Efficacy and safety of lebrikizumab in adult patients with mild-to-moderate asthma not receiving inhaled corticosteroids.

BACKGROUND: Asthma is a heterogeneous and complex disease in both its clinical course and response to treatment. IL-13 is central to Type 2 inflammation and contributes to many features of asthma. In a previous Phase 2 study, lebrikizumab, an anti-IL-13 monoclonal antibody, did not significantly improve FEV1 in mild-to-moderate asthma patients not receiving ICS therapy. This Phase 3 study was designed to further assess the efficacy and safety of lebrikizumab in adult patients with mild-to-moderate asthma treated with daily short-acting ß2-agonist therapy alone. METHODS: Adult patients with mild-to-moderate asthma were randomised to receive lebrikizumab 125 mg subcutaneously (SC), placebo SC, or montelukast 10 mg orally for 12 weeks, with an 8-week follow-up period. The primary efficacy endpoint was absolute change in pre-bronchodilator FEV1 from baseline at Week 12. FINDINGS: A total of 310 patients were randomised and dosed in the study. The mean absolute change in FEV1 from baseline at Week 12 was higher in the lebrikizumab-treated arm compared with placebo (150 mL versus 67 mL); however, this improvement did not achieve statistical significance (overall adjusted difference of 83 mL [95% CI: -3, 170]; p = .06). Montelukast did not improve FEV1 as compared with placebo. Lebrikizumab was generally safe and well tolerated during the study. INTERPRETATION: Lebrikizumab did not significantly improve FEV1 in mild-to-moderate asthma patients at a dose expected to inhibit the IL-13 pathway. Inhibiting IL-13 in this patient population was not sufficient to improve lung function. These data support the findings of a previous trial of lebrikizumab in patients not receiving ICS. CLINICAL TRIALS REGISTRY NUMBER: This trial was registered under NCT02104674 at http://www.clinicaltrials.gov.

Emergency hospitalizations for unsupervised prescription medication ingestions by young children.

BACKGROUND: Emergency department visits and subsequent hospitalizations of young children after unsupervised ingestions of prescription medications are increasing despite widespread use of child-resistant packaging and caregiver education efforts. Data on the medications implicated in ingestions are limited but could help identify prevention priorities and intervention strategies. METHODS: We used nationally representative adverse drug event data from the National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance project and national retail pharmacy prescription data from IMS Health to estimate the frequency and rates of emergency hospitalizations for unsupervised prescription medication ingestions by young children (2007-2011). RESULTS: On the basis of 1513 surveillance cases, 9490 estimated emergency hospitalizations (95% confidence interval: 6420-12,560) occurred annually in the United States for unsupervised prescription medication ingestions among children aged <6 years from 2007 through 2011; 75.4% involved 1- or 2-year old children. Opioids (17.6%) and benzodiazepines (10.1%) were the most commonly implicated medication classes. The most commonly implicated active ingredients were buprenorphine (7.7%) and clonidine (7.4%). The top 12 active ingredients, alone or in combination with others, were implicated in nearly half (45.0%) of hospitalizations. Accounting for the number of unique patients who received dispensed prescriptions, the hospitalization rate for unsupervised ingestion of buprenorphine products was significantly higher than rates for all other commonly implicated medications and 97-fold higher than the rate for oxycodone products (200.1 vs 2.1 hospitalizations per 100,000 unique patients). CONCLUSIONS: Focusing unsupervised ingestion prevention efforts on medications with the highest hospitalization rates may efficiently achieve large public health impact.

Concomitant use of isotretinoin and contraceptives before and after iPledge in the United States.

