Reporting on Adverse Clinical Events

Epstein-Barr Virus Gastric Ulcer

A 77-year-old male patient was hospitalized for severe diarrhea approximately 6 months after starting ruxolitinib (20 mg twice daily) for the treatment of primary myelofibrosis. Concurrent medications were not noted. The dose of the drug was tapered to 5 mg twice daily because of repeated infections, including herpes zoster. A computed tomography scan revealed massive thickening of the gastric wall, and an upper gastrointestinal endoscopy revealed multiple open-type gastric ulcers. Although no active infection was noted in the plasma, there was laboratory evidence of severe impairment of cell-mediated immunity (eg, CD4+ T cells, CD8+ T cells, and NK cell activity). Treatment included the initiation of empiric ganciclovir and the discontinuation of ruxolitinib. Within 24 hours, the frequency of diarrhea was reduced. Epstein-Barr virus DNA was identified from the gastric ulcer. After approximately 2 weeks of ganciclovir therapy, the patient was discharged with improved status. An additional week of valganciclovir resulted in completion ulcer healing. Three months after the discontinuation of ruxolitinib, cell-mediated immunity began to improve.

The authors concluded that this patient experienced an Epstein-Barr virus gastric ulcer related to ruxolitinib-induced severe immunosuppression. This conclusion was based on the temporal relationship between the administration of the drug and the appearance and resolution of the symptoms.

Ruxolitinib [“Jakafi”]

Kusano Y et al (Y Kusano, Department of Hematology and Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto-ward, Tokyo 135-8550, Japan; e-mail: yoshiharu.kusano@jfcr.or.jp) Epstein-Barr virus gastric ulcer associated with ruxolitinib. Ann Hematol 95:1741–1742 (Oct) 2016

Interference With Glucometer Testing

A 28-year-old pregnant patient reported a malfunction with her glucometer during a routine prenatal visit. Using a LifeScan OneTouch Ultra meter 4 times within a 5- to 10-minute period, she reported widely varied fasting blood glucose results (range = 107-160 mg/dL). On her next visit to the clinic, the patient’s method for site preparation and meter use were evaluated. The patient had been using 10% povidone iodine solution administered with a cotton ball to clean her finger approximately 1 minute prior to testing. The patient confirmed that the finger was dry before using the glucometer. Using another brand of glucometer and the One Touch Ultra, the patient was asked to wash her hand with soap and water. The readings were 86 mg/dL and 76 mg/dL, respectively. The patient was provided with a new glucometer and strips and asked to wash her hands with soap and water prior to glucometer use and to discontinue the use of povidone iodine. Further readings appeared to be accurate. The possible interaction was further evaluated by one of the authors (who did not have diabetes), who compared hand washing methods (soap/water vs povidone iodine). The blood glucose readings were obtained approximately 30 minutes after eating lunch using the Freestyle Freedom Lite meter. The readings were 140 mg/dL, 138 mg/dL, and 137 mg/dL when utilizing the recommended hand washing technique. After using 10% povidone iodine, the blood glucose readings were 45 mg/dL, 147 mg/dL, and 97 mg/dL. When using an Accu-Chek Nano meter at 60 minutes postprandial after the recommended hand washing, the readings were 117 mg/dL, 118 mg/dL, and 116 mg/dL. When using the 10% povidone iodine solution, the readings were 103 mg/dL, 136 mg/dL, 114 mg/dL, and 104 mg/dL.

Based on this patient report and additional testing, the authors concluded that using povidone iodine to wash the testing area can interfere with accurate glucometer readings. Using the Naranjo causality scale, this interaction/effect was rated as “probable.”

