Reporting on Adverse Clinical Events

Use During Pregnancy and Risk of Gestational Diabetes

A systematic review using Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines to evaluate the risk of gestational diabetes associated with antipsychotic use during pregnancy. Articles were selected from a comprehensive search method including published literature from January 1, 1996, through March 31, 2018. Experimental studies involving animals, reviews, case reports, editorials, and comments on the reports were excluded from the review. A total of 10 relevant studies that met the review criteria were included in the evaluation. The prevalence rates of gestational diabetes in pregnant women taking antipsychotic drugs and the nonmedication group were 2.6% to 22% and 0.95% to 10.7%, respectively. In 4 studies, the reported adjusted risk ratio for gestational diabetes mellitus in the antipsychotic group compared with the control group ranged from 0.95 to 1.78. A total of 5 studies reported no significant difference in gestational diabetes between the groups. In addition, the study results also suggested that underlying maternal psychopathologies might affect the risk of developing gestational diabetes mellitus.

Based on the results of this review, the author concluded that there is conflicting evidence regarding the risk of developing gestational diabetes and antipsychotic use during pregnancy. Some studies found an increased risk, while others found no significant differences when antipsychotic use was compared with nonmedication use.

Antipsychotics [Antipsychotics]

Uguz F (F Uguz, Necmettin Erbakan Üniversitesi Meram Tıp Fakültesi, Psikiyatri Anabilim Dalı Meram, 42080 Konya, Turkey; e-mail: farukuguz@gmail.com) Antipsychotic use during pregnancy and the risk of gestational diabetes mellitus: a systematic review. J Clin Psychopharmacol 39:162–167 (Mar) 2019

Injuries Associated With Auto-Injectors

A retrospective review of unintentional epinephrine auto-injector exposures was performed using the American Association of Poison Control Center’s National Poison Data System records from January 1, 2013, to December 31, 2014. A total of 6806 cases of unintentional epinephrine auto-injector exposures were reported; of which 3933 cases occurred with EpiPen, 2829 cases with EpiPen Jr, and 44 cases with Auvi-Q. No case were reported with Adrenaclick. The majority of reported cases (41%) occurred in children 5 years or younger and in males (54%). Minor clinical effects occurred in 42% of the cases. Moderate effects occurred in 8%. Serious sequelae were reported in only 2 cases. The most common site for unintentional injection with the traditional epinephrine auto-injectors (EpiPen and EpiPen Jr) was 58% and 39% in the digit or thumb, respectively. With Auvi-Q, the most common site was the leg (78%). It was noted that the number of reports in this analysis was higher than the number reported in 2006 and 2007.

Based on the results of this review, the authors concluded that the number of unintentional epinephrine auto-injector cases reported to American Poison Centers in 2013-2014 has increased compared with previous data. They also noted that there are inherent limitations of voluntary reporting data and that more research is needed to identify incidence of unintentional exposures and the effectiveness of epinephrine auto-injector redesign.

Epinephrine [“EpiPen,” “EpiPen Jr,” “Auvi-Q”]

Anshien M et al (BK Wills, Virginia Commonwealth University Medical Center, Virginia Poison Center, 830 E Main St, Richmond, VA 23219; e-mail: brandon.wills@vcuhealth.org) Unintentional epinephrine auto-injector injuries: a national poison center observational study. Am J Ther 26:e110–e114 (Jan) 2019

Withdrawal Syndrome

A 53-year-old male developed abiraterone withdrawal syndrome, a transient decrease in the prostate-specific antigen, when abiraterone (1000 mg every 24 hours) was stopped after 11 months of treatment for metastatic prostate adenocarcinoma. Previous treatment with leuprolide acetate plus bicalutamide had resulted in bicalutamide withdrawal syndrome for 1 year followed by biochemical progression but radiological stability. Concurrent medications included prednisone (5 mg every 12 hours) and leuprolide. When prostate-specific antigen increased to 277 ng/mL and clinical progression with lumbar pain and bone metastases occurred on treatment, abiraterone was discontinued. Prednisone and leuprolide were continued. Pain disappeared after 4 weeks, repeat prostate-specific antigen indicated a biochemical response (98 ng/mL), and radiologic stability was present. Six months later, prostate-specific antigen was 26 ng/mL; however, 8 months after discontinuation of abiraterone, prostate-specific antigen increased to 50 mg/dL and bone metastases progressed with a new bone lesion. Additional treatment included docetaxel.

