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Background Recent suggestions of therapeutic inequivalence of brand and generic sertraline have raised concerns about disproportionately higher adverse events among generic users. Objective To assess the impact of confounding in a comparison of the risks of worsening depression and intentional self-harm (ISH) between users of brand name sertraline and its pharmaceutically equivalent authorized generic (AG). Methods Using a retrospective new-user cohort design, we identified patients with a diagnosis code for depression aged ≥12 years who were continuously enrolled in a Sentinel Data Partner health plan for ≥180 days before their first sertraline dispensing between June 30, 2006 and September 30, 2015. New use was defined as no evidence of sertraline dispensing in the 180 days before index date. We matched each brand name user to up to 10 AG users using propensity scores (PS) and conducted case-centered logistic regression to assess the risks of hospitalized depression and ISH. Results Before PS matching, brand name users were significantly less likely to be hospitalized for depression [Hazard Ratio (HR) = 0.70 (95% confidence interval (CI): 0.53-0.94)]. However, in the matched analysis, we observed no statistical difference between brand and AG users [HR = 0.84 (95% CI: 0.59-1.21)]. The risk of ISH did not significantly differ between the exposure groups in unmatched (HR = 0.99 (95% CI: 0.60-1.62) and matched analyses [HR = 0.91 (95% CI: 0.49-1.70). Conclusion In depressed patients receiving brand versus AG sertraline, patient characteristics confounded the association with hospitalization. Baseline differences were ameliorated by PS matching resulting in no statistical difference between brand and AG sertraline users.

Background There have been conflicting results from observational studies regarding the risk of psychiatric adverse events (PAEs) with montelukast use. Objective To determine whether there are associations of depressive disorders, self-harm, and suicide with use of montelukast compared with inhaled corticosteroid (ICS) use. Methods Using data from the Sentinel Distributed Database from January 1, 2000, to September 30, 2015, patients (n = 457,377) exposed to montelukast or ICS, aged 6 years and older with a diagnosis of asthma, were matched 1:1 on propensity scores. Hazard ratios (HRs) and 95% CIs were estimated for each study outcome overall and by age, sex, psychiatric history, and pre-/post-2008 labeling updates using Cox proportional hazards regression models. Results Exposure to montelukast was associated with a lower risk of treated outpatient depressive disorder (HR, 0.91; 95% CI, 0.89-0.93). No increased risks of inpatient depressive disorder (HR, 1.06; 95% CI, 0.90-1.24), self-harm (HR, 0.92; 95% CI, 0.69-1.21), or self-harm using a modified algorithm (HR, 0.81; 95% CI, 0.63-1.05) were observed with montelukast use compared with ICS use. Most PAEs occurred in the roughly one-third of patients having a past psychiatric history. Conclusions When compared with use of ICS, we did not find associations between montelukast use and hospitalizations for depression or self-harm events. Our findings should be interpreted considering the study's limitations. Psychiatric comorbidity was common, and most PAEs occurred in patients with a past psychiatric history.

Objective To evaluate stroke risk among users of typical antipsychotics compared to users of atypical antipsychotics in a non-elderly and non-demented US population. Methods New users of antipsychotics aged 18-64 years without dementia were identified via electronic health care data from 13 health plans participating in the Sentinel System from January 2001 to September 2015. The risk of hospitalized stroke events, identified via ICD-9-CM diagnostic criteria, was compared between typical and atypical antipsychotic users using 1:1 matching on propensity score. Adjusted hazard ratios (HRs) and 95% CIs during the entire follow-up period and during 1- to 15-day and 16- to 90-day risk windows were estimated. The risk associated with haloperidol use was estimated separately. Results A total of 45,495 typical antipsychotic users were matched 1:1 to atypical antipsychotic users. While unmatched HRs suggest an increased stroke risk among typical antipsychotic users compared to atypical antipsychotic users, no increased risk was observed after matching during the entire follow-up period (HR = 0.87; 95% CI, 0.54-1.41), the 1- to 15-day risk window (HR = 1.16; 95% CI, 0.41-3.32), or the 16- to 90-day risk window (HR = 0.52; 95% CI, 0.20-1.36). The adjusted HR for haloperidol was 1.31 (95% CI, 0.54-3.21). Conclusion These findings were not suggestive of an increased stroke risk in typical antipsychotic users compared to atypical antipsychotic users in a non-elderly and non-demented population.