PURPOSE: The major concern associated with isotretinoin treatment is its high teratogenic potential. Therefore, ensuring use of contraception while on therapy is an important strategy for at-risk patients and has been emphasized in all risk management programs. iPledge, the latest and most rigorous isotretinoin program, requires, among other stipulations, monthly assessments of contraceptive use for patients undergoing isotretinoin treatment. The purpose of this study is to evaluate isotretinoin usage patterns and assess concomitant use of isotretinoin and contraceptives before and after iPledge. METHODS: Female patients aged 13-45 years with a new prescription for isotretinoin products during 2004-2008 were identified in the IMS Health longitudinal prescription claims database. Monthly concomitant use of isotretinoin and contraceptives was estimated. Segmented regression analysis of interrupted time series data was used to assess changes in monthly proportion of concomitant use in the 24 months preceding versus following iPledge implementation. RESULTS: The number of isotretinoin prescriptions decreased after iPledge implementation. A small but significant increase in monthly proportion of patients concomitantly using isotretinoin and contraceptive therapies was observed immediately after iPledge implementation (1.3%, p-value = 0.02), particularly among younger patients (2.5%, p-value < 0.01). No changes in the proportion of concomitancy over time (i.e. slope) between the periods before and after iPledge implementation were observed. CONCLUSION: The findings of this pharmacy prescription claims-based study suggest a small increase in concomitant use of isotretinoin and contraceptives coincident with the time of implementation of iPledge, particularly among younger women. Published 2013. This article is a U. S. Government work and is in the public domain in the USA.

Trends of outpatient prescription drug utilization in US children, 2002-2010.

OBJECTIVE: To describe trends in outpatient prescription drug utilization in US children and the changes in major areas of pediatric therapeutic use for the years 2002 through 2010. METHODS: Large prescription databases (the IMS Vector One: National and Total Patient Tracker) were used to examine national drug utilization patterns for the US pediatric population (ages 0-17 years) from 2002 through 2010. RESULTS: In 2010, a total of 263.6 million prescriptions were dispensed to the US pediatric population, 7% lower than in 2002, while prescriptions dispensed to the adult population increased 22% during the same time. Analysis of pediatric drug utilization trends for the top 12 therapeutic areas in 2010 compared with 2002 showed decreases in systemic antibiotics (-14%), allergies (-61%), pain (-14%), depression (-5%), and cough/cold without expectorant (-42%) prescriptions, whereas asthma (14%), attention-deficit/hyperactivity disorder (46%), and contraceptive (93%) prescriptions increased. In 2010, amoxicillin was the most frequently dispensed prescription in infants (aged 0-23 months) and children (aged 2-11 years). Methylphenidate was the top prescription dispensed to adolescents (aged 12-17 years). Off-label use was identified, particularly for lansoprazole; ~358,000 prescriptions were dispensed in 2010 for infants <1 year old. CONCLUSIONS: Changes in the patterns of pediatric drug utilization were observed from 2002 to 2010. Changes include a decrease in antibiotic use and an increase in attention-deficit/hyperactivity disorder medication use during the examined time. This article provides an overview of pediatric outpatient drug utilization, which could set the stage for further in-depth analyses.

Shifts in propylthiouracil and methimazole prescribing practices: antithyroid drug use in the United States from 1991 to 2008.

CONTEXT: The thionamide antithyroid drugs methimazole and propylthiouracil are the mainstay of pharmacologic therapy for Graves' disease. However, little is known about the rate of use of these drugs and the prescribing practices of physicians treating hyperthyroidism. OBJECTIVE: The objective of the study was to examine the frequency of methimazole and propylthiouracil use from years 1991 to 2008. METHODS: The data were acquired by the U.S. Food and Drug Administration's Division of Epidemiology through two databases: IMS National Sales Perspectives and the Surveillance Data, Inc. Vector One: National database. RESULTS: There was a 9-fold increase in the annual number of methimazole prescriptions during the study period, from 158,000 to 1.36 million per year. There was a 19% increase in the annual number of propylthiouracil prescriptions, from 348,000 to 415,000 per year. Propylthiouracil, which held two thirds of the market from 1991 to 1995, was surpassed by methimazole in 1996. Patient demographic data indicated that although 72% of methimazole prescriptions were for females, males were more likely to be on methimazole (82%) than females (74%) (P < 0.001, two tailed chi(2) test). The only demographic group in which methimazole use decreased was women of child-bearing age (5% decrease, P < 0.001, two tailed chi(2)). The incidence of hyperthyroidism in 2008 was estimated based on the number of new prescriptions of thionamides by age group and data from the 2008 U.S. census: 0.44 per 1000 for ages 0-11 yr, 0.26 per 1000 for ages 12-17 yr, 0.59 per 1000 for ages 18-44 yr, 0.78 per 1000 for ages 45-64 yr, and 1.01 per 1000 for ages 65+ yr. CONCLUSIONS: Methimazole has become the most frequently prescribed antithyroid drug. The remarkable increase in the total number of dispensed thionamide prescriptions over the last 18 yr may indicate a trend toward pharmacological treatment as primary treatment of Graves' disease in the United States.

