Abstract
Keywords
METOCLOPRAMIDE No. 1
Acute dystonic reaction
A 6-year-old male patient was hospitalized with sudden involuntary abnormal neck and facial movements which started approximately 30 minutes after the administration of metoclopramide for the management of pertussis-associated vomiting. No other medications were noted in the report. A physical examination revealed torticollis, facial grimacing, and repetitive tongue protrusions. A neurological examination revealed no focal deficits, and vital signs were within normal limits. The drug was immediately discontinued, and treatment with intramuscular benztropine was initiated. Within a few hours after benztropine administration, the movements gradually improved. The patient was discharged on hospital day 3 without further event during follow-up.
The authors concluded that this patient developed acute dystonia related to metoclopramide therapy based on the temporal relationship between the administration of the drug and the appearance and resolution of symptoms.
Metoclopramide [Metoclopramide]
Elendu C et al (Chukwuka Elendu, University of California, Santa Cruz 95064; e-mail:
5-FLUOROURACIL No. 2
Hyperammonemic encephalopathy
A 49-year-old male patient became unconscious during the administration of the seventh cycle of FOLFIRI (Folinic Acid, Fluorouracil, Irinotecan: every 3 weeks for 12 cycles) for the treatment of stage IV sigmoid adenocarcinoma with liver metastases. Concurrent medications included ondasentron and dexamethasone. A neurological examination revealed a normal light pupillary response, weakness in the right limbs, and no meningeal sign or pathological reflex. A brain scan without contrast revealed a subacute infarction in the left capsula externa. The diagnosis was an acute ischemic stroke, which fully resolved with antiplatelet treatment. After completing the eighth cycle of FOLFIRI, the patient was discharged with only mild nausea. However, a few hours after discharge, the patient became unconscious and developed symptoms similar to those that occurred after the seventh cycle. During the ninth cycle, the patient again became unconscious near the end of the 5-fluorouracil (FU) infusion with similar symptoms presenting. Diagnosis was 5-FU-induced encephalopathy which responded to rehydration and laxatives with uneventful recovery and discharge 2 days later. The ammonia level was elevated (152.6 ug/dL). The regimen was switched from 5-FU to capecitabine.
The authors concluded that this patient developed hyperammonemic encephalopathy related to 5-FU infusions based on the temporal relationship between the administration of the drug and the appearance and resolution of symptoms. According to the Naranjo’s probability score for adverse drug reactions, there was a probable association between 5-FU administration and encephalopathy.
5-Fluorouracil [5-FU]
Yuwono KA et al (Dhite Bayu Nugroho, Clinical Epidemiology and Biostatistics Unit, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia; e-mail:
HERBAL TEAS/SUPPLEMENTS No. 3
FDA safety notification: Undeclared prescription ingredients
On November 17, 2023, the U.S. Food and Drug Administration (FDA) notified patients, consumers, and health care professionals regarding significant health risks potentially associated with several herbal teas promoted for the treatment of pain or gout that contain hidden active drug ingredients. The FDA testing identified active drug ingredients not listed on the product labels, in some cases these hidden ingredients have been prescription drugs. Tested products revealed the presence of prescription pain drugs (e.g., diclofenac) and steroids (e.g., dexamethasone). Inadvertent exposure of these products could cause potentially serious side effects or drug interactions. The FDA notification also stated that the problem of hidden drug ingredients in dietary supplements, beverages, and food products is an ongoing safety concern and that they encourage consumers and health care professionals to report any adverse events to the agency’s MedWatch Adverse Event Reporting program.
Herbal Teas/Supplements [Himalayan Pain Relief Tea, Tepee Herbal Tea, Notoginseng Formula Special Gout Granule]
FDA Safety Notifications: Himalayan Pain Relief Tea contains hidden drug ingredients. https://www.fda.gov/drugs/medication-health-fraud/himalayan-pain-relief-tea-contains-hidden-drug-ingredients; Tepee Herbal Tea contains hidden drug ingredients. https://www.fda.gov/drugs/medication-health-fraud/tepee-herbal-tea-contains-hidden-drug-ingredient; Notoginseng Formula Special Gout Granule contains hidden drug ingredients. https://www.fda.gov/drugs/medication-health-fraud/notoginseng-formula-special-gout-granule-contains-hidden-drug-ingredients (Nov 17) 2023
TIANEPTINE No. 4
FDA safety notification: Serious risks associated with use
On November 21, 2023, the U.S. Food and Drug Administration (FDA) notified patients, consumers, and health care professionals regarding significant health risks potentially associated with the use of all tianeptine products specifically to not purchase or use any Neptune’s Fix products. The safety notification emphasized that this product is not FDA approved for any medical use and is illegally sold with claims to improve brain function and treat anxiety, depression, pain, opioid use disorder, and other conditions. Several adverse reports have been received by the FDA regarding serious adverse events after the use of Neptune’s Fix products, including seizures and loss of consciousness requiring hospitalization. In addition, Neptune’s Fix products may contain other harmful ingredients not listed on the label. Previous safety notifications by the FDA have detailed serious adverse events that have been described in medical journals, in calls to U.S. poison control centers, and in reports to the FDA. Evidence suggests that tianeptine has potential for abuse, particularly in individuals with a history of opioid use disorder or dependence.
Tianeptine [Tianeptine]
FDA Safety Notification: Tianeptine Products Linked to Serious Harm, Overdoses, Death. https://www.fda.gov/consumers/consumer-updates/tianeptine-products-linked-serious-harm-overdoses-death (Feb 10) 2022. FDA Safety Notification: FDA warns consumers not to purchase or use Neptune’s Fix or any tianeptine product due to serious risks. https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-consumers-not-purchase-or-use-neptunes-fix-or-any-tianeptine-product-due-serious-risks?utm_medium=email&utm_source=govdelivery (Nov 21) 2023
ALCOHOL No. 5
Risk of glaucoma
A case-control study in Japanese adults (over the age of 40 years) evaluated the association between alcohol consumption patterns and glaucoma in 3207 glaucoma cases and 3207 matched controls.