Purpose/background Stimulant abuse is associated with cardiomyopathy, but cardiomyopathy rates with therapeutic use of stimulants for attention-deficit/hyperactivity disorder (ADHD) are poorly characterized. Labels for methylphenidate, amphetamine, and atomoxetine caution against use in patients with cardiovascular disease. We sought to assess the incidence of new-onset heart failure or cardiomyopathy among initiators of these medications. Methods/procedures Using the Sentinel distributed database, we analyzed new-onset heart failure or cardiomyopathy among initiators of selected ADHD medications (amphetamine products including lisdexamfetamine, methylphenidate, and atomoxetine), by duration of use (0-90, 91-180, 181-270, 271-365, 366-730, and 731-1095 days) and age group ( Findings/results In our sample of 2,012,948 initiators of ADHD medications, 44.6% were female, and 54.1% were younger than 22 years. Heart failure/cardiomyopathy rates in the age groups younger than 22 and 22 to 44 years old were less than 50 per 10,000 person-years, without clear trends by duration of use. The highest rates occurred soon after treatment initiation in the age group 65 years or older, with 1 case per 10.5 person-years of follow-up, or 950 cases per 10,000 person-years, for days 0-90. Implications/conclusions Heart failure/cardiomyopathy rates were not higher over 3 years of ADHD medication use compared with shorter-term treatment. In older age groups, lower rates later in treatment could reflect depletion of patients predisposed to the outcome if they develop it soon after starting treatment.

In a retrospective cohort study of patients enrolled in the UK Clinical Practice Research Datalink during 2000-2013, we evaluated long-term risks of death, stroke, and acute myocardial infarction (AMI) in adults prescribed clarithromycin. Patients were outpatients aged 40-85 years, who were prescribed clarithromycin (n = 287,748), doxycycline (n = 267,729), or erythromycin (n = 442,999), or Helicobacter pylori eradication therapy with a proton pump inhibitor, amoxicillin, and either clarithromycin (n = 27,639) or metronidazole (n = 14,863). We analyzed time to death, stroke, or AMI with Cox proportional hazards regression. The long-term hazard ratio for death following 1 clarithromycin versus 1 doxycycline prescription was 1.29 (95% confidence interval (CI): 1.21, 1.25), increasing to 1.62 (95% CI: 1.43, 1.84) for ≥5 prescriptions of clarithromycin versus ≥5 prescriptions for doxycycline. Erythromycin showed smaller risks in comparison with doxycycline. Stroke and AMI incidences were also increased after clarithromycin but with smaller hazard ratios than for mortality. For H. pylori eradication, the hazard ratio for mortality following clarithromycin versus metronidazole regimens was 1.09 (95% CI: 1.00, 1.18) overall, and it was higher (hazard ratio = 1.65, 95% CI: 0.88, 3.08) following ≥2 prescriptions in subjects not on statins at baseline. Outpatient clarithromycin use was associated with long-term mortality increases, with evidence for a similar, smaller increase with erythromycin.

Purpose To compare cardiovascular and mortality risks in elderly patients treated with varenicline or bupropion for smoking cessation. Methods Elderly Medicare beneficiaries were entered into new-user cohorts of varenicline or bupropion for smoking cessation and followed on therapy for primary outcomes of acute myocardial infarction (AMI), stroke, mortality, and a composite of any of these events. Secondary outcomes were unstable angina, coronary revascularization, and a composite of any primary or secondary outcome event. Propensity score stratification was used to adjust for baseline differences in potential confounding factors. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox proportional hazards, with bupropion as reference. Results In cohorts of 74 824 varenicline and 14 133 bupropion users, there were 164 AMI, 96 stroke, 87 death, 317 primary composite, and 814 secondary composite events while on therapy. The HRs (95%CI) were 0.79 (0.50–1.24) for AMI, 1.27 (0.63–2.55) for stroke, 0.58 (0.30–1.13) for death, 0.84 (0.58–1.23) for the primary composite, and 0.92 (0.73–1.14) for the secondary composite. The risk of AMI or the primary composite outcome did not differ in subgroups defined by age, diabetes status, or presence of underlying ischemic heart disease. Only 30% of patients remained on either study drug beyond their first prescription. Conclusion Cardiovascular and mortality risks were not increased in older patients treated with varenicline compared with bupropion for smoking cessation. A potential increase in the risk of stroke with varenicline could not be excluded. Treatment persistence with either drug was low. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.