The authors concluded that this case described abiraterone withdrawal syndrome in a patient not previously treated with chemotherapy. The proposed mechanism was androgen receptor activation induced by abiraterone metabolites.

Abiraterone [“Yonsa,” “Zytiga”]

Marin S et al (S Marin, Pharmacy, Consorci Sanitari del Maresme, Mataro, Catalunya, Spain; e-mail: sergiomarinrubio@gmail.com) Long-term abiraterone withdrawal syndrome. J Clin Pharm Ther 43:714–716 (Oct) 2018

FDA Safety Communication: Undeclared Prescription Ingredient

On February 25, 2019, the US Food and Drug Administration released an announcement regarding the recall of a dietary supplement used for weight loss due to the detection of undeclared ingredients, including sibutramine and phenolphthalein. Sibutramine, an appetite suppressant, is no longer available on the US market having been withdrawn due to safety concerns. Specifically, this agent was associated with increases in blood pressure and pulse rate, posing a particular risk in patients with cardiovascular disease. Phenolphthalein, an ingredient formerly used in nonprescription laxatives, was also withdrawn from the US market due to concerns regarding carcinogenicity. Additional health risks include serious gastrointestinal disturbances, irregular heartbeat, and cancer with long-term use. The use of either of these ingredients is not recommended, and renders it an unapproved drug for which safety and efficacy has not been established and, therefore, subject to recall. It should also be noted that no reports of adverse events have been related to this recall.

Dietary Supplement [“Golean DETOX”]

FDA Safety Communication: Golean Detox USA issues voluntary nationwide recall of Golean DETOX capsules due to presence of undeclared sibutramine and phenolphthalein. https://www.fda.gov/Safety/Recalls/ucm632004.htm?utm_campaign=FDA%20MedWatch%20Recall%20Notice%20-%20Golean%20DETOX%20Capsules%20by%20Golean%20Detox%20USA%3A%20Recall%20-&utm_medium=email&utm_source=Eloqua (Feb 25)2019

Acute Angle Glaucoma

A 52-year-old female patient developed acute bilateral ocular pain and decreased visual acuity approximately 1 day after starting Ma-Huang for weight loss. No other medications were noted in the report. Additional symptoms included headache, nausea, and vomiting. An initial ocular vision examination revealed best corrected visual acuity of 0.7 in the right and left eyes, respectively. Intraocular pressures were 64 mm Hg and 68 mm Hg in the right and left eyes, respectively. On slit lamp examination, the cornea was mildly edematous. On ocular ultrasonography, the choroid was thickened, but choroidal effusion was not observed. A diagnosis of bilateral angle-closure glaucoma was determined. Treatment included intravenous 20% mannitol, ocular brimonidine, and ocular dorzolamide/timolol. By the following day, intraocular pressures had decreased to 7 mm Hg in both eyes on average. After 4 weeks, pressures were was 13 mm Hg and 12 mm Hg, respectively. No further events occurred during follow-up.

The authors concluded that this patient experienced acute angle glaucoma associated with the use of Ma-Huang (which contains ephedra) based on the temporal relationship between the administration of the product and the appearance and resolution of symptoms.