Drinking frequency was associated with higher risk for glaucoma for “a few days/week” (odds ratio [OR]: 1.19; 95% confidence interval [CI]: [1.03, 1.38]) and “almost every day/week” (OR: 1.40; 95% CI: [1.18, 1.66]). Mean daily drinks (0-2 daily drinks) was also associated with higher risk (OR: 1.16; 95% CI: [1.03, 1.32]).
Total lifetime drinks was also associated with increased risk. Alcohol consumption levels differed between men and women, with men having positive associations for drinking frequency, mean daily drinks, and total lifetime drinks. In contrast, women had no associations with drinking frequency, average daily drinks, or total lifetime drinks.
Based on the results of this case-control study in Japanese adults older than 40 years of age, the authors suggested that both drinking frequency and amounts consumed were associated with an increased risk of glaucoma. They also suggested that further study investigate potential differences between men and women.
Alcohol [Alcohol]
Sano K et al (Kota Fukai, Department of Preventive Medicine, Tokai University School of Medicine Tokyo 105-8461, Japan; e-mail:
GLUCOSE, ORAL No. 6
FDA Safety Notification: Undeclared Prescription Ingredients
On November 15, 2023, the U.S. Food and Drug Administration announced an important recall of specific lot glucose capsules distributed by SugarMDs LLC because an FDA analysis detected the presence of undeclared prescription antidiabetic agents used to treat type 2 diabetes: glyburide and metformin. Glyburide and metformin are active ingredients found in several FDA-approved prescription drugs used to treat type 2 diabetes. Products containing glyburide and metformin cannot be marketed as dietary supplements. The inadvertent ingestion of these tainted capsules could pose serious and potentially life-threatening risks to individuals, including lactic acidosis and serious hypoglycemia, resulting in seizures, coma, or death. Consumers are advised to report any side effects associated with the use of this product.
Glucose, Oral [Glucose]
FDA Safety Notification: SugarMDs LLC Issues Voluntary Nationwide Recall of Advanced Glucose Support Supplements Capsules Due to Presence of Undeclared Glyburide and Metformin. https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/sugarmds-llc-issues-voluntary-nationwide-recall-advanced-glucose-support-supplements-capsules-due?utm_medium=email&utm_source=govdelivery (Nov 15) 2023
ANLOTINIB No. 7
Pneumothorax
A male patient in his early 70s was hospitalized with right shoulder and back pain with dyspnea approximately during the third cycle of oral anlotinib (Days 1 to 14: 12 mg every 3 weeks) for the treatment of small-cell lung cancer. Previous treatment had included 6 cycles of chemotherapy with carboplatin, target area under the curve (AUC) 5 mg/mL/min on day 1, and intravenous etoposide (100 mg/m2 on days 1-3) every 3 weeks. No concurrent medications were mentioned in the report. The patient had a negative history of previous pneumothorax events. Upon admission, a physical examination revealed the absence of lung sounds in the right lung. A chest X-ray revealed a right pneumothorax assessed as a grade 3 event. Treatment included the discontinuation of anlotinib and the initiation of closed chest drainage and oxygenation. A follow-up chest X-ray 2 days later revealed reduced extent of the right pneumothorax. A computed tomography of the chest performed 5 days later showed a reduced extent of the right pneumothorax and bilateral emphysema. The patient’s condition improved, and he was eventually discharged. Postdischarge follow-up approximately 1 year later was uneventful with no recurrence of pneumothorax evident.
The authors concluded that this patient developed right pneumothorax related to anlotinib therapy based on the temporal relationship between the administration of the drug and the appearance and resolution of symptoms. The exact mechanism of action related to the event has not been established.
Anlotinib [Anlotinib]
Lu H et al (Dong Zhao, Ward 2, Department of Medical Oncology, Lixin County People’s Hospital, Feihe Road, Lixin County, Bozhou City, Anhui Province 236700, China; e-mail:
DIETARY SUPPLEMENTS No. 8
FDA safety notification: Presence of undeclared sildenafil
On November 21, 2023, the U.S. Food and Drug Administration (FDA) notified patients, consumers, and health care professionals regarding significant health risks potentially associated with dietary supplements promoted for the treatment of erectile dysfunction that contain hidden active drug ingredients, including sildenafil. The FDA testing identified active drug ingredients not listed on the product labels, in some cases these hidden ingredients have been prescription drugs. Inadvertent exposure to sildenafil could cause potentially serious and significant side effects or drug interactions. The FDA notification also stated that the problem of hidden drug ingredients in dietary supplements is an ongoing safety concern.
Dietary Supplements [The Rock Capsule]
FDA Safety Notification: Noah’s Wholesale, LLC Issues Voluntary Nationwide Recall of the Rock Due to Presence of Undeclared Sildenafil. https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/noahs-wholesale-llc-issues-voluntary-nationwide-recall-rock-due-presence-undeclared-sildenafil?utm_medium=email&utm_source=govdelivery (Nov 21) 2023
ANTICOAGULANTS No. 9
Risk of bleeding
A pharmacovigilance safety study using a nationwide register was performed to compare major bleeding rates with the use of anticoagulants (e.g., warfarin, rivaroxaban, and apixaban) in 45 116 cancer patients with a first-time venous thromboembolism (VTE). The median age was 68 years with more than half (54.7%) being male. Major bleeding rates were assessed during initial (first 6 months) and extended treatment (6 months up to 5 years). A total of 6558 patients received warfarin, 18 196 received rivaroxaban, and 19 498 received apixaban. Dabigatran and edoxaban treatment was initiated in 642 and 220 patients, respectively. At 6 months, approximately 72%, 62%, and 61% of the patients were still receiving warfarin, rivaroxaban, and apixaban, respectively. Major bleeding was defined as any primary inpatient diagnosis of bleeding, including intracranial, gastrointestinal, hematuria, airway bleeding, anemia related to bleeding or iron deficiency, hemopericardium, gynecological bleeding, or bleeding on a death certificate. Fatal bleeding was defined as a diagnosis of bleeding documented on a death certificate or bleeding as primary diagnosis requiring hospitalization and death within 30 days of discharge from the hospital. During the first 6 months of treatment (initial treatment phase), major bleeding rates were 3.86 (95% CI: [3.14, 4.58]), 2.93 [2.55, 3.31], and 1.95 [1.65, 2.25] per 100 patient-years for warfarin, rivaroxaban, and apixaban, respectively. Adjusted hazard ratios (aHRs) were 0.89 (95% CI: [0.71, 1.12]) for rivaroxaban versus warfarin, 0.55 [0.43, 0.71] for apixaban versus warfarin, and 0.62 [0.50, 0.76] for apixaban versus rivaroxaban. During the extended treatment phase, major bleeding rates were 1.55 [1.19, 1.91], 1.05 [0.85, 1.26], and 0.96 [0.78, 1.15] per 100 patient-years for warfarin, rivaroxaban, and apixaban, respectively. Identified risk factors included previous bleeding and increased age.