This study investigates the potential association between montelukast use and psychiatric adverse events by monitoring changes in antidepressant medication dispensing rates before and after initiating montelukast.The primary study group of montelukast initiators was identified using the Wolters Kluwer's SOURCE Lx® pharmacy claims database (WK). This group included 232,159 patients ≤45 years old who had at least two montelukast prescriptions from 2003 to 2007. Comparison groups comprised of 264,704 fluticasone initiators and 89,635 long-acting β-agonist corticosteroid (LABA/ICS) initiators were also identified. Antidepressant medication dispensing rates in these three groups were determined using WK, and changes in rates before and after the first asthma controller medication prescription date were evaluated using interrupted time-series analysis (ITS). ITS was performed separately for four age categories, with a focus on youth (12-17 years) and young adult (18-24 years).For patients 18-24 years old, antidepressant medication dispensing rates increased significantly after initiating montelukast [1.93% (1.55-2.32%, p 0.001)] but also after initiating fluticasone and LABA/ICS [1.72% (1.30-2.15%, p 0.001) and 2.76% (2.35-3.17%, p 0.001)]. Similar patterns were observed across the three medication groups for other age categories but these differences were not all significant.Small increases in antidepressant medication dispensing rates occurred after initiating montelukast. However, similar increases were observed in the fluticasone and LABA/ICS comparison groups. The results of this study cannot support a specific association between initiation of montelukast treatment and an increase in psychiatric adverse effects.

The FDA recently approved labeling changes advising against the use of azithromycin in patients with known cardiovascular risk factors such as QT-interval prolongation, hypokalemia, hypomagnesemia, bradycardia, or use of class IA or class III antiarrhythmic agents.

Please cite this paper as: Borders-Hemphill and Mosholder (2012) U.S. utilization patterns of influenza antiviral medications during the 2009 H1N1 influenza pandemic. Influenza and Other Respiratory Viruses 6(601), e129–e133. Background The 2009 H1N1 influenza pandemic in the United States occurred from April 2009 to April 2010. The 2009 H1N1 influenza virus was susceptible to neuraminidase inhibitors (oseltamivir and zanamivir). Objectives To characterize the 2009 H1N1 influenza pandemic in the United States from April 2009 to April 2010 using weekly influenza antiviral prescription utilization data and the CDC’s weekly reports of the number of visits for influenza-like-illnesses by the Influenza Sentinel Provider Surveillance Network. Methods A proprietary outpatient data source used by the FDA, which captures adjudicated U.S. prescription claims for select influenza antiviral drugs, was used to conduct this analysis. Data were extracted weekly and analyzed for surveillance during the pandemic. Results were compiled at the end of the pandemic. Results Oseltamivir has dominated the U.S. influenza antiviral market share of dispensed prescriptions since approval in October 1999 and was the primary influenza antiviral drug used during the 2009 H1N1 influenza pandemic. However, commercial availability of the suspension formulation of oseltamivir was reduced by high demand during the pandemic. Dispensed prescription trends of other influenza antiviral medications studied followed that those of oseltamivir, even antivirals for which the 2009 H1N1 strains showed resistance. Conclusion Weekly prescription utilization of all influenza antivirals used to treat influenza during the seasonal influenza outbreak followed the same trend of weekly reports of the number of visits for influenza-like-illnesses (ILI) by the Influenza Sentinel Provider Surveillance Network. The ILI epidemic curve resembled dispensed antiviral prescription trends (both overall and stratified by age), providing some corroboration for the surveillance data.

