse drug events were identified after medical chart review by pharmacists. The dermatologic system was the most commonly involved. The positive predictive value for a flagged code representing an adverse drug event was 57%.
Based on the results of this study, the authors concluded that the use ICD-10-CM T codes was insufficient for identifying adverse drug events during hospitalization. However, the authors suggested that the ICD code code system may be used as an auxiliary resource to identify potential adverse drug events along with pharmacist review.
Adverse Drug Event Reporting [Adverse Drug Event Reporting]
Cheng YF et al (YF Cheng, Department of Clinical Pharmacy Service, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan; e-mail:
METHIMAZOLE No. 113
Insulin Autoimmune Syndrome
A retrospective review was performed of the literature regarding methimazole-induced insulin autoimmune syndrome. A total of 106 case reports were identified in the Chinese and English medical literature. The median age of the 106 patients with methimazole-induced insulin autoimmune syndrome was 37 years (range = 15-76 years). The onset of symptoms occurred within days or up to 6 months after initiation of resumption of therapy with symptoms manifesting at night or early morning. Symptoms were neuropathic (65.31%) or related to the autonomic nervous system (33.67%). Median blood glucose concentrations during the hypoglycemic phase was 1.7 mmol/L and insulin concentrations were elevated (≥100 mU/L). The majority of patients were positive for immunoglobulin G insulin autoantibodies (98.02%). Pancreatic imaging was unremarkable. Treatment with corticosteroids or discontinuation of methimazole reduced the hypoglycemic episodes within days to 3 months. Follow-up at a median of 5 months (range = 1-60 months) revealed no recurrent episodes.
Based on the results of this literature review of induced insulin autoimmune syndrome, the authors concluded that this complication occurs rarely during medication treatment but when manifested should be treated promptly.
Methimazole [Methimazole]
Sun L et al (C Wang, Department of Pharmacy, The Third Xiangya Hospital, Central South University, No. 138 Tongzipo Road, YueLu District, Changsha, Hunan 410013, China; e-mail:
METAMIZOLE, SERTRALINE No. 114
Drug Interaction: Decreased Sertraline Concentrations
In a double-blinded study, the impact of metamizole and ibuprofen on plasma concentrations of the sertraline was evaluated. A total of 3 groups of patients were compared: patients receiving sertraline and metamizole (n = 15), patients receiving sertraline and ibuprofen (n = 19), and a matched control group without the analgesics (n = 19). Metamizole was associated with 67% lower median sertraline plasma concentrations compared with the control group (14 vs 42 ng/mL, P < .001). However, there were no differences between the ibuprofen group and the control group (31 vs 42 ng/mL, P = .128). In addition, the metamizole group exhibited a higher proportion of patients with sertraline concentrations below the therapeutic reference range when compared with the ibuprofen and control groups (40% vs 5% vs 0%, respectively; P = .005).
Based on the results of this study, the authors noted that this preliminary evidence possibly supports the theory that metamizole acts as a potent inductor of cytochrome P450 isoenzymes CYP2B6 and CYP3A4. Due to this potentially significant interaction, they cautioned clinicians to consider alternative drug combinations and adjust sertraline doses to maintain therapeutic concentrations.
Metamizole [Metamizole]
Sertraline [Sertraline]
Gaebler AJ et al (AJ Gaebler, Department of Psychiatry, Psychotherapy and Psychosomatics and JARA—Translational Brain Medicine, RWTH Aachen University, Pauwelsstr. 30, 52074 Aachen, Germany; e-mail:
CURCUMA LONGA No. 115
Hepatotoxicity
A retrospective review was performed of spontaneous reports received by the Italian Phytovigilance system regarding suspected adverse events of acute hepatotoxicity related to Curcuma longa–containing dietary supplements. In addition, a systematic literature review was performed to identify all case reports and case series regarding these events. The Roussel Uclaf Causality Assessment Method and the World Health Organization-The Uppsala Monitoring Centre causality assessment tools were used to evaluate the causal relationship between the use of dietary supplement and acute hepatitis. A total of 7 cases of acute hepatitis associated with Curcuma longa formulations occurring in Tuscany up to September 2019 were identified. In all cases, hepatotoxicity was associated with formulations with high bioavailability and high dosage of curcumin/curcuminoids. The causal relationship was also validated by positive dechallenges in most of the cases. In the systematic review, 23 cases were identified. The majority of patients also took at least one other medication and most of them (16) experienced a positive dechallenge.