Povidone Iodine [Povidone Iodine]

Lipshutz AM & Hawes EM (EM Hawes, UNC Family Medicine Center, 590 Manning Drive, Campus Box 7595, Chapel Hill, NC 27599; e-mail: emily_hawes@med.unc.edu) Probable glucometer interference caused by topical iodine solution test site preparation. J Clin Pharm Ther 41:583–855 (Oct) 2016

Dyspnea, Cheyne-Stokes Respiration

A patient (age not reported) experienced dyspnea within a few hours after starting double antiplatelet therapy with aspirin and ticagrelor after revascularization for 3-vessel disease. Breathing was affected at night and in the supine position. Measures of ventricular and pulmonary function were within normal limits. During follow-up 1 month later, dyspnea persisted and abnormal breathing pattern was also observed, which was confirmed as Cheyne-Stokes respiration. The dyspnea improved immediately after ticagrelor was switched to clopidogrel, and eventually resolved with normal values for the apnea-hypopnea index (the number of occurrences of apnea or hypopnea/hour). Similar abnormal breathing patterns were noted in 3 additional patients who were receiving ticagrelor.

The authors concluded that these patients experienced ticagrelor-related dyspnea with Cheyne-Stokes respiration based on the temporal relationship between the administration of the drug and appearance and resolution of symptoms. Although the mechanism of action is not established, they suggested that it might be related to P2Y12 receptor activity.

Ticagrelor [“Brilinta”]

Giannoni A et al (A Giannoni, Fondazione Toscana Gabriele Monasterio, Pisa, Italy; e-mail: alberto.giannoni@gmail.com) Cheyne-Stokes respiration, chemoreflex, and ticagrelor-related dyspnea. N Engl J Med 375:1004–1006 (Sep) 2016

FDA Safety Communication: Serious Risks and Death When Combining Opioids With Benzodiazepines

On August 31, 2016, the US Food and Drug Administration (FDA) announced changes in safety product labeling regarding the risk of serious adverse events, including death, associated with the combined use of opioids and benzodiazepines. This safety communication was based on a review of 2 studies conducted by the FDA along with data from the published literature. The studies conducted by the FDA demonstrated an increasing trend in the combined use of opioid analgesics and benzodiazepines. Between 2002 and 2014, overlapping benzodiazepine/opioid prescriptions increased by 41%, an increase of more than 2.5 million opioid analgesic users. In addition, this combination of drugs has been associated with misuse, abuse, and overdose, as measured by national emergency department visits and overdose-related fatalities (from prescribed or greater than prescribed doses). Patients with the highest probability of receiving concomitant prescriptions were women, patients older than 65, and chronic users of opioid analgesics. Between 2004 and 2011, drug overdose fatalities related to opioid analgesics and benzodiazepines increased from 0.6 to 1.7 per 100 000 (P trend <.0001). Data from an additional published study revealed that the rates of overdose death among patients codispensed opioid analgesics and benzodiazepines were 10 times higher (7.0 per 10 000 person-years; 95% confidence interval = 6.3-7.8) than among patients dispensed opioid analgesics alone (0.7 per 10 000 person-years; 95% confidence interval = 0.6-0.9). In the Veterans Health Administration population, data from 2004 to 2009 revealed that patients taking opioid analgesics with a history of a benzodiazepine prescription had an increased risk of fatal overdose (hazard ratio = 2.33; 95% confidence interval = 2.05-2.64), when compared to patients without use of the drugs. Based on these data and trends of increased combined use of opioid analgesics and benzodiazepines and evidence of increased harms, the FDA has announced that a new Boxed Warning to be added to the labeling of opioid analgesic and opioid cough medications and benzodiazepines.

Benzodiazepines [Diazepam, Clonazepam, Alprazolam, Flurazepam]

Opioids [Morphine, Meperidine, Fentanyl, Codeine, Hydrocodone]

FDA Safety Communication: FDA warns about serious risks and death when combining opioid pain or cough medicines with benzodiazepines; requires its strongest warning. http://www.fda.gov/downloads/Drugs/DrugSafety/UCM518672.pdf (Aug 31) 2016

FDA Public Notification: Elevated Lead Levels in Product

On August 30, 2016, the US Food and Drug Administration (FDA) alerted health care professionals and patients to an expanded recall of all lots purchased prior to August 24 of a dietary supplement (DHCZ-2 Tablets) manufactured by Ton Shen Health/Life Rising Corporation. FDA analysis confirmed that the samples contained 56 times the amount of lead above that which would pose a health risk for children. The initial recall was prompted by a report to the FDA of 2 children with elevated lead levels who had a potential history of taking the supplement. The FDA is investigating a total of 6 cases where potential adverse effects may be associated with the use of the dietary supplement. This notification from the FDA is a reminder that there is a trend of hidden drugs and chemicals in dietary supplements or conventional foods.