Changes in US antidepressant and antipsychotic prescription patterns during a period of FDA actions.

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(R), US Census, and IMS Health(R). 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.

Identifying patterns of adverse event reporting for four members of the angiotensin II receptor blockers class of drugs: revisiting the Weber effect.

PURPOSE: To evaluate the evidence for temporal reporting patterns, such as the Weber effect, in spontaneous post-marketing adverse event (AE) reports submitted to the Food and Drug Administration (FDA), for four members of the angiotensin II receptor blockers drug class (ARBs). METHODS: For losartan, valsartan, irbesartan, and candesartan, we evaluated temporal trends in reporting for the total number of AE reports, serious AE reports, and direct reports from consumers or health care providers (direct reports) to FDA. Reporting patterns were considered consistent with the Weber effect when the peak occurred 2 years after US marketing and the number of reports declined thereafter. We tabulated the number of reports by year since the first report. We adjusted the total number of reports, number of serious AE reports, and number of direct reports by the number of US dispensed prescriptions. RESULTS: There were no clear temporal reporting patterns for the total number of reports, direct reports, or serious AE reports. We observed a consistent trend for the adjusted number of direct and serious AE reports. The adjusted number was highest in the first year and continually decreased over time for all four ARBs. For the adjusted total number of reports, the decline was not constant over time. CONCLUSION: A characteristic temporal pattern in the adjusted number of reports, in which the adjusted number was highest in the first year and declined thereafter, was identified. However, we did not observe a pattern consistent with the Weber effect for these four ARBs.

Outpatient use of anticoagulants, rate-controlling drugs, and antiarrhythmic drugs for atrial fibrillation.

BACKGROUND: The first clinical practice guidelines for management of atrial fibrillation (AF) were published in 2001. We explored the use of anticoagulants, rate-controlling drugs, and antiarrhythmic drugs in patients with AF during the 4 years surrounding publication of these guidelines. METHODS: Mentions of warfarin, beta-blockers, digoxin, diltiazem, verapamil, and all class I and class III antiarrhythmic drugs made by US office-based physicians during patient visits for AF between October 1999 and September 2003 were evaluated using the IMS Health National Disease and Therapeutic Index (Plymouth Meeting, PA). Medication use by patient age, sex, and physician specialty was explored. Trends in use during the study period were estimated. RESULTS: Warfarin was mentioned in an average of 37% of all AF-related visits across the observation period, with no statistically significant change over time. Digoxin was the most commonly mentioned rate-controlling drug in 23% of patient visits, followed by beta-blockers in 11% and calcium-channel blockers in 8%. Over the study period, mentions of digoxin significantly decreased, and mentions of beta-blockers significantly increased. Mentions of antiarrhythmic drugs were reported in an average of 12% of patient visits, with no significant change over the study period. CONCLUSIONS: Observed trends in use of digoxin, beta-blockers, and class Ia antiarrhythmic drugs were consistent with evidence-based recommendations. However, only approximately one third of patient visits for AF included mentions of warfarin, even among patients aged > or = 60 years. These results indicate the need for continued education and interventions, especially regarding stroke prevention, in patients with AF.