Based on the results of this pharmacovigilance study in cancer patients, the authors concluded that apixaban had a lower bleeding risk than warfarin or rivaroxaban during initial treatment. In contrast, during extended treatment, bleeding risk was similar for apixaban and rivaroxaban, and higher with warfarin.
Anticoagulants [Apixaban, Rivaroxaban, Warfarin]
Glise Sandblad K et al (Katarina Glise Sandblad, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska University Hospital/Östra, Göteborg SE 416 85, Sweden; e-mail:
EYE DROPS No. 10
FDA safety alert: Risk of ocular infections due to contamination
On November 15, 2023, the U.S. Food and Drug Administration (FDA) published a safety notice alerting patients and health care professionals about several voluntary recalls related to several brands of nonprescription ophthalmic products intended for the use of lubrication or relief of ocular irritation. Although there have not been reports of eye infection received by the FDA at this time, the FDA is warning that eye infections related to the use of these products could results in partial vision loss or blindness. A list of products and NDC codes are maintained on the FDA announcement page.
Eyedrops [Various]
FDA Safety Alert: Kilitch Healthcare India Limited Issues Voluntary Nationwide Recall of Various Eye Drops for Potential Safety Reasons
COVID VACCINE No. 11
Neurological toxicities
A pharmacovigilance safety study evaluated the neurological complications after the first and/or second dose of COVID-19 vaccines in an Italian adult population (Milan, Lombardy). The NEURO-COVAX-cohort included 19 108 vaccinated people: 15 368 with BNT162b2, 2077 with mRNA-1273, 1651 with ChAdOx1nCov-19, and 12 with Ad26.COV2.S who were not included in the analysis. The mean ages of vaccine groups were 45.9, 43.7, and 66.1 years, respectively. A questionnaire was developed to assess neurological complications and contributing factors. The adherence to filling in the questionnaire was greater than 99% in the 9 days of enrollment. Approximately, one-third (31.2%) of the study population developed postvaccination neurological complications. An increased risk was found for ChAdOx1nCov-19 of tremors (vs BNT162b2, odds ratio [OR]: 5.12, 95% CI: [3.51, 7.48]); insomnia (vs mRNA: 1273, OR: 1.87, 95% CI: [1.02, 3.39]); muscle spasms (vs BNT162b2, OR: 1.62, 95% CI: [1.08, 2.46]); and headaches (vs BNT162b2, OR: 1.49, 95% CI: [0.96, 1.57]). For mRNA-1273, there were increased risks of parethesia (vs ChAdOx1nCov-19, OR: 2.37, 95% CI: [1.48, 3.79]); vertigo (vs ChAdOx1nCov-19, OR: 1.68, 95% CI: [1.20, 2.35]); diplopia (vs ChAdOx1nCov-19, OR: 1.55, 95% CI: [0.67, 3.57]); and sleepiness (vs ChAdOx1nCov-19, OR: 1.28, 95% CI: [0.98, 1.67]). No hospitalizations or deaths related to severe complications related to COVID-19 vaccinations were reported.
Based on the results of this regional pharmacovigilance study, the authors provided estimates regarding the prevalence and risk for neurological complications potentially associated with COVID-19 vaccination. The authors also noted that a limitation may have been over-reporting of side effects based on self-reporting.
COVID Vaccine [BNT162b2, mRNA-1273, ChAdOx1nCov-19]
Salsone M et al (Maria Salsone, Institute of Molecular Bioimaging and Physiology, National Research Council, 20125 Milan, Italy; e-mail:
ANTICONVULSANTS No. 12
FDA safety alert: Serious side effects, DRESS
On November 28, 2023, the U.S. Food and Drug Administration (FDA) published a warning regarding new safety data associated with the use of certain anticonvulsants including levetiracetam (Keppra, Keppra XR, Elepsia XR, Spritam) and clobazam (Onfi, Sympazan). Specifically the notification addressed the potential of a rare but serious reaction termed Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). The concern is that if not recognized early and appropriately treated, this reaction can be life-threatening. In addition, the FDA has stated that warnings regarding this risk will be added to the product prescribing information and patient Medication Guides for these drugs. The notification also noted that symptoms of DRESS can include fever, rash, swollen lymph nodes, or injury to organs including the liver, kidneys, lungs, heart, or pancreas. The product information warnings for both levetiracetam and clobazam medicines will include information that early symptoms of DRESS such as fever or swollen lymph nodes can be present even when a rash is not present.