Ma-Huang [Ma-Huang]

Ryu SJ et al (M Seong, Department of Ophthalmology, Hanyang University College of Medicine, #222 Wangimni-ro, Seongdong-gu, Seoul 04763, Republic of Korea; e-mail: goddns76@gmail.com) Bilateral acute myopia and angle closure glaucoma induced by Ma-Huang (Ephedra): a case report. Medicine (Baltimore). 96:e9257 (Dec) 2017

Heart Block

A 61-year-old female inpatient developed lightheadedness approximately 1 day after her dose of paliperidone was increased (from 6 mg to 9 mg daily) to manage increased symptoms of schizoaffective disorder. Long-term concurrent medications included metoprolol tartrate and losartan (no dosages provided). The lightheadedness was intermittent and more pronounced on standing up. A cardiovascular assessment revealed bradycardia (45 beats/min) and hypotension (90 mm Hg/50 mm Hg). Telemetry also demonstrated nonconducted P waves and AV block with prolonged QTc (470 ms). Despite the discontinuation of metoprolol, the symptoms persisted. Reevaluation of other medications caused paliperidone to be considered as a possible causative agent. It was discontinued with resultant improvement in symptoms. A transthoracic echocardiography and coronary angiography revealed no further associated events. The patient was eventually discharged in stable condition without further events on hospital day 6.

The authors concluded that this patient developed atrioventricular block associated with an increase in dose of paliperidone based on the temporal relationship between the dosage changes and the appearance and resolution of symptoms. According to the Naranjo adverse reaction probability scale, this reaction was rated as likely.

Paliperidone [“Invega”]

Yasin M et al (M Yasin, Charleston Area Medical Center, Charleston, WV) Paliperidone-associated atrioventricular block. Am J Ther 25:e730–e732 (Nov) 2018

Acute Pancreatitis

A 61-year-old male patient was hospitalized with an acute onset of nausea, vomiting, and worsening epigastric abdominal pain over a 2-day period approximately 1 month after starting an intravenous regimen of clofazimine and tigecycline for the outpatient management of a bilateral leg infection with nontuberculous Mycoplasma chelonae. Previous unsuccessful therapy prior to this regimen included quinolones and linezolid. The intended duration of the clofazimine and tigecycline regimen was for 6 months, which resulted in significant improvement at the 4-week mark after initiation. Specific dosages for the drugs were not provided in this report. On hospitalization, abnormal laboratory values included an elevated white blood cell count and lipase level (1835 U/L). In addition, results from an abdominal computed tomography suggested acute pancreatitis. The patient was admitted to the intensive care unit for the management of sepsis secondary to acute pancreatitis. As other potential causative etiologies were evaluated, it was decided to discontinue tigecycline. Within 24 to 48 hours after the discontinuation of the drug, the lipase level decreased to 450 U/L. Clofazimine treatment was continued without further event.

The authors concluded that this patient developed acute pancreatitis related to tigecycline based on the temporal relationship between the administration of the drug and the appearance and resolution of symptoms. According to the Naranjo adverse reaction probability scale, this reaction was rated as probable.

Tigecycline [“Tygacil”]

Akthar S et al (S Akthar, Department of Medicine, SUNY Upstate Medical University, Syracuse, NY) Tigecycline-associated acute pancreatitis. Am J Ther 25:e749–e750 (Nov) 2018

Hyponatremia

An 80-year-old female inpatient developed nausea, vomiting, headache, and dizziness approximately 3 days after switching treatment to intravenous lacosamide (100 mg every 12 hrs) from levetiracetam for the management of generalized tonic-clonic seizures. Concurrent medications in the hospital included intravenous vancomycin, ceftriaxone, and trimethoprim/sulfamethoxazole. At the time of symptom development, abnormal laboratory values included serum sodium (127 mmol/L), urinary serum sodium (135 mmol/L), urine osmolality (409 mOsm/kg), and serum osmolality (266 mOsm/kg). It was noted that on hospital admission, the serum sodium levels were within normal limits (140 mmol/L). A diagnosis of syndrome of inappropriate secretion of antidiuretic hormone was made. Despite treatment with fluid restriction to 500 mL/day, the serum sodium levels continued to decrease and mental status worsened. After admission to the medical intensive care unit, the nadir level of sodium was 109 mmol/L. Additional treatment included the administration of 3% hypertonic saline, which resulted in transient improvement in the mental status. At this point in time, an evaluation of the medication list resulted in the assumption that the most likely causative agent might be lacosamide, which was then discontinued. Levetiracetam was reinitiated with a gradual increase in serum sodium levels accompanied by the general improvement in mental status. The remainder of the hospital stay was uneventful with the eventual discharge of the patient with serum sodium levels within normal limits.