Trends in outpatient prescription drug use and related costs in the US: 1998-2003.

OBJECTIVE: To present a brief synopsis of trends in the number of prescriptions and retail costs of outpatient drugs dispensed in the US between 1998 and 2003. METHODS: Data were extracted from IMS Health, the National Prescription Audit Plus and the National Disease and Therapeutic Index databases. RESULTS: In 1998, 2.7 billion outpatient prescriptions were dispensed versus 3.6 billion in 2003. This equates to a 33.3% increase over the 6-year period. Of the top 20 most dispensed drugs by volume, 40% were launched in the 1990s or 2000s. Retail costs for the total market of dispensed outpatient prescription drugs were 96.1 billion US dollars in 1998 and 196 billion US dollars in 2003, a 104% increase. Of the top 20 most dispensed drugs by retail cost, all were tradename drugs and were launched in the 1990s or 2000s. CONCLUSIONS: These data indicate a large increase in the US over a short time period in dispensed outpatient prescriptions and their associated retail costs.

Comparison of reporting of Stevens-Johnson syndrome and toxic epidermal necrolysis in association with selective COX-2 inhibitors.

BACKGROUND: Stevens-Johnson syndrome and toxic epidermal necrolysis are closely related severe acute life-threatening, drug-induced skin disorders. The US FDA Adverse Events Reporting System (AERS) has received reports of Stevens-Johnson syndrome and toxic epidermal necrolysis associated with the use of the recently introduced selective cyclo-oxygenase (COX)-2 inhibitor NSAIDs, two of which are also sulfonamides. OBJECTIVE: The objective of this study is to review cases of Stevens-Johnson syndrome and toxic epidermal necrolysis reported to the FDA associated with the use of the selective COX-2 inhibitor NSAIDs celecoxib, rofecoxib and valdecoxib, and to compare reporting rates of the two conditions associated with these drugs to each other, meloxicam (an oxicam NSAID that came on the US market at a similar time) and the background incidence rate. METHODS: We reviewed all US cases of Stevens-Johnson syndrome and toxic epidermal necrolysis reported to the FDA AERS database associated with the use of celecoxib, rofecoxib, valdecoxib and meloxicam since these agents were first marketed. We utilised AERS and drug use data to calculate reporting rates for each drug after the first 2 years of marketing. We obtained the background rate from the medical literature. RESULTS: Up to the end of March 2004, there were 63 cases of Stevens-Johnson syndrome/toxic epidermal necrolysis reported with valdecoxib use, 43 with celecoxib, 17 with rofecoxib (the non-sulfonamide coxib) and none for meloxicam. In the first 2 years of marketing the reporting rate for Stevens-Johnson syndrome/toxic epidermal necrolysis with valdecoxib was 49 cases per million person-years of use, 6 cases per million person-years for celecoxib and 3 cases per million person-years for rofecoxib. The reporting rates for the sulfonamide coxibs were substantially higher than the background rate of 1.9 cases per million population per year, with the valdecoxib rate being 8-9 times that of celecoxib and approximately 25 times that of the background rate. CONCLUSION: There is a strong association between Stevens-Johnson syndrome/toxic epidermal necrolysis and the use of the sulfonamide COX-2 inhibitors, particularly valdecoxib. Physicians should be aware of the possibility of this serious life-threatening event when prescribing these drugs and advise patients to discontinue use at the earliest possible sign or symptom.

Changes in isotretinoin prescribing before and after implementation of the System to Manage Accutane Related Teratogenicity (SMART) risk management program.