Anticonvulsants [Keppra, Keppra XR, Elepsia XR, Spritam, Onfi, Sympazan]
FDA Safety Communication: FDA warns of rare but serious drug reaction to the antiseizure medicines levetiracetam (Keppra, Keppra XR, Elepsia XR, Spritam) and clobazam (Onfi, Sympazan). https://www.fda.gov/media/174157/download?attachment (Nov 28) 2023
DENOSUMAB, IRON (IV) No. 13
Severe hypocalcemia
A 66-year-old female patient developed paresthesias and fatigue approximately 2 weeks after receiving subcutaneous denosumab (60 mg) for the management of osteoporosis and intravenous iron carboxymaltose (1 gram) in an outpatient setting. Abnormal laboratory assessments included decreased values for corrected calcium (1.59 mmol/L), phosphate (0.60 mmol/L), magnesium (0.62 mmol/L), and 25(OH)-vitamin D (45 nmol/L). Elevated values included parathyroid hormone (PTH) (29 pmol/L). Baseline values taken 1 month prior to this event reavealed normal values for corrected calcium (2.44 mmol/L), normal phosphate (1.10 mmol/L) but chronic hypomagnesaemia (0.61 mmol/L). Management of the interaction was not provided in the report.
The authors concluded that this patient developed severe hypocalcemia related to the concurrent administration of denosumab and intravenous iron based on the temporal relationship between the administration of the drugs and the appearance of symptoms. They suggested that the co-administration of these drugs, iron induced hypophosphatemia can contribute to a profound decrease in serum calcium levels.
Denosumab [Denosumab]
Iron, Intravenous [Iron]
Cuthberston L et al (Laura Cuthberston, Departments of Nephrology, Royal Hobart Hospital, Hobart, Tasmania, Australia; e-mail: None provided) Severe hypocalcaemia after denosumab and intravenous iron: a cautionary tale. Intern Med J 53:2139–2140 (Nov) 2023
COVID VACCINE No. 14
Vertigo
Over a 1-year period, a prospective observational study evaluated 50 patients with episodic vertigo or dizziness which developed post-COVID vaccination. Most (n = 35) patients were female with a mean age of 35 years. Approximately two-thirds (66%) of the study participants had received Moderna vaccine, 20% had received the Astra Zeneca vaccine, and 14% received the Pfizer-BioNTech (BNT) vaccine. More than half (58%) had received 2 doses, 32% had received 2 to 4 doses, and 10% had 1 dose only. The authors noted that patients who had received multiple doses did not necessarily receive the same type of vaccine for all doses. The mean age of the groups was 60, 53, and 38 years, respectively. Symptoms included vertigo/dizziness (100%), tinnitus (70%), headache (66%), nausea/vomiting (62%), hearing loss (46%), and fullness sensation (42%). Diagnosis was determined as Meniere’s disease (MD) (26 %), vertebrobasilar artery insufficiency (VBI) (18%), vestibular migraine (16%), benign paroxysmal positional vertigo (16%), autonomic dysfunction (12%), and other (12%). Overall, the median time to onset of vertigo/dizziness postvaccination was 10 (range: 0-30) days. For the Moderna, Astra Zeneca, and BNT groups, the median onset was 12, 6, and 6 days, respectively. Supportive treatment was provided in all patients; resolution of symptoms occurred within 1 month.
Based on the results of this observational study, the authors concluded that postvaccination vertigo/dizziness is a potential side effect of COVID vaccination and may manifest as exacerbation of previous neuro-otological disorder. They noted that symptomatic relief as eventually achieved and thus, the benefit-risk ratio of COVID vaccination is maintained.
COVID Vaccine [COVID Vaccine]
Yan HY et al (Yi-Ho Young, Department of Otolaryngology, National Taiwan University Hospital, 1, Chang-Te St., Taipei, Taiwan; e-mail:
OFLOXACIN (OCULAR) No. 15
Stevens Johnson syndrome
A 36-year-old female patient was hospitalized with a fever, lip edema, conjunctival redness, rash over the palms, and blistering beneath the tongue which developed within 24 hours after starting ofloxacin ophthalmic solution. No other medications were noted in the report. A skin examination upon admissions revealed desquamation and edema of the lips and oral mucosa. Bilateral conjunctival injections were noted. Serological screenings for infectious causes were negative. A bunch biopsy revealed vacuolar interface dermatitis. Empiric treatment included the initiation of intravenous vancomycin, piperacillin/tazobactam, oral nystatin, and intravenous methylprednisolone. The patient was eventually discharged with follow-up care. By day 20, the rash had resolved and by day 30, the blistering and ulceration had healed.
The authors concluded that this patient developed Stevens Johnson Syndrome related to the ocular use of ofloxacin based on the temporal relationship between the administration of the drug and the appearance and resolution of symptoms.
Ofloxacin, Ocular [Ofloxacin]
Shaw B et al (Stephen Carlan, Division of Academic Affairs and Research, Orlando Regional Medical Center, Orlando, FL; e-mail:
CLOZAPINE No. 16
Adverse drug reactions
A cross-sectional study using data from the Clozapine International (CLOZIN) consortium evaluated the prevalence of clozapine-associated adverse drug reactions (ADRs) in patients (n = 698) receiving the drug for the management of schizophrenia. A standardized questionnaire was used to survey patients regarding specific ADRs, including drowsiness, dizziness, hypersalivation, increased sleep necessity, nausea, urinary incontinence, heart palpitations, weight gain, decreased libido, and constipation. The mean age of the patient group was 43.6 years with more than half (68.5%) being male. The mean dose of clozapine was 310.4 mg daily with a mean serum level of 421.6 mcg/L. Slightly more than half (55.6%) of the patients received clozapine monotherapy; the remaining received the drug with 1 to 4 other antipsychotics. The mean number of ADRs during clozapine treatment was 4.8; 2.4% of participants reporting no ADRs. The most frequently reported ADRs included hypersalivation (74.6 %), weight gain (69.3 %), and increased sleep necessity (65.9 %). The mean weight prior to clozapine therapy was 78.7 kg which increased to 88.6 kg during clozapine therapy. Patients with lower a lower body mass index prior to treatment were more likely to experience significant weight gain (>10%). There were no differences in ADR prevalence rates between participants receiving clozapine monotherapy and polytherapy.
Based on the results of this study, the authors concluded that there was a high prevalence of certain ADRs.