Dietary Supplement [“DHCZ-2 Tablets”]

FDA Safety Communication: Dietary supplements by Ton Shen Health/Life Rising: Recall—elevated lead levels. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm518482.htm (Aug 30) 2016

Cardiovascular Events

A retrospective cohort analysis was performed to evaluate the association between clarithromycin use and cardiac events in 28 552 patients treated for Helicobacter pylori. Of these 91% (n = 26 029) received clarithromycin-based therapy and 9% (n = 2523) received a non–clarithromycin-based regimen. Mean age at exposure was 53 years, and the median follow-up was 3 years. Clarithromycin-based therapy was associated with a reduced incidence of first arrhythmia (adjusted rate ratio = 0.37; 95% confidence interval = 0.22-0.63; P = .001) and first stroke (adjusted rate ratio = 0.47; 95% confidence interval = 0.26-0.84; P = .01); however, no association was observed with regard to first myocardial infarction, all-cause mortality, or cardiovascular mortality. An increased risk of myocardial infarction at year 1 to 2 postexposure (rate ratio = 1.27; 95% confidence interval = 1.01-1.61; P = .04) was observed in the 962 patients exposed to clarithromycin that experienced a myocardial infarction. An increased risk of first arrhythmia from days 30 to 90 postexposure was observed in the 562 patients exposed to clarithromycin that developed a first arrhythmia. There was no evidence of increased risk of myocardial infarction or first arrhythmia for other time periods observed or for stroke. A total of 82 708 patients experienced an myocardial infarction during the time period evaluated in the Clinical Practice Research Datalink database. Of these 74 769 were matched to 258 696 controls. No association between exposure to clarithromycin-based therapy and myocardial infarction within the first year of exposure (odds ratio = 0.86; 95% confidence interval = 0.59-1.26; P = .44), first arrhythmia, or stroke was observed. A sensitivity analysis including 359 patients revealed an age-adjusted rate ratio for first incident myocardial infarction within 30 days of clarithromycin exposure compared with the rest of follow-up of 3.77 (95% confidence interval = 1.85-7.68; P < .001).

The authors concluded that results of this study provided some evidence for a short-term association for clarithromycin use and first myocardial infarction and arrhythmia, but no long-term association with myocardial infarction, stroke, or arrhythmia. The proposed mechanism was clarithromycin-induced prolonged QT interval.

Clarithromycin [“Biaxin”]

Root AA et al (AA Root, Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK; e-mail: Adrian.root@lshtm.ac.uk) Evaluation of the risk of cardiovascular events with clarithromycin using both propensity score and self-controlled study design. Br J Clin Pharmacol 82:512–521 (Aug) 2016

Pustulopapular Rash

A 30-year-old female patient was hospitalized with a generalized pustular eruption that developed approximately 3 days after the initiation of lincomycin (no dosage provided) for acute pharyngitis. No other medications were taken. A physical examination revealed extensive erythematous eruption, with pinpoint pustules over the trunk and extremities. The patient had a fever. Abnormal laboratory values included an elevated white blood cell count. Screenings for infectious etiologies were negative. A biopsy of the area revealed subcorneal and intraepidermal spongiform pustules and changes in the superficial dermis, which was suggestive of acute generalized exanthematous pustulosis. Within 48 hours of discontinuing the medication and initiating hydroxyzine and topial steroids, the fever subsided and the rash improved. Patch and intradermal skin tests performed 6 weeks later with 1% and 10% lincomycin in distilled water revealed positive results on day 2.