Based on this retrospective review of Curcuma longa–induced acute hepatitis spontaneous reports received by an Italian pharmacovigilance database and case reports/series in the medical literature, the authors confirmed the association between Curcuma longa and hepatotoxicity.
Curcuma longa [“Tumerica”]
Lombardi N et al (N Lombardi, Department of Neurosciences, Psychology, Drug Research and Child Health, Viale G. Pieraccini, 6-50139, Florence, Italy; e-mail:
ALCOHOL No. 116
Deaths in Poland After Weakening of Alcohol Control Measures
Alcohol-related mortality was evaluated in Poland using data between 2002 and 2017. In 2002, there were 3256 alcohol-related deaths and a mortality rate of 13.9/100 000 in men, which increased in 2017 to 7604 deaths and a mortality rate of 28.0/100 000. Thus, between 2002 and 2017, the average annual percentage change was 4.9% in this group (95% confidence interval = 3.2% to 6.6%; P < .001). In women there was a 9.7% average annual percentage change (95% confidence interval = 7.0% to 12.4%; P < .001) between 2002 and 2017. In 2002, a total of 429 alcohol-related deaths and a mortality rate of 1.7/100 000 occurred in women, which in 2017 increased to 1870 and 6.4/100 000, respectively. Mortality rates were highest in the 45- to 64-year age groups in both men (88.8/100 000) and women (21.3/100 000).
Based on the data from this evaluation, the authors concluded that alcohol-related mortality increased during the study period in both men and women. They noted that these increases coincided with the weakening of alcohol control measures.
Alcohol [Alcohol]
Zatoński WA et al (WA Zatoński, Institute-European Observatory of Health Inequalities, Calisia University, Nowy Świat 4, 62-800 Kalisz, Poland; e-mail:
BETA-BLOCKERS No. 117
Lack of Risk of Congenital Abnormalities With Use in Early Pregnancy
The risk of congenital malformations associated with the use of β-blockers during early pregnancy was evaluated in a meta-analysis that included 20 observational studies. Two reviewers independently extracted data and assessed study quality. Analysis revealed that β-blocker use during early pregnancy was not associated with an increased risk of congenital malformations (odds ratio = 1.01; 95% confidence interval = 0.93-1.09). However, in subgroup analysis, β-blocker use was associated with an increased risk of heart malformations (odds ratio = 1.29; 95% confidence interval = 1.02-1.63) and an increased risk of cleft lip or palate (odds ratio = 1.5; 95% confidence interval = 1.18-1.91). It should be noted, however, that these associations were not significant when the adjusted data were pooled. Beta-blocker use was not associated with increased risks of central nervous system malformations, neural tube defects, or hypospadias.
Based on the results of this meta-analysis, the authors suggested that the use of β-blockers during early pregnancy does not appear to be associated with congenital malformations or cardiovascular malformations.
Beta-Blockers [Propranolol, Metoprolol, Atenolol]
Wu Y et al (L Wan, Department of Oral Diseases, Tongxiang First People’s Hospital, Jiaochang Road 1918, 314500 Tongxiang, Zhejiang, China; e-mail:
MEDICATIONS No. 118
Predictors for Risk of Falls in Older Patients
A retrospective cohort study evaluated data from a pharmacy dispensing system and self-reported falls among 3454 Dutch individuals aged at least 65 years of age. Medication exposure was defined as drug burden index for cumulative anticholinergic and sedative medication exposure and drugs that increased fall risk and analysis evaluated the use of these definitions as predictors. Analysis of the data revealed that there were 521 single fallers (15%) and 485 recurrent fallers (14%). There was a significant associations between the use of at least one drug burden index and single falling (adjusted odds ratio = 1.30; 95% confidence interval = 1.02-1.66) and recurrent falling (adjusted odds ratio = 1.60; 95% confidence interval = 1.25-2.04). The prediction utility of the drug burden index model was 0.41 (95% confidence interval = 0.39-0.42) and 0.45 (95% confidence interval = 0.43-0.47) with drugs that increased fall risk, indicating that this was a poor model for predicting falls.