Clozapine [Clozapine]
van der Horst MZ, Meijer Y, de Boer N, Guloksuz S, Hasan A, Siskind D, Wagner E; CLOZIN consortium; Okhuijsen-Pfeifer C, Luykx JJ. Comprehensive dissection of prevalence rates, sex differences, and blood level-dependencies of clozapine-associated adverse drug reactions. Psychiatry Res 330:115539 (Dec) 2023
LENALIDOMIDE No. 17
Symmetrical drug-related intertriginous and flexural exanthema
An 80-year-old male patient developed a rash in the intertriginous areas during chronic maintenance lenalidomide therapy for the treatment of multiple myeloma for 2 years. Concurrent medications were not noted in the report. Initially, the diagnosis was a yeast infection which was treated unsuccessfully with topical miconazole compounded with betamethasone. Prior history indicated that the patient had a previous similar rash 3 months prior to this event which resolved upon discontinuation of lenalidomide. The same rash recurred approximately 10 days after re-initiation of the drug. A physical examination revealed symmetric, scaly erythematous patches involving the walls of the axillae, bilateral dorsal forearms, bilateral inner thighs, and lower pannus. Screenings for fungal and yeast causes were negative. A punch biopsy indicated chronic dermatitis with dermal plasma cells. Lenalidomide was discontinued with significant improvement of symptoms within 24 hours. Diagnosis was made as symmetrical drug-related intertriginous and flexural exanthema (SDIFE).
The authors concluded that this patient developed a SDIFE related to the use of lenalidomide based on the temporal relationship between the administration of the drug and the appearance and resolution of symptoms. In addition, a positive rechallenge confirmed the causality of the reaction associated with the drug administration. Based on the Naranjo causality algorithm, the reaction in relation to the administration of the drug was rated as probable.
Lenalidomide [Lenalidomide]
Patel RT et al (Mariana A Phillips, 1 Riverside Circle, Suite 300, Roanoke, VA 24016; e-mail:
IMMUNE CHECKPOINT INHIBITORS No. 18
Facial palsy
A systematic review evaluated the risk of facial nerve palsy associated with the use of immune checkpoint inhibitor (ICI) therapy based on data from a total of 21 randomized controlled trials (RCTs; n = 19 305 patients) and a separate retrospective pharmacovigilance study of FDA Adverse Event Reporting System (FAERS) database. Search terms used for ICI therapy included the following ICIs: nivolumab, pembrolizumab, cemiplimab, atezolizumab, avelumab, durvalumab, ipilimumab, and tremelimumab. The primary outcome was the risk of facial palsy events associated with ICIs. A fixed model analysis was used. Analysis of the RCTs indicated that there was an increased risk of facial palsy associated with the use of ICI therapy occurring in 23/10 779 patients (odds ratio [OR]: 3.07, 95% CI: [1.43, 6.58]). However, subgroup analysis indicated that this risk was not significantly impacted by tumor type, ICIs treatment schedule, case of events, study design, median PFS, and publication status. No publication bias was observed for the outcome of ICI-facial nerve palsy. The pharmacovigilance study using data from the FAERS database identified a total of 274 cases of ICI associated cases of facial palsy with most (79.6%) cases from the United States, Europe, and Japan. More than half (63.8%) of the cases were in males with a median age at onset of 65 years. The most common indications for ICIs use were melanoma (35.4%), lung cancer (23.0%), and renal cancer (10.9%). Immune checkpoint inhibitors were significantly associated with over-reporting frequencies of facial palsy (reporting odds ratio [ROR]: 3.03, 95% CI: [2.69, 3.42]). The median onset time of facial palsy was 5.5 weeks after the initiation of ICI therapy. In cases where drug therapy discontinuation was provided (~78%), symptoms resolved/abated with drug withdrawal in most cases (positive dechallenge: 82.8%).
Based on the results of this systematic review of the medical literature and a retrospective pharmacovigilance study of FAERS database, the authors concluded that therapy with ICIs were significantly associated with increased risk of facial palsy in both trial settings and in clinical practice.
Immune Checkpoint Inhibitors [Nivolumab, Pembrolizumab, Cemiplimab, Atezolizumab, Avelumab, Durvalumab, Ipilimumab and Tremelimumab]
Zhu J et al (Xiaoxia Yu amd Junyan Wu, Department of Pharmacy, Sun-Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yanjiang West Road, Guangzhou 510120, PR China; e-mails:
DIETARY SUPPLEMENTS No. 19
FDA safety notification: Presence of undeclared sildenafil
On November 29, 2023, the U.S. Food and Drug Administration (FDA) notified patients, consumers, and health care professionals regarding significant health risks potentially associated with dietary supplements promoted for the treatment of erectile dysfunction that contain hidden active drug ingredients, including sildenafil. The FDA testing identified active drug ingredients not listed on the product labels, in some cases, these hidden ingredients have been prescription drugs. Inadvertent exposure to sildenafil could cause potentially serious and significant side effects or drug interactions. The FDA notification also stated that the problem of hidden drug ingredients in dietary supplements is an ongoing safety concern.
Dietary Supplements [Magnum XXL 9800]
FDA Safety Notification: Meta Herbal Issues Voluntary Nationwide Recall of Magnum XXL 9800 Due to Presence of Undeclared Sildenafil. https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/meta-herbal-issues-voluntary-nationwide-recall-magnum-xxl-9800-capsules-due-presence-undeclared?utm_medium=email&utm_source=govdelivery (Nov 29) 202
CAR T-CELL IMMUNOTHERAPIES No. 20
FDA safety notification: Risk of T-cell malignancies
On November 28, 2023, the U.S. Food and Drug Administration (FDA) published a safety notification alerting the health care community and patients regarding reports of T-cell malignancies in patients who received treatment with BCMA- or CD19-directed autologous CAR T cell immunotherapies. These reports were received from clinical trials and/or postmarketing adverse event data sources. Based on analysis of these reports, the FDA has determined that the risk of T-cell malignancies is applicable to all currently approved BCMA-directed and CD19-directed genetically modified autologous CAR T cell immunotherapies. The statement also noted that at this time, the overall benefits of these products continue to outweigh their potential risks for their approved uses. The FDA will investigate the risk of T cell malignancy and evaluate the need for regulatory action, include changes in product labeling. Currently, the risk of developing secondary malignancies is labeled as a class warning in the prescribing information for approved BCMA-directed and CD19-directed genetically modified autologous T cell immunotherapies. The notification also stated that patients and clinical trial participants receiving treatment with these products should be monitored life-long for new malignancies.