Based on the temporal relationship between the administration of the drug and the appearance and resolution of the rash, the authors concluded that this patient experienced acute generalized exanthematous pustulosis related to lincomycin therapy. According to the Naranjo causality assessment, this reaction was classified as probable in relation to the drug therapy.

Lincomycin [Lincomycin]

Salem CB et al (CB Salem, Department of Pharmacovigilance, Sousse, Tunisia) Lincomycin-induced acute generalized exanthematous pustulosis confirmed by delayed reading of intradermal testing. Ann Pharmacother 50:894–895 (Oct) 2016

Drug Interaction: Increased Everolimus Exposure

A 56-year-old male developed an elevated serum everolimus trough concentration and acute kidney injury approximately 12 days after empiric therapy for Helicobacter pylori (amoxicillin, clarithromycin, omeprazole, doses not reported) was started while treated with everolimus (10 mg daily) for clear-cell renal cell carcinoma. Significant laboratory findings included elevated blood urea nitrogen (32 mg/dL), serum creatinine (2.8 mg/dL; baseline, 1.8 mg/dL), serum everolimus trough level (110 ng/mL), hyperkalemia (range = 4.8-6.1 mmol/L), mild proteinuria (30 mg/dL), and no urine eosinophils. Treatment included interruption of everolimus therapy and administration of intravenous hydration, calcium gluconate, furosemide, insulin, and sodium polysterene sulfonate (doses not reported). Serum creatinine and potassium decreased to 2.0 mg/dL and 5.4 mmol/L. Everolimus was restarted at the prior dose (10 mg daily); however, Helicobacter pylori treatment was not restarted. Although no further everolimus trough levels were attained, everolimus dose was empirically reduced to 5 mg daily a month later.

The authors concluded that the elevated everolimus serum concentration and acute kidney injury described in this case was related to a probable severe drug interaction between clarithromycin and everolimus as assessed via the Naranjo score. The proposed mechanism was clarithromycin-induced inhibition of cytochrome P450 3A4 and P-glycoprotein resulting in increased everolimus exposure.

Clarithromycin [“Biaxin”]

Everolimus [“Afinitor,” “Zortress”]

Miesner AR et al (AR Miesner, Drake University College of Pharmacy and Health Science, Des Moines, IA) Probable drug interaction between everolimus and clarithromycin. Ann Pharmacother 50:689–690 (Aug) 2016

Blood Pressure Changes

A meta-analysis of prospective clinical trials evaluated the effects of energy drinks on blood pressure and heart rate. Initially, 361 studies were identified with 15 studies (n = 340) included for analysis of the primary systolic blood pressure end point, 14 studies (n = 322) for analysis of diastolic blood pressure, and 15 studies (n = 340) for analysis of heart rate. All but one study employed a crossover design. A total of 12 studies had a placebo (noncaffeinated) control drink arm, 2 had a caffeinated control arm, and 2 had no control arm. When compared to baseline values, systolic blood pressure was significantly increased (+4.44 mm Hg; 95% confidence interval = 2.71-6.17; P = .001) as was diastolic blood pressure (+2.73 mm Hg; 95% confidence interval = 1.52-3.95; Cochrane Q P = .050). These effects remained when caffeine doses greater or less than 200 mg were considered. In contrast, there were no significant changes in heart rate (0.80 beats per minute; 95% confidence interval = −1.26 to 2.87; P = .111) except when analyzed via a fixed-effects model.

Based on these data, the authors concluded that consuming energy drinks is associated with significant increases in systolic blood pressure and diastolic blood pressure. They noted that the caffeine component in these beverages is most likely responsible for hemodynamic changes but that ingredients (eg, guarana, taurine, and ginseng) other than caffeine may also contribute to these effects and should be considered and further evaluated. The impact of long-term consumption also requires further study.