PURPOSE: To assess changes in isotretinoin prescribing following the implementation of the System to Manage Accutane Related Teratogenicity (SMART) risk management program. METHODS: Using nationally representative commercial data resources on prescription drug dispensing patterns, surveys of office-based physician practices, and a large, claims database from a pharmacy benefits manager (PBM), we examined the total number of isotretinoin prescriptions (new and refill), prescriber speciality, and patient characteristics (age, gender, severity of acne indication) in the year before (April 2001-March 2002) and the year following (April 2002-March 2003) implementation of the SMART program. RESULTS: In the 12-months prior to SMART, 1 508 000 prescriptions were dispensed for isotretinoin, declining approximately 23% to 1 160 000 prescriptions in the year following SMART. There was little or no change in prescriber specialty, severity of acne, and patient age and gender. CONCLUSION: SMART may have lead to a decrease in isotretinoin prescriptions. Further research is needed to determine whether the reduced number of isotretinoin prescriptions reflects appropriate use or inhibited use resulting in loss of access to the product's benefits.

Use of menopausal hormones in the United States, 1992 through June, 2003.

PURPOSE: The Women's Health Initiative (WHI) study that documented an unfavorable benefit to risk ratio of Prempro and subsequently an increased risk of stroke with menopausal estrogen prompted us to investigate the use during 1992 through June 2003 of menopausal hormones in the United States. METHODS: Two pharmaceutical research databases from IMS Health, the National Prescription Audit Plus and the National Disease and Therapeutic Index, were accessed and analyzed. RESULTS: The number of dispensed outpatient prescriptions for oral menopausal estrogens and oral combination estrogen-progestins increased 2.5-fold (153%) from 34.5 million dispensed in 1992 to a high of 87.3 million in 2000. For July 2002 through June 2003, the year following the publication of the results of the WHI trial, prescriptions for these products declined to 59.6 million, a 32% decrease from their peak in 2000. Prescriptions for transdermal estrogen and transdermal combination estrogen-progestin products increased from 5.2 million dispensed in 1992 to their peak of 8.3 million in 2000, and declined 10% to 7.5 million during July 2002 through June 2003. By contrast, prescriptions for oral menopausal progestins rose to 17.5 million in 1995 and then steadily declined. In the year after the WHI, prescriptions for oral progestins decreased 49% to 8.9 million from their peak in 1995. The earlier decline in oral progestin prescriptions was primarily due to the marketing in 1995 of the popular oral combination estrogen-progestin drugs. CONCLUSIONS: Prescriptions dispensed for menopausal hormones increased substantially between 1992 and peaked in 2000. By June 2003, prescriptions for oral menopausal estrogens and oral combination estrogen-progestins had declined by about one-third from their peak year.

Rapid increase in the use of oral antidiabetic drugs in the United States, 1990-2001.

OBJECTIVE: To describe the use of oral antidiabetic drugs for management of type 2 diabetes in the U.S. from 1990 through 2001. RESEARCH DESIGN AND METHODS: Data on oral antidiabetic drugs were derived from two pharmaceutical marketing databases from IMS Health, the National Prescription Audit Plus and the National Disease and Therapeutic Index. RESULTS: In 1990, 23.4 million outpatient prescriptions of oral antidiabetic agents were dispensed. By 2001, this number had increased 3.9-fold, to 91.8 million prescriptions. Glipizide and glyburide, two sulfonylurea medications, accounted for approximately 77% of prescriptions of oral antidiabetic drugs in 1990 and 35.5% of prescriptions in 2001. By 2001, the biguanide metformin (approved in 1995) had captured approximately 33% of prescriptions, and the thiazolidinedione insulin sensitizers (rosiglitazone and pioglitazone marketed beginning in 1999) accounted for approximately 17% of market share. Compared with patients treated in 1990, those in 2001 were proportionately younger and they more often used oral antidiabetic drugs and insulin in combination. Internists and general and family practitioners were the primary prescribers of this class of drugs. CONCLUSIONS: Consistent with the reported increase in the prevalence of type 2 diabetes, the number of dispensed outpatient prescriptions of oral antidiabetic drugs increased rapidly between 1990 and 2001. This period was marked by an increase in the treatment of younger people and the use of oral antidiabetic drugs in combination. With the approval in the last decade of several new types of oral antidiabetic medications with different mechanisms of action, options for management of type 2 diabetes have expanded.