Based on the results of this study, the authors noted that there is a significant association between medication use and falling. However, the medication-based models evaluated in this study were insufficient to determine predictive risk.
Medications [Medications]
Gemmeke M et al (E Koster, Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, PO Box 80082, 3508 TB Utrecht, The Netherlands; e-mail:
ATORVASTATIN No. 119
Toxic Epidermal Necrolysis
A 68-year-old female patient was hospitalized with a diffuse body rash that had persisted for 4 days prior to admission. Medications on admission included digoxin (0.125 mg daily), furosemide (0.125 mg daily), potassium chloride (1 g twice daily), warfarin, and atorvastatin (20 mg daily). A physical examination on admission noted lesions fused together, blisters, itching, tolerability, fever, no skin breakage, subcutaneous nodules, bleeding, and ulcers. Laboratory values included albumin (34.6 g/L), γ-glutamyl transpeptidase (45 U/L), glucose (13.24 mmol/L), creatine kinase MB subtype (18.0 U/L), creatine kinase (20 U/L), lactic dehydrogenase (398 U/L), and sodium (135.9 mmol/L). All drugs used prior to admission were discontinued, and treatment was initiated with loratadine (10 mg daily), cetirizine (10 mg daily), vitamin C (100 mg 3 times daily), methylprednisolone (120 mg every 12 hours), omeprazole, and topical calamine and ethacridine. Symptoms progressed to additional blisters that ruptured over a large area of skin. On day 4, intravenous immunoglobulin was administered. On day 5, facial skin peeling began, and blisters on the trunk began to rupture and peel. Mupirocin ointment was added to the therapeutic regimen. On day 17, face and trunk skin involvement resolved. The patient was discharged on day 22 without further event. On follow-up at 60 days post discharge, the patient’s skin had regrown. Testing revealed that the patient carried the HLA-A*02:07, HLA-A*11:01, HLA-B*15:02, HLA-B*40:01, HLA-C*03:04, and HLA-C*08:01 alleles.
The authors concluded that this patient developed toxic epidermal necrolysis rated as probably related to atorvastatin therapy. They noted that the allele profile may be a genetic factor involved with predisposition.
Atorvastatin [Atorvastatin]
Lv M et al (J Zhang, Department of Pharmacy, Fujian Medical University Union Hospital, #29 Xinquan Road, Fuzhou 350001, China; e-mail:
IBRUTINIB No. 120
Acute Kidney Injury
A 76-year-old male patient developed acute kidney injury approximately 4 weeks after starting ibrutinib (420 mg daily). Concurrent medications included tianeptine, enalapril, and spironolactone. A significant increase in serum creatinine was noted on admission (296 µmol/L). Because of rapidly deteriorating renal function, parenteral methylprednisolone was initiated (1 mg/kg), and ibrutinib was discontinued. Renal biopsy confirmed acute interstitial nephritis. Lower limb numbness completely resolved on day 11 of treatment, and serum creatinine was reduced to 125 µmol/L. Methylprednisolone was gradually tapered over 3 months, and estimated glomerular filtration rate stabilized at 56 mL/min/1.73 m2.
The authors concluded that this patient developed drug-induced nephritis, which was confirmed by laboratory evaluations.
Ibrutinib [Ibrutinib]
Markoth C et al (C Markoth, Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary) Ibrutinib-induced acute kidney injury via interstitial nephritis. Ren Fail 43:335-339 (Jan) 2021