Energy Drinks [“Red Bull,” “Rock Star,” “5-Hour Energy”]

Shah SA et al (SA Shah, David Grant Medical Center, University of the Pacific, Thomas J. Long School of Pharmacy and Health Sciences, 3601 Pacific Ave, Stockton, CA 95204; e-mail: sshah@pacific.edu) Impact of acute energy drink consumption on blood pressure parameters: a meta-analysis. Ann Pharmacother 50:808–815 (Oct) 2016

Gout

A case-control study was performed to characterize the clinical and genetic features of diuretic-associated gout in 1365 adult patients with gout. A total of 426 (31.2%) participants received at least 1 diuretic. Two hundred and eighty-one received a loop diuretic, and 145 received a thiazide diuretic. As compared to no diuretic, the diuretic group had more women (male sex, 70.2% vs 88.3%; P = 2.9 × 10⁻¹⁶), fewer Maˉ  ori or Polynesian persons (51.6% vs 58.9%, P = .012), older mean age (65.3 vs 53.9 years; P = 8.3 × 10⁻⁴⁸), and higher body mass index (34.8 vs 33.1 kg/m²; P = 7.2 × 10⁻⁴). Participants on diuretics also had higher rates of cardiac disease (61.9% vs 18.6%; P = 1.1 × 10⁻⁵⁶), hypertension (83.3% vs 44.2%; P = 5.3 × 10⁻⁴¹), type 2 diabetes (34.5% vs 13.0%; P = 2.9 × 10⁻²⁰), and lower mean estimated glomerular filtration rate (50.2 vs 68.5 mL/min/1.73 m²; P = 1.4 × 10⁻⁴⁶) compared to those not taking diuretics. Gout duration, frequency of gout flares, and presence of tophi were similar between participants with or without diuretic exposure. Comparison between loop and thiazide-type diuretics revealed a higher rate of cardiac disease (79.5% vs 28.3%), type 2 diabetes (40.5% vs 22.9%), and lower estimated glomerular filtration rate (mean 46.6 mL/min/1.73 m² vs 57.0 mL/min/1.73 m²) in the loop-diuretic group compared to thiazide diuretics. A similar age of onset of gout, frequency of tophaceous disease, and gout flare frequency was observed for participants on loop and thiazide diuretics. A higher mean serum urate concentration was observed for participants on loop compared to thiazide diuretics (0.55 mmol/L vs 0.51 mmol/L; post hoc P = 5.6 × 10⁻³). Genetic analysis revealed the ABCG2 rs2231142 and SLC22A11 rs2078267 risk alleles were present less frequently in the group taking any diuretic compared to those not on diuretics (36.1% vs 47.6%, P = 1.2 × 10⁻⁴, and 83.4% vs 87.8%, P = .032, respectively). This risk allele positivity was similar in participants taking loop and thiazide diuretics. A significant association was not observed for the SLC2A9 rs11942223 risk allele. The ABCG2 rs2231142 risk allele was present less frequently in both men and women on diuretics (male allelic odds ratio = 0.75; 95% confidence interval = 0.61-0.95; P = 9.1 × 10⁻³; female allelic odds ratio = 0.54; 95% confidence interval = 0.34-0.86; P = 7.8 × 10⁻³). No significant differences were observed in the SLC2A9 rs11942223 or SLC22A11 rs2078267 risk alleles in the gender-based analysis. The gender-based analysis results were similar when adjusted for ethnicity.

The authors concluded that results of this study demonstrated similar clinical features of gout in persons on diuretics and not on diuretics. They further stated that some genetic factors may play a role in diuretic-associated gout.

Diuretics [Loop Diuretics, Thiazides]

Mitnala S et al (N Dalbeth, Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, 85 Park Rd, Grafton, Auckland, New Zealand; e-mail: n.dalbeth@auckland.ac.nz) Clinical and genetic features of diuretic-associated gout: a case-control study. Rheumatology (Oxford) 55:1172–1176 (Jul) 2016

FDA Public Notification: Undeclared Drug Ingredient

On August 30, 2016, the US Food and Drug Administration (FDA) alerted health care professionals and patients regarding a hidden drug ingredient in a natural herbs coffee (Kopi Jantan Tradisional Natural Herbs Coffee). A laboratory analysis of the product confirmed that it contained desmethyl carbodenafil, an ingredient that is structurally similar to sildenafil, which has been associated with hypotension and may cause significant interactions with other drugs, notably nitrates. This notification from the FDA is a reminder that there is a trend of hidden drugs and chemicals in dietary supplements or conventional foods.