The authors concluded that this patient developed hyponatremia related to lacosamide therapy based on the temporal relationship between the administration of the drug and the appearance and resolution of symptoms. According to the Naranjo adverse reaction probability scale, this reaction was rated as probable. The authors noted that lacosamide has a neuronal hyperexcitability partially through the selective slow sodium channel inactivation.

Lacosamide [“Vimpat”]

Gupta SS et al (SS Gupta, Departments of Pulmonary Medicine and Critical Care, Maimonides Medical Center, Brooklyn, NY) Lacosamide: associated hyponatremia. Am J Ther 25:e729–e730 (Nov) 2018

Weight Loss

A 14-year-old male developed weight loss after atomoxetine (titrated over 4 weeks to 80 mg daily) was initiated for treatment of early-onset schizophrenia. Concurrent medications included clozapine (300 mg daily). Early-onset schizophrenia had responded well to clozapine, but weight gain and sialorrhea occurred on treatment. The addition of atomoxetine resulted in better interpersonal socialization, negative symptomology improvement, and gains in academic tasks. Weight decreased from 70 kg to 61 kg. Sialorrhea improved from a drooling severity and frequency rating scale score of 9 to 4. Atomoxetine was continued, and further treatment included social skills training and nutrition and dietary interventions.

The authors concluded that the weight loss described in this case was related to atomoxetine administration. Proposed mechanisms included anorexigenic effects of atomoxetine induced by norepinephrine reuptake inhibition.

Atomoxetine [“Strattera”]

Naguy A et al (A Naguy, Al-Manara CAP Centre, Kuwait Centre for Mental Health, Shuwaikh, Kuwait) Weight loss during atomoxetine add-on to clozapine-responsive schizophrenia. Am J Ther 25:e774–e775 (Nov) 2018

Acute Liver Injury

A 40-year old male inpatient developed elevated liver function tests approximately 4 days after starting rifampicin (600 mg daily) in the management of chronic osteomyelitis during a postsurgical recovery period (eg, T11-L4 posterior spinal fusion with L1 and L2 decompression laminectomies and bilateral facetectomies). Concurrent medications at the time of the event included intravenous vancomycin (2.5 g/day) and oral acetaminophen (1.5-3 g/daily), both of which had been tolerated alone and in combination without event. Approximately 3 to 4 days after the introduction of rifampicin, laboratory tests peaked, including alanine transaminase (735 IU/L), aspartate transaminase (2682 IU/L), and total bilirubin (2.1 mg/dL). Additional elevations included prothrombin time (32.5 seconds) and international normalized ratio (3.14). Screenings for other infectious etiologies, including hepatitis, were negative with the exception of a known hepatitis C antibody. Rifampicin was stopped and vancomycin was switched back to cefazolin therapy. Within approximately 1 week after rifampicin discontinuation, the elevated laboratory values gradually decreased and normalized.

The authors noted that this patient was taking 3 possible causative agents associated with possible liver injury, including vancomycin, acetaminophen, and rifampicin. Vancomycin and acetaminophen had been tolerated without event when administered alone and in combination. Increased laboratory values did not occur until all 3 drugs were concurrently taken. According to the Naranjo adverse drug reaction probability algorithm score, it was calculated as a “5” for rifampicin suggestive of a probable adverse drug reaction, as a “1” each for acetaminophen and vancomycin, suggestive of a possible adverse drug reaction, and as a “7” for the combination, suggestive of a probable adverse drug reaction.