CAR T-Cell Immunotherapies [Abecma, Breyanzi, Carvykti, Kymriah, Tecartus, Yescarta]
FDA Safety Notification: FDA Investigating Serious Risk of T-cell Malignancy Following BCMA-Directed or CD19-Directed Autologous Chimeric Antigen Receptor (CAR) T cell Immunotherapies. https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/fda-investigating-serious-risk-t-cell-malignancy-following-bcma-directed-or-cd19-directed-autologous (Nov 28) 2023
COVID VACCINE No. 21
Herpes zoster
An 82-year-old male patient developed left-sided chest and upper back pain approximately 1 week after receiving the COVID vaccine booster (BNT162b2). Concurrent medications at the time of event included metformin extended-release (1 g nightly), gliclazide modified-release (30 mg once daily), amlodipine (5 mg once daily), atorvastatin (10 mg nightly), and aspirin (100 mg once daily). Specific symptoms included intermittent, burning pain which interrupted sleep. Treatment with acetaminophen (1 gm) as needed alleviated the pain but did not resolve it. A medical history revealed that he had no recent direct contact with anyone with active shingles prior to development of his symptoms, had no prior history of herpes zoster, and was uncertain regarding varicella zoster during childhood. A physical examination revealed several clustered erythematous vesicular lesions within the left T3 dermatome affecting the anterior and posterior regions. The patient was diagnosed with herpes zoster. Treatment included the initiation of acyclovir (800 mg 5 times daily for 10 days) and gabapentin (300 mg daily). At follow-up 1 week later, the vesicles had begun healing and the pain was significantly decreased.
The authors concluded that this patient developed herpes zoster following a booster dose of the COVID (BNT162b2) vaccine based on the temporal relationship between the administration of the dose and the appearance and resolution of symptoms.
COVID Vaccine [BNT162b2 Vaccine]
Shahrudin MS et al (Mohamed-Syarif Mohamed-Yassin, Department of Primary Care Medicine, Universiti Teknologi MARA, Batu Caves, Selangor, Malaysia; e-mail:
ALPRAZOLAM No. 22
Severe withdrawal symptoms: Psychosis and delirium
A 27-year-old male patient was hospitalized with acute behavioral disturbances 4 days after stopping benzodiazepines in an attempt at self detoxification. Specific symptoms included marked agitation, illogical speech, paranoia, and perceptual disturbances, and auditory hallucinations. Concurrent medications were not noted in the report but a medical history from relatives indicated that the patient had a long history of substance use, including benzodiazepine (high-dose alprazolam) and cannabis use for a decade. A urine screen was positive for benzodiazepines and cannabis. Treatment upon admission included olanzapine, haloperidol, promethazine, and lorazepam for the management of psychosis and agitation. Despite treatment, the patient continued to be highly agitated with extreme restlessness and purposeless motor activity, which resulted in a metatarsal fracture. Chlordiazepoxide therapy was initiated, and haloperidol was tapered and discontinued. Gradually, the patient became less disorientated and displayed more organized thinking with partial control of symptoms with increased doses of chlordiazepoxide (200 mg) and diazepam. Although the patient substantially improved, he subsequently was discharged against medical advice on hospital day 8. The diagnosis was delirium and psychosis related to severe alprazolam withdrawal. Postdischarge follow-up with a tapering diazepam detoxification regimen over a 6-month period. Eventually, the patient developed a relapse of illicit benzodiazepine use following completion of the detoxification program.
The authors concluded that this patient developed severe delirium and psychosis related to severe alprazolam withdrawal.
Alprazolam [Xanax]
Conaty O et al (Oisín Conaty, Department of Psychiatry, St. Vincent’s Hospital, Richmond Road, Fairview, Dublin, Ireland; e-mail:
COCAINE No. 23
Venous thromboembolism
A 34-year-old male patient was hospitalized with severe dyspnea. Medications were not reported upon admission, but the patient denied substance abuse. Abnormal laboratory tests included decreased hemoglobin (5.6 mg/dL) and elevated D-dimer (1445 ng/mL). A computed tomography chest scan revealed acute pulmonary embolism with right upper and lower lobe infiltrates. Additional scans indicated other venous thromboses in the ileac, femoral, and right renal veins. Treatment was initiated with heparin, ceftriaxone, azithromycin, and 2 units of packed red blood cells. An echocardiogram showed a severely enlarged right ventricular chamber. Although a coagulation disorder was suspected, the coagulation panel was negative. Despite negative serological test for infectious or immunological hepatic causes, the liver function tests were increasing. On hospital day 8, the patient admitted to snorting cocaine. The diagnosis was venous thromboembolism and acute livery injury related to cocaine use. Gradually, the patient’s condition improved, and he was discharged with treatment including oral apixaban (5 mg for up to 6 months) and oxygen.
The authors concluded that his patient developed significant venous thromboembolism, and acute liver injury related to cocaine abuse based on the temporal association between the substance abuse and the appearance and resolution of symptoms.
Cocaine [Cocaine]
Patel KH et al (Khyati Patel, Department of Hospital Medicine, Mayo Clinic Health System, La Crosse, WI; e-mail:
OFLOXACIN No. 24
Fixed drug eruption
A 62-year-old male patient developed painful erosions in his oral cavity, nose, and perianal area after ofloxacin treatment (3 days) that was started postdental visit. No other medications were mentioned in the report. A physical examination revealed bilateral conjunctival hyperemia, erosions, and ulcers on the lips; buccal, gingival, and glossal mucosae; and palate. Laboratory values were within normal limits. Histopathological results revealed dense subepithelial infiltrates of inflammatory cells, including lymphocytes and neutrophils. Immunological testing revealed IgA reactivity with 200-kDa p200/laminin γ1. Treatment with a tapering regimen of oral prednisolone over 2 weeks resulted in resolution of the mucosal lesions. However, the patient experienced 3 more episodes of similar lesions lasting approximately 5 to 12 days at 3, 8, and 10 months after the first episode. At the time, the patient denied taking any medication but a thorough medical history revealed that he was prescribed oral ofloxacin (for 3 days) after every dental visit. The dose of prednisolone to manage the lesions was increased to 30 mg/day with resolution of symptoms within approximately 1 week. A provocation test with a dose of ofloxacin produced an itchy sensation on the oral, conjunctival, and perianal areas within 1 hour. Once ofloxacin was stopped, there were no further recurrences.