Purpose To determine if paroxetine versus non-paroxetine selective serotonin reuptake inhibitors (SSRIs) prescribing changed after the June 2003 FDA Paroxetine Public Health Advisory (PPHA) and if antidepressant and antipsychotic prescribing changed after the February 2004 FDA Advisory Committee Meeting (FDACM). Methods Ecologic analysis using estimates of patients dispensed antidepressants and antipsychotics, census data, and promotional spending data. Data sources were SDI: Vector One®, US Census, and IMS Health®. Measures were monthly use levels (number of patients dispensed antidepressants, antipsychotics, paroxetine, and non-paroxetine SSRIs prescriptions by age group per population count). Percent changes pre- to post-PPHA were used to assess changes in paroxetine versus non-paroxetine SSRIs prescribing. Interrupted time series (ITS) analysis was performed to examine use level changes post-FDACM by drug groups (all antidepressants and all antipsychotics). Results Post-PPHA mean paroxetine use levels decreased for all age groups (range: 5.5–34.1%). Mean non-paroxetine SSRIs use levels increased (range: 4.6–17.1%). Post-PPHA changes were greatest for 6–12 and 13–17 year olds. Decreased mean antidepressant drug use levels from pre- to post-FDACM were observed in all groups under 25 years old. A statistically significant decrease in the slopes from pre- to post-FDACM was observed for persons aged 13–17 and 18–24 years. The difference between the forecasted mean use level and the observed mean use level (in 12-month intervals) was statistically significant for all ages combined (−107.26; 95% CI: −166.32, −48.20) and 1–5 (−3.1; 95% CI: −4.62, −1.58), 6–12 (−36.02; 95% CI: −62.92, −9.12) and 25 years, and older groups (−83.17; 95% CI: −153.95, −12.39). For all age groups, decreases in the slopes of antipsychotic drugs use from pre- to post-FDACM were observed, although these slope changes were not statistically significant. The difference between the forecasted mean antipsychotic drugs use level and the observed mean use level (in 12-month intervals) was statistically significantly lower for all age groups. Conclusions Antidepressant use changed post-PPHA and -FDACM, with a differential pattern by age. There was no evidence of increased antipsychotic use post-FDACM. Ecologic data cannot determine if changes were due to depression not treated with medications or the prescribing of fewer antidepressants for other conditions. Published in 2009 by John Wiley & Sons, Ltd.

To assess spontaneous reports of rhabdomyolysis associated with simvastatin (SV) and pravastatin (PV) for evidence of CYP3A4 interaction. Clinical trial results advocate cholesterol lowering in high-risk patients including diabetics and the elderly. Given the association between advancing age, metabolic, and cardiovascular disease, many patients are treated with concomitant medications upon statin initiation. Although statins are generally safe, minor and severe adverse reactions arise, especially when given to patients taking concomitant medications that inhibit the statin clearance and lead to increased statin plasma concentration.We conducted a comparative case series of rhabdomyolysis reports associated with SV and PV. Domestic spontaneous reports were obtained from the FDA's Adverse Event Reporting System (AERS). Drug utilization data were obtained from IMS HEALTH and the National Ambulatory Medical Care Survey (NAMCS). Adverse event reporting rates (AER) and ratios (AERR) of rhabdomyolysis associated with SV and PV-with and without stratification by CYP3A4 inhibitor concomitancy were determined.Stratification by CYP3A4 inhibitor concomitancy did not change the rhabdomyolysis AER for PV with or without a CYP3A4 inhibitor (2.4 cases and 3.1 cases per 10 million Rx, respectively). However, stratification of SV reports with or without a concomitant CYP3A4 inhibitor resulted in a rhabdomyolysis AER (38.4 and 6.0 cases per 10 million Rx, respectively). The corresponding AERR with or without a CYP3A4 inhibitor were 0.77 for PV and 6.43 for SV.Spontaneous adverse event reports provide evidence of increased risk for rhabdomyolysis based on interaction between SV and selected CYP3A4 inhibitors.

SUMMARY Background We detected disproportionate reporting of amyotrophic lateral sclerosis (ALS) with HMG-CoA-reductase inhibitors (statins) in the Food and Drug Administration’s (FDA) spontaneous adverse event (AE) reporting system (AERS). Purpose To describe the original ALS signal and to provide additional context for interpreting the signal by conducting retrospective analyses of data from long-term, placebo-controlled clinical trials of statins. Methods The ALS signal was detected using the multi-item gamma Poisson shrinker (MGPS) algorithm. All AERS cases of ALS reported in association with use of a statin were individually reviewed by two FDA neurologists. Manufacturers of lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin, cerivastatin, and rosuvastatin were requested to provide the number of cases of ALS diagnosed during all of their placebo-controlled statin trials that were at least 6 months in duration. Results There were 91 US and foreign reports of ALS with statins in AERS. The data mining signal scores for ALS and statins ranged from 8.5 to 1.6. Data were obtained from 41 statin clinical trials ranging in duration from 6 months to 5 years and representing approximately 200 000 patient–years of exposure to statin and approximately 200 000 patient–years of exposure to placebo. Nine cases of ALS were reported in statin-treated patients and 10 cases in placebo-treated patients. Conclusions Although we observed a data mining signal for ALS with statins in FDA’s AERS, retrospective analyses of 41 statin clinical trials did not reveal an increased incidence of ALS in subjects treated with a statin compared with placebo. Copyright # 2008 John Wiley & Sons, Ltd.