Acetaminophen [“Tylenol”]

Rifampicin [“Rifampicin”]

Vancomycin [“Vancomycin”]

Khanal S et al (S Khanal, Department of Medicine, SUNY Upstate Medical University, Syracuse, NY) Liver injury during treatment with rifampicin, vancomycin, and acetaminophen. Am J Ther 25:e735–e736 (Nov) 2018

FDA Safety Communication: Increased Risk of Blood Clots and Death With Higher Dose in Rheumatoid Arthritis Patients

On February 25, 2019, the US Food and Drug Administration published a safety communication regarding a possible increased risk of pulmonary embolism and death associated with tofacitinib when used as 10 mg twice daily dosing in patients with rheumatoid arthritis. The safety announcement noted that this dosage regimen is not approved for use in rheumatoid arthritis but is an approved regimen for patients with ulcerative colitis. These new data were detected in an ongoing safety trial in rheumatoid arthritis patients who were receiving the higher dose. Patients in the trial are currently being transitioned to the lower dose (5 mg twice daily), and the trial will continue with further evaluation of the resultant data.

Tofacitinib [“Xeljanz,” “Xeljanz XR”]

FDA Safety Communication: Safety trial finds risk of blood clots in the lungs and death with higher dose of tofacitinib (Xeljanz, Xeljanz XR) in rheumatoid arthritis patients; FDA to investigate. https://www.fda.gov/downloads/Drugs/DrugSafety/UCM631989.pdf (Feb 25) 2019

No Increased Risk for Macular Degeneration

A retrospective population-based study, using a nationwide cohort from a variety of clinics and hospitals in South Korea, evaluated the risk of neovascular age-related macular degeneration associated with the long-term use of low-dose aspirin. Long-term regular users of low-dose aspirin were defined as those who maintained aspirin use of up to 100 mg with greater than 1044 days prescription for 5 years (1826 days) between 2005 and 2009. Nonregular aspirin users included occasional users and nonusers. All included patients were at least 45 years of age. The groups were not matched for characteristics. A total of 482 613 participants met the inclusion criteria, including 12 387 regular aspirin users and 470 226 nonregular aspirin users. There were significant differences between the groups for baseline characteristics; the regular aspirin users were older, belonged to higher income groups, and more likely to rate higher on the Charlson Comorbidity Index than nonregular aspirin users. The incidence of newly developed neovascular age-related macular degeneration was higher in the aspirin group (0.40% vs 0.18%; P < .001, or 7.2 vs 3.5/10 000 person-years). After 5:1 propensity matching, all variables, including the incidence of newly developed neovascular age-related macular degeneration (0.40% vs 0.42%, respectively; P = .759), were similar between the 2 groups. In addition, the propensity scored matched analyses demonstrated no association when crude hazard ratios were considered (0.94; 95% confidence interval = 0.70-1.28).

Based on this population-based cohort study in South Korea, the authors found no association between the long-term regular use of low-dose aspirin for 5 years and the incidence of newly developed age-related macular degeneration. They noted that the study had several limitations, including a lack of assessment of other contributing factors to age-related macular degeneration (eg, smoking habits, the use of antiplatelet drugs) and the inherent inaccuracies that may accompany data collection via diagnostic codes.

Aspirin [Aspirin]

Rim TH et al (SS Kim, Department of Ophthalmology, Severance Hospital, Institute of Vision Research, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea; e-mail: semekim@yuhs.ac) Long-term regular use of low-dose aspirin and neovascular age-related macular degeneration: national sample cohort 2010-2015. Ophthalmology 126:274–282 (Mar) 2019

Methemoglobinemia

A 22-year-old female patient developed shortness of breath and cyanosis immediately after receiving benzocaine during endoscopy. Treatment included administration of oxygen to maintain adequate oxygen saturation. Respiratory distress continued, and oxygen saturations remained approximately 85% on 5 L of supplemental oxygen. Significant laboratory findings included elevated methemoglobin level (27.8%) and a partial pressure of oxygen of 409 mm Hg. No further treatment was administered, and methemoglobin level declined to 8.3% 6 hours later. Symptoms of shortness of breath and cyanosis improved.