The authors concluded that his patient developed fixed drug eruption related to ofloxacin based on the temporal association between the administration of the drug and the appearance and resolution of symptoms.
Ofloxacin [Ofloxacin]
Yoshida N et al (Fumi Miyagawa, Department of Dermatology, Nara Medical University School of Medicine, 840 Shijo, Kashihara, Nara 634-8522, Japan; e-mail:
LINEZOLID No. 25
Purpuric drug eruption
An 89-year-old patient was hospitalized with whole-body rash and generalized pruritus that began 5 days after receiving oral linezolid (600 mg every 12 hours) for iatrogenic pneumonia. Concurrent medications were not noted in the report. The rash continued to worsen within 48 hours after discontinuation of the drug. Upon admission, a physical examination revealed disseminated, warm and nonblanchable, purpuric macules and patches over the bilateral upper extremities, abdomen, inguinal area, and bilateral lower extremities. Most laboratory values were within normal limits, with the exception C-reactive protein, which was elevated. Microbiological cultures were negative. A punch biopsy revealed a superficial and perivascular lymphocytic infiltrate with dermal eosinophils. Treatment included the initiation of intravenous methylprednisolone (80 mg every 8 hours), betamethasone dipropionate cream (twice a day), pramoxine 1% lotion (as needed), and oral cetirizine (10 mg daily). Symptoms significantly improved within 1 week of therapy.
The authors concluded that this patient developed a purpuric drug eruption associated with linezolid based on the temporal association between the administration of the drug and the appearance and resolution of symptoms.
Linezolid [Linezolid]
Tirú-Vega MA et al (Marilee A Tiru-Vega, Department of Internal Medicine, VA Caribbean Healthcare System, San Juan, Puerto Rico; e-mail:
LOSARTAN No. 26
Visceral angioedema
An 81-year-old female patient had several emergency room visits for abdominal pain, nausea, with a single episode of bloody diarrhea within 5 weeks after the initiation of losartan therapy for the management of hypertension. Other medications were not noted in the report. Diagnostic workup and scans revealed mucosal thickening and submucosal edema of the transverse, descending, and sigmoid colon. Symptoms persisted after the initial assessment. It was proposed that angioedema could be responsible for the mucosal thickening noted on her scan images. Treatment included the discontinuation of losartan. Follow-up assessment revealed that the abdominal pain resolved within 3 days after the withdrawal of losartan without recurrence over the following 7-week period.
The authors concluded that this patient developed a rare case of visceral angioedema related to the use of losartan.
Losartan [Losartan]
Rosas S et al (Steven Rosas, Mayo Clinic Health System, 2321 Stout Road, Menomonie, WI 54751; e-mail:
METHOTREXATE No. 27
Osteopathy, traumatic stress fractures
Two cases of traumatic stress fractures associated with low dose methotrexate therapy are described.
Patient #1: A 69-year-old female patient developed significant left ankle pain resulting in limping during chronic therapy for the management of seropositive rheumatoid arthritis. Medications at the time of the pain presentation included methotrexate (25 mg weekly), hydroxychloroquine, and denosumab (60 mg every 6 months). A computed tomography (CT) scan to measure bone mineral density performed 5 years prior to this event showed a T-score of 1.76 at L1-L3 and a femoral neck bone density T-score of 2.89. A physical examination demonstrated tenderness over both ankles without signs of active joint disease. However, a technetium bone scan showed bilateral calcaneal stress fractures with bony sclerosis. Levels of vitamin D, calcium, phosphate, alkaline phosphatase, and parathyroid hormone (PTH) levels were normal. Methotrexate was discontinued. Ankle pain resolved over a 6-week period with immobilization. A repeat bone density evaluation showed a T-score of 0.2 at L3-L4, 3.0 in the left femur and 2.0 at the left radius. Denosumab was continued and ankle pain resolved.
Patient #2: A 56-year-old female patient discomfort in both ankles approximately 2 years after starting methotrexate therapy (25 mg weekly) for the management of arthritis. Concurrent therapy at the time of event included intermittent short courses of low-dose prednisolone and ustekinumab for the management of Crohn’s disease. Though X-rays of the ankles were normal, magnetic resonance imaging (MRI) scans revealed an incomplete fracture of the left cuboid and an incomplete fracture of the right talus. A scan to measure bone density showed a T-score of 2.4 in the hip and 2.3 in the lumbar spine.
Levels of calcium, phosphate, alkaline phosphatase, and PTH levels were normal. Treatment with immobilization for 6 weeks and the discontinuation of methotrexate resulted in complete resolution of the ankle pain. Intravenous zoledronic acid (5 mg) was also initiated.
The authors concluded that these patient developed traumatic stress fractures related to methotrexate therapy based on the temporal relationship between the administration of the drug and the appearance and resolution of symptoms.