Natural Herbs Coffee [“Kopi Jantan Tradisional Natural Herbs Coffee”]

Public Notification: Kopi Jantan Tradisional Natural Herbs Coffee contains hidden drug ingredient. http://www.fda.gov/Drugs/ResourcesForYou/Consumers/BuyingUsingMedicineSafely/MedicationHealthFraud/ucm518588.htm?source=govdelivery&utm_medium=email&utm_source=govdelivery (Aug 30) 2016

Risk of Myocardial Infarction

A systematic review and meta-analysis of observational studies was performed to evaluate if the use of antipsychotics was associated with a risk of myocardial infarction. Criteria for study selection included case-control or case-crossover or self-controlled case series or cohort study, if antipsychotics were compared with non-antipsychotics, myocardial infarction was a primary or secondary outcome, and if risk estimates with confidence intervals (or sufficient information to calculate these values). The final analysis included 9 observational studies that compared the incidence of myocardial infarction among patients receiving antipsychotics compared to no treatment.

The odds for developing a myocardial infarction were 1.88-fold higher (odds ratio = 1.88; 95% confidence interval = 1.39-2.54) in antipsychotic users compared with individuals who had not received such therapy. Subgroup analyses also found an increased risk in patients with schizophrenia (odds ratio = 2.48; 95% confidence interval = 1.66-3.69) and in those who received short-term (<30 days) antipsychotics (odds ratio = 2.64; 95% confidence interval = 2.48-2.81).

Based on this review, the authors indicated that the data supported a moderately increased risk of myocardial infarction associated with antipsychotic use. They noted that these data are limited by observational studies only as no randomized controlled trials are available. In addition, there was a high heterogeneity.

Antipsychotics [Phenothiazines, Typical Antipsychotics, Atypical Antipsychotics]

Yu Z et al (B Ruan, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; e-mail: hzruanbing@gmail.com). Use of antipsychotics and risk of myocardial infarction: a systematic review and meta-analysis. Br J Clin Pharmacol 82:624–632 (Sep) 2016

Reports in Neonates

A review of 1688 adverse drug reaction reports in neonates (1 month or less of age) that were registered in the French pharmacovigilance database from 1986 to 2012 was performed. A total of 1688 reports were analyzed that described 3127 adverse drug reactions involving 2238 suspected drugs. The most commonly reported type of reaction was injury, poisoning, and procedural complications (n = 492, 16%), followed by general disorders and administration site conditions (n = 391, 12.5%). The median age at the time of event was 9 days. The most frequently cited routes of administration included enteral (43%) and parenteral (39%). Approximately 7% of the cases involved topical use of drugs. The therapeutic class of drugs most commonly cited included anti-infective drugs, nervous system agents, and alimentary tract drugs. In the majority of cases reported (73%), the infants fully recovered. A total of 88 neonates died (median age = 14 days) after median of 1 day from first reported adverse drug reaction. More than half of the reactions were classified as serious (n = 995), with the most frequently cited drugs in these reports including zidovudine, ibuprofen, and nevirapine.

Based on this review of reports, the authors noted that anti-infective drugs, primarily antiretroviral agents, account for the majority of adverse drug reactions reported in neonates. Drug maladministration and medication errors were identified as problems in neonatal drug events.