Published literature suggests that attention-deficit/hyperactivity disorder (ADHD) affects 4% of adults and that as many as 60% of children with a diagnosis of ADHD will continue to have problems with inattention and impulsivity in adulthood. We analyzed cross-sectional prescription claims data and data from a national survey of office-based physicians for further inference on the likelihood of treatment with ADHD medications into adulthood.This study used data from a proprietary, national survey of office-based physicians (the IMS Health National Disease and Therapeutic Index, NDTI) to describe the indication associated with office visits with mention of common stimulant medications and atomoxetine. Enrollment and prescription claims data maintained by a large national health-care company were analyzed for age-specific utilization of these same agents.Data from the NDTI suggest that the vast majority of visits associated with a stimulant medication or atomoxetine was coded with a diagnosis consistent with a mental health condition and not obesity/weight loss. The health plans included in this study processed 222,096 prescriptions for stimulant medications and atomoxetine among 43,175 unique patients aged 1-64 years during the calendar year 2004. Analyses of pharmacy claims data showed a steep increase in use through age 11 (prevalence=70.3 per 1,000 covered lives) followed by a marked decrease and plateau from age 25 through age 64 years (prevalence=5 to 10 per 1,000 covered lives).On the basis of comparison of the prevalence rate peak of 70 per 1,000 around age 11 years to a plateau of 7 per 1,000 during the early career years, our results are consistent with a prediction that at least one child in 10 placed on an ADHD medication in childhood will receive treatment in to adulthood. The decrease in the prevalence of use of these medications with advancing age as seen in this cross-sectional study may reflect upon several clinical and secular factors.

We explored nonsteroidal anti-inflammatory drug (NSAID) and aspirin (ASA) use and mortality in the U.S. Department of Health and Human Services' registry of 683 adult and 838 pediatric critically ill pandemic 2009 H1N1 influenza (pH1N1) patients. Among adults, 88 (12.9%) and 101 (14.8%) reported pre-admission use of an NSAID and ASA, respectively; mortality was similar (23-24%) regardless of NSAID or ASA use. Mortality among 89 pediatric NSAID users and 749 nonusers did not differ significantly (10.1% and 8.8%, respectively). One of 16 pediatric ASA users died. Among pediatric patients, the adjusted relative risk estimate for NSAID use and 90-day mortality was higher when influenza vaccination was included in the model (risk ratio [RR] = 1.5; 95% confidence interval, 0.7-3.2), although not statistically significant. Among adults, RR estimates did not change appreciably after adjusting for age, sex, health status, or vaccine status. We found no compelling evidence that NSAID or ASA use influenced mortality in severe pH1N1.