The authors concluded that the symptoms described in this case were a probable adverse drug reaction to benzocaine as evaluated by the Naranjo scale for adverse drug reactions. Proposed mechanisms included oxidation of ferrous ions of heme to the ferric state resulting in inhibition of heme from reversibly binding to oxygen and creating a functional state of anemia.

Benzocaine [Benzocaine]

Khanal S et al (S Khanal, Internal Medicine, State University of New York Upstate Medical University, Syracuse, NY) Benzocaine-associated methemoglobinemia. Am J Ther 25:e771–e772 (Nov) 2018

Complete Heart Block

A 51-year-old female patient was hospitalized with bradycardia (39 beats/min) and intermittent dizziness for the last few days prior to admission. A medication and smoking history revealed the use of 1 to 2 bags of marijuana approximately 4 to 5 times a week for several years. Most laboratory values were within normal limits, and physical examination was unremarkable for notable symptoms. An electrocardiogram showed sinus rhythm with third-degree atrioventricular block and a ventricular rate of 38 beats/minute. The P-P intervals had no relation to QRS complexes. Screenings for metabolic and infectious etiologies were negative. Serial cardiac biomarkers were within normal limits. A urine drug screen was positive only for cannabis. Continuous tele-monitoring revealed intermittent 2:1 atrioventricular block and third-degree atrioventricular block that failed to resolve after 5 days. A coronary angiogram revealed angiographically normal coronary arteries. Management included the implantation of a chamber pacemaker; the patient was discharged home in stable condition. The patient was counseled to stop marijuana use. An electrocardiogram follow-up at 3 months later revealed atrial sensed ventricular paced rhythm at 96 beats/minute. A pacemaker interrogation revealed persistent underlying complete heart block. The patient denied marijuana use after hospital discharge.

The authors concluded that this patient developed complete heart block requiring a permanent pacemaker associated with chronic marijuana use. They noted that the patient had no other risk factors associated with heart block.

Marijuana [Cannabis]

Mithawala P et al (P Shah, Department of Cardiology, Phoebe Putney Memorial Hospital, 417 W 3rd Avenue, Albany, GA 31701; e-mail: priyank_221084@yahoo.com) Complete heart block from chronic marijuana use. Am J Med Sci 357:255–257 (Mar) 2019

Pigmentation of the Ocular Conjunctiva and Hard Palate

A 71-year-old female patient developed brownish subepithelial pigmentation on the superior tarsal conjunctiva of both eyes after receiving imatinib therapy (dosages not provided) for the management of a gastrointestinal stromal tumor. The time frame between the administration of the drug and the appearance of symptoms were not described. No other medications were noted in the report. In addition to the ocular pigmentation, a blue-greyish lesion was also observed on the hard palate. A conjunctival biopsy revealed reactive hyperplasia of the lining epithelium, mild hyperemia of the lamina propria, edema, and mononuclear infiltrate.

The authors concluded that this patient developed pigmentation of the ocular conjunctiva and hard palate related to imatinib therapy based on the temporal relationship between the administration of the drug and the appearance of the symptoms. The authors also noted that there have been other reports of skin pigmentation associated with this drug.

Imatinib [“Gleevec”]

do Carmo LL et al (LL do Carmo, Ophthalmology Department of Instituto dos Servidores do Estado de Minas Gerais, Belo Horizonte, Brazil) Imatinib-related conjunctival pigmentation. Ophthalmology 125:1002 (Jul) 2018