Adverse Drug Reactions [Adverse Drug Reactions]

Kaguelidou F et al (F Kaguelidou, Department of Pediatric Pharmacology and Pharmacogenetics, Clinical Investigations Center, CIC Inserm 1426, Hôpital Robert Debré 48 boulevard Sérurier 75019, Paris, France; e-mail:florentia.kaguelidou@rdb.aphp.fr) Neonatal adverse drug reactions: an analysis of reports to the French pharmacovigilance database. Br J Clin Pharmacol 82:1058–1068 (Oct) 2016

Reports of Jaw Osteonecrosis in Pharmacovigilance Database

The identification of reports for bisphosphonate-associated osteonecrosis of the jaw was investigated using data from the French national pharmacovigilance database. A standardized MedDRA query “osteonecrosis” was employed. The dates of inclusion ranged between 1985 and December 31, 2014, producing a total of 629 reports. The reviewed reports primarily involved women (n = 443, 71%) with an oncological indication (n = 440, 70%). The mean age of the patients was 66.5 years (±12 years). The majority of reports (81%) involved only one bisphosphonate, with 2 bisphosphonates reported in 17% of the patients, and 3 in only 2% of the cases. The most frequently reported agents associated with osteonecrosis of the jaw included zoledronate (n = 442; 70%), alendronate (n = 102; 16%), pamidronate (n = 71; 11%), or clodronate (n = 66; 10%). Median duration of bisphosphonate treatment ranged from 14.3 months (clodronate) to 51.9 months (etidronate). The effects were considered serious in the vast majority of cases (91%) with unfavorable outcomes in 92% of cases. Associated factors were identified for 70% of the patients, with dentoalveolar surgery identified in 266 patients. Other factors included the administration of chemotherapy (31%), glucocorticoids (20%), anti-angiogenic agents (8%), and denosumab (3%).

The authors noted that they were able to identify approximately 600 cases of jaw osteonecrosis with the standardized MedDRA query “osteonecrosis” and suggested that this query approach could be used to improve case detection. The majority of cases occurred in patients with cancer, treated with intravenous bisphosphonates for several months.

Bisphosphonates [“Zolendronate,” “Clodronate,” “Etidronate,” “Alendronate,” “Pamidronate”]

de Boissieu J et al (P de Boissieu, Department for Pharmacovigilance and Pharmacoepidemiology, Reims University Hospital, Avenue du General Koenig, 51100 Reims, France; e-mail: pdeboissieu@chu-reims.fr) Bisphosphonate-related osteonecrosis of the jaw: data from the French national pharmacovigilance database. Fundam Clin Pharmacol 30:450–458 (Oct) 2016

Increase in Platelet Count

A 46-year-old female patient with chronic idiopathic thrombocytopenic purpura and HIV infection was noted to have a platelet count of 213 × 10³/mm³ approximately 3 days after completing a 5-day course of oseltamivir therapy for influenza infection. Concurrent therapy included immunoglobulins, corticosteroids, emtricitabine, tenofovir, and dolutegravir. Prior to oseltamivir therapy, platelet counts remained below 100 × 10³/mm³ despite treatment. The last blood count had been performed 1 day prior to oseltamivir therapy at 9 × 10³/mm³. Additional platelet counts, performed 7 and 11 days after the end ofoseltamivir, were 71 and 27 × 10³/mm³, respectively. Treatment with immunoglobulins was continued.

The authors concluded that this patient experienced an increase in platelet count associated with the administration of oseltamivir based on the temporal relationship between the administration of the drug and the appearance and resolution of symptoms. They noted that prior to oseltamivir, platelet counts were not affected by antiretroviral therapy. According to the Naranjo causality algorithm, this reaction was rated as probable in relation to the therapy. A mechanism of action is not established. The authors noted that the effect on platelets does not appear to be long lasting.

Oseltamivir [“Tamiflu”]

Bigott P et al (M Auffret, Regional Pharmacovigilance Center, Lille University Hospital, Lille, France; e-mail: marine.auffret@chru-lille.fr) Unexpected platelets elevation in a patient with idiopathic thrombocytopenia treated with oseltamivir for influenza infection. Fundam Clin Pharmacol 30:483–485 (Oct) 2016

INDEX

JANUARY–SEPTEMBER 2016