During the 2009 H1N1 influenza pandemic, the UK Medicines and Healthcare Products Regulatory Agency received case reports suggesting a potentiation of warfarin anticoagulation by the antiviral drug oseltamivir. We evaluated this putative interaction using Medicare data.To determine the frequency of bleeding following addition of oseltamivir or comparator drugs among Medicare beneficiaries taking warfarin.This was a retrospective cohort evaluation using Medicare nationwide data. Cohort members were Medicare Parts A, B, and D beneficiaries from June 30, 2006 to October 31, 2010 receiving warfarin for at least 1 month prior to a concomitant drug of interest (oseltamivir, ampicillin, trimethoprim-sulfamethoxazole (TMP-SMX), and angiotensin-converting enzyme (ACE) inhibitors). Bleeding within 14 days of new prescriptions for oseltamivir or comparators was identified using inpatient or emergency department ICD-9 (International Classification of Diseases, ninth revision) discharge diagnosis codes for gastrointestinal hemorrhage, epistaxis, hematuria, and intracranial bleeding. Patients with bleeding within 30 days preceding the prescription concomitant to warfarin were excluded.With concomitant ACE inhibitors as reference, adjusted odds ratios (ORs) for any bleeding events within 14 days were 1.47 (95% confidence interval [CI] = 1.08-1.88), 1.24 (95% CI = 0.97-1.57), and 2.74 (95% CI = 2.53-3.03), for warfarin plus ampicillin, oseltamivir, and TMP-SMX, respectively. In a sensitivity analysis, adjusted ORs over a 7-day period were 1.89 (95% CI = 1.29-2.59), 1.47 (95% CI = 1.06-2.02), and 3.07 (95% CI = 2.76-3.49) for warfarin plus ampicillin, oseltamivir, and TMP-SMX, respectively.Bleeding with oseltamivir plus warfarin was not significantly increased over a 14-day observation period; a sensitivity analysis showed a statistically significant increase over a 7-day period; in contrast, the data consistently showed the known tendency of TMP-SMX to potentiate the effects of warfarin. The results should be interpreted with the limitations of this approach in mind, including the inability to control for unmeasured confounders.

We reviewed Food and Drug Administration postmarketing reports of central nervous system (CNS) anticholinergic effects in association with oxybutynin. Taking domestic usage by age group into account, there is a disproportionately higher number of CNS adverse event cases reported in pediatric patients as compared with adult patients. CNS stimulation was prominent in the pediatric cases.

OBJECTIVE: The aim of this analysis was to delineate trends in spontaneous postmarketing reporting data with antidepressant drugs for adverse events involving suicidal behaviors in children and adolescents. METHODS: The U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) was searched for postmarketing adverse event reports of suicidal thoughts and behaviors occurring in children and adolescents treated with 10 antidepressant drugs. The search covered the period from market launch of each drug through November 2003. RESULTS: A total of 524 reports were returned by the search. All drugs had reports, and most drugs demonstrated 15 or fewer reports annually, with the following two exceptions. We observed a peak of reporting for fluoxetine in the early 1990s, and another peak of reporting for paroxetine in recent years. Further investigation revealed that the peak in recent paroxetine reporting was accounted for by reports from consumers, whereas reporting by health professionals remained fairly constant. In contrast, the earlier peak in reports for fluoxetine was not accounted for by an increase in consumer reporting. CONCLUSIONS: Spontaneous reporting data for suicidal events in pediatric patients treated with antidepressant drugs appears to be highly variable and subject to various influences. The most appropriate method to assess an association of antidepressant drug treatment with suicidal behaviors is examination of systematically collected data with appropriate comparison groups, such as randomized, controlled trial data. Language: en

Background Nonsteroidal anti-inflammatory drugs (NSAIDs) have been reported to increase serum lithium concentrations. We sought to determine whether NSAIDs that selectively inhibit cyclooxygenase (COX) 2 also elevate serum lithium concentrations. Method The U.S. Food and Drug Administration's Adverse Event Reporting System (AERS) database was searched in January 2003 for reports of interactions between lithium and rofecoxib or celecoxib, the selective COX-2 inhibitors marketed in the United States. Additionally, a literature search was performed using PubMed with the MeSH terms anti-inflammatory agents, nonsteroidal and lithium. Reports of interactions between NSAIDs and lithium were selected for review based on titles of retrieved citations. Results Eighteen cases of increased serum lithium concentrations after the addition of one of the COX-2 inhibitors to stable lithium therapy were retrieved from AERS, 13 with rofecoxib and 5 with celecoxib. Serum lithium concentration increases of up to 99% and 448% with concomitant celecoxib and rofecoxib use, respectively, were reported. Thirty-six English-language literature articles report interactions between lithium and various NSAIDs. Although some articles report no effect or decreased serum lithium concentrations with concomitant aspirin or sulindac, increased serum lithium concentration reports exist for aspirin, sulindac, and 14 other NSAIDs, including celecoxib and rofecoxib. Conclusion Clinicians should consider NSAID use in the differential diagnosis of lithium toxicity, monitor patients' serum lithium concentrations during the initiation or discontinuation of NSAID therapy, and be aware that the selective COX-2 inhibitors can increase serum lithium concentrations leading to toxicity.