Methotrexate [MTX]
Youssef M et al (Peter Youssef, Royal Prince Alfred Hospital and Institute of Musculoskeletal Medicine, Faculty of Medicine and Health, Sydney University Medical School, Sydney, New South Wales, Australia; e-mail:
DICLOFENAC, TOPICAL No. 28
DRESS, liver injury
A 64-year-old male patient developed a rash involving the scalp, neck, back, and trunk accompanied by abdominal fullness and anorexia approximately 2.5 weeks after initiating topical diclofenac 1% gel to the foot several times a day. Concurrent medications included topical metronidazole for rosacea. The patient had allergies to piroxicam and topical ivermectin. The rash was initially attributed to a photosensitivity reaction, thus no treatment was initiated. However, the abdominal symptoms worsened, and symptoms progressed to diarrhea and fever. A physical examination upon admission revealed diffuse abdominal tenderness without rebound or guarding. Abnormal laboratory values included elevated white blood cell count with 25% eosinophils, elevated levels of creatinine (116.69 μmol/L), aspartate aminotransferase (236 U/L), alanine aminotransferase (445 U/L), and alkaline phosphatase (293 U/L). A computed tomography scan was suggestive of gastroenteritis and nonspecific distension of the gallbladder. An abdominal ultrasound scan demonstrated acute cholecystitis. Treatment included the initiation of intravenous fluids and piperacillin-tazobactam. Serological screenings for infectious causes were negative but empiric treatment was started with praziquantel on hospital day 7 because of recent international travel. The diagnosis was drug reaction with eosinophilia and systemic symptoms (DRESS) with skin, gallbladder, and liver involvement related to topical diclofenac therapy. Gradually, the symptoms and laboratory values improved with discharge occurring on hospital day 10.
The authors concluded that this patient developed DRESS related to topical diclofenac therapy based on the temporal relationship between the administration of the drug and the appearance and resolution of symptoms.
Diclofenac, Topical [Voltaren]
Tsevat RK et al (Rebecca K. Tsevat, 1100 Glendon Ave, Suite 900, Los Angeles, CA 90024; e-mail:
AZITHROMYCIN No. 29
Drug induced liver injury
A 76-year-old male patient was hospitalized with jaundice, and urinary discoloration approximately 20 days after starting azithromycin (250 mg for 42 days) and atovaquone (750 mg twice daily). Other concurrent medications included simvastatin. A computed tomography of the abdomen revealed normal liver parenchyma, nonobstructive cholestasis, and patent portohepatic vasculature. An N-acetylcysteine treatment protocol was initiated for suspected drug-induced liver injury (DILI). Abnormal laboratory values included elevated total bilirubin (477 μmol/L), aspartate transaminase (158 units/L), and alkaline phosphatase (255 units/L). The diagnosis was DILI secondary to prolonged azithromycin therapy. Serological screenings for infectious causes were negative. An expedited liver transplant evaluation was initiated in light of overall poor prognosis. The patient was discharged with outpatient hepatology and surgery follow-up.
The authors concluded that this patient developed DILI related to prolonged azithromycin tehrapy based on the temporal relationship between the administration of the drug and the appearance and resolution of symptoms.
Azithromycin [Azithromycin]
Dawkins M et al (Makeda Dawkins, Department of Internal Medicine, Westchester Medical Center, Taylor Care Pavilion—Room C-343, Valhalla, New York 10595; e-mail:
ANTIBIOTICS No. 30
Diarrhea
A retrospective pharmacovigilance study evaluated the risk signals of antibiotic-related diarrhea associated with various antibiotics using data from the FDA Adverse Event Reporting System (FAERS) database from the first quarter of 2004 to the third quarter of 2022. A total of 5397 reports were identified and met the inclusion requirements. Almost all antibiotics, except tobramycin and minocycline (reporting odds ratio [ROR]: 0.98; 95% CI: 0.64-1.51 and 0.42; 95% CI: 0.16-1.11, respectively), showed a significant correlation with antibiotic-related diarrhea. The top 3 antibiotics associated with diarrhea included lincomycins (ROR: 29.19; 95% CI: 27.06-31.50), third-generation cephalosporins (ROR: 15.96; 95% CI: 14.58-17.47), and first/second-generation cephalosporins (ROR: 15.29; 95% CI: 13.74-17.01). The vast majority (91.35%) of antibiotics had an onset time of less than 4 weeks with approximately half (52.47%) occurring less than 1 week and 38.88% with an onset of 1 to 4 weeks. The median time onset was within 2 weeks for most antibiotics. The shortest median time to onset was for cefoperazone (3; range: 2-10 days) and cefazolin (3; range: 1-6 days). Approximately one-fourth (23.8%) of the cases were classified as serious and most cases being classified as mild and moderate. Novel cephalosporins had the highest mortality rate (37.5%).
Based on the results of this real-world disproportionality study using data from the FAERS database, the authors concluded that there is a significant correlation between almost all antibiotics and antibiotic-related diarrhea, particularly lincomycins and β-lactam antibiotics.
Antibiotics [Cephalosporins, Lincomycins]
Huang H et al (Jing Peng, Department of Clinical Pharmacy, Affiliated Hospital of Jining Medical University, Jining, Shandong, China; e-mail:
NAB-PACLITAXEL No. 31
Stress cardiomyopathy
A 64-year-old female patient was hospitalized after developing severe dyspnea and hypoxia shortly after the initiation of the first cycle pf nab-paclitaxel infusion for the management of lung adenocarcinoma. Premedicants included dexamethasone, diphenhydramine, and famotidine. Treatment included intramuscular epinephrine, intravenous methylprednisone, diphenhydramine, and albuterol-ipratropium nebulization. A 12-lead electrocardiogram revealed sinus tachycardia and ST segment and T wave abnormalities suggestive of prior septal infarction. A transthoracic echocardiogram (TTE) showed an ejection fraction of 25%. Akinesis of the apical anterior segment, suggesting stress-induced/Takotsubo cardiomyopathy. The patient’s condition stabilized and was discharged with acubitril-valsartan and metoprolol succinate as guideline-directed medical therapy for Takotsubo cardiomyopathy. At follow-up 3 months later, the patient remained asymptomatic. Chemotherapy was modified with a lower dose.
The authors concluded that this patient developed stress cardiomyopathy related to paclitaxel.
Nab-Paclitaxel [Abraxane]
Singh H et al (Harjinder Singh, Graduate Medical Education, Henry Ford Allegiance Health, 205 N East Avenue, Jackson, MI 49201; e-mail: