James P. Wilson

FDA Adverse Event Reports on Statin-Associated Rhabdomyolysis

OBJECTIVE: To determine the number of cases of statin-associated rhabdomyolysis reported to the Food and Drug Administration for 6 statins and to profile the cases. METHODS: A retrospective analysis of all domestic and foreign reports of statin-associated rhabdomyolysis between November 1997 and March 2000 was conducted. Outcome measures included the total number of reports (initial plus follow-up), the number of unique cases, age, gender, percentages of report codes and role codes, and frequencies of concomitant interacting drugs that may have precipitated rhabdomyolysis, outcomes codes, and report source codes. RESULTS: There were 871 reports of statin-associated rhabdomyolysis in the 29-month time frame examined, representing 601 cases. The following number of cases were associated with each of the individual statins: simvastatin, 215 (35.8%); cerivastatin, 192 (31.9%); atorvastatin, 73 (12.2%); pravastatin, 71 (11.8%); lovastatin, 40 (6.7%); and fluvastatin, 10 (1.7%). Drugs that may have interacted with the statins were present in the following number of cases: mibefradil (n = 99), fibrates (n = 80), cyclosporine (n = 51), macrolide antibiotics (n = 42), warfarin (n = 33), digoxin (n = 26), and azole antifungals (n = 12). The reports of 62.1% of cases were classified as expedited. Statins were designated as the primary suspect in 72.0% of the cases. Death was listed as the outcome in 38 cases. The majority of reports (n = 556) were from health professionals. CONCLUSIONS: Compared with the other statins, simvastatin and cerivastatin were implicated in a relatively higher number of reports. Because of the various limitations of a spontaneous reporting-system database, caution is urged when interpreting the relative number of cases reported.

Rhabdomyolysis and HMG-CoA Reductase Inhibitors

OBJECTIVE: To review rhabdomyolysis and discuss the role of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) and their interactions with other agents in precipitating this condition, and to present case reports of statin-induced rhabdomyolysis. DATA SOURCE: Relevant clinical literature was accessed using MEDLINE (January 1985–October 2000). The following search terms were used: rhabdomyolysis, adverse events, drug interactions, statins, and HMG-CoA reductase inhibitors. DISCUSSION: Rhabdomyolysis occurs when extensive muscle damage results in the release of cellular contents into systemic circulation. Major complications include acute renal failure, cardiac abnormalities, and compartment syndrome. Treatment of rhabdomyolysis is supportive, with the primary aim of preventing renal and cardiac complications. Statin monotherapy or combination therapy may result in myopathy, which rarely progresses to rhabdomyolysis. The mechanism for drug interactions with the statins involves their property of lipid or water solubility. This characteristic determines the degree of hepatoenteric or renal metabolism of the statins. All statins except pravastatin undergo metabolism via the cytochrome P450 enzyme system. Other pharmacologic agents that are also metabolized via this pathway may interact with the statins and cause rhabdomyolysis. The risk of statin-induced rhabdomyolysis is increased significantly when statins are used concomitantly with such drugs as fibrates, cyclosporine, macrolide antibiotics, and azole antifungals. CONCLUSIONS: Rhabdomyolysis is a rare but clinically important adverse event of statin monotherapy or combination therapy. Thorough understanding of this condition may help prevent or minimize adverse health outcomes in patients receiving statin therapy.

Assessment of Adherence Measures with Different Stimulants Among Children and Adolescents

Study Objective. To examine adherence measures with different stimulants in children and adolescents.

Replication of the Weber effect using postmarketing Adverse Event reports voluntarily submitted to the United States food and Drug Administration

Study Objective. To validate or refute a widely accepted epidemiologic phenomenon known as the Weber effect by replicating Webers original observation by using drugs that were marketed in the United States and using reports from a U.S. database.

Temporal Relationship between Use of NSAIDs, Including Selective COX-2 Inhibitors, and Cardiovascular Risk

AbstractBackground and Objective: The search for NSAIDs with less gastrointestinal toxicity led to the introduction of the selective cyclo-oxygenase-2 (COX-2) inhibitors. However, following their introduction into the market, concerns have developed regarding their safety, particularly their cardiovascular safety. The purpose of this study was to assess the cardiovascular risk (events included were myocardial infarction, stroke and myocardial infarction-related deaths) associated with long-term (>180 days of exposure) and short-term (≤180 days of exposure) use of non-selective NSAIDs, including ‘preferential COX-2 inhibitors’ (i.e. etodolac, nabumetone and salsalate), and selective COX-2 inhibitors. Methods: A retrospective analysis of the Veterans Integrated Service Network 17 Veterans Affairs (VA) database was conducted. Medicare data and Texas Department of Health mortality data were incorporated to capture events occurring outside the VA healthcare network. Patients ≥35 years of age who received celecoxib, rofecoxib, ibuprofen, etodolac and naproxen from 1 January 1999 through 31 December 2001, were included. Multivariate Cox proportional hazard models were used to analyse the relationship between cardiovascular risk and NSAID use, including selective COX-2 inhibitor use, while adjusting for various risk factors. Results: We identified 12 188 exposure periods (11 930 persons) and 146 cardiovascular events over the entire study period. Compared with long-term ibuprofen use, long-term use of celecoxib (adjusted hazard ratio [HR] 3.64; 95% CI 1.36, 9.70) and rofecoxib (adjusted HR 6.64; 95% CI 2.17, 20.28) was associated with a significant increase in cardiovascular risk. When restricted to patients ≥65 years of age, the cardiovascular risks associated with long-term celecoxib (adjusted HR 7.36; 95% CI 1.62, 33.48) and rofecoxib (adjusted HR 13.24; 95% CI 2.59, 67.68) use increased. Short-term use of celecoxib (adjusted HR 0.75; 95% CI 0.42, 1.35) and rofecoxib (adjusted HR 0.85; 95% CI 0.39, 1.86) was not associated with any significant change in cardiovascular risk when compared with short-term ibuprofen use. Neither long- nor short-term exposure to naproxen and etodolac was associated with cardionegative or cardioprotective effects when compared with ibuprofen use. Conclusions: The findings of this observational study, along with recent clinical trial results, suggest that prolonged exposure to selective COX-2 inhibitors may be associated with an increased risk of adverse cardiovascular outcomes.

Patterns of antihypertensive use among patients in the US Department of Defense database initially prescribed an angiotensin-converting enzyme inhibitor or calcium channel blocker

The US Department of Defense recently assembled electronic records of outpatient prescriptions dispensed through the Uniformed Services Prescription Database Project (USPDP) going back to 1990. The objectives of this portion of a larger study were: (1) to examine longitudinally the patterns of antihypertensive drug use during the first year of therapy in patients whose initial therapy was with an angiotensin-converting enzyme (ACE) inhibitor or a calcium channel blocker (CCB); (2) to determine continuous and noncontinuous users of antihypertensive drugs; and (3) to estimate the direct medication costs for each pattern of medication use. Filtering criteria for patient and prescription identification were developed, because the USPDP contains no records of confirmatory diagnoses of hypertension. Once data filters were implemented, information for 771 patients was analyzed. An ACE inhibitor was the initial therapy for 328 patients, accounting for 1935 antihypertensive medication prescription fills, and a CCB was the initial therapy for 443 patients, accounting for 2459 fills (including refills). Slightly more than half of the patients (n = 401, 52.0%) were classified as continuous users (> or = 80% medication-possession ratio [supply of medication in days divided by the number of days in the 12-month study period]). In the first year, 177 of these continuous users (44.1%) had no change in therapy in the first year, 49 (12.2%) had an increase in dose, 8 (2.0%) had a decrease in dose, 15 (3.7%) had a change to a different therapeutic class of antihypertensive medication, 14 (3.5%) were changed to a different medication in the same therapeutic class, 20 (5.0%) had a new medication added to the regimen, and 118 (29.4%) had complex regimens involving more than one change. For continuous users, the mean medication supply in days was 354.6, and the average time before a medication change was 152.1 days for those continuous users who had one change in therapy. The overall average wholesale price (AWP) and average manufacturer price (AMP) for continuous users during 1 year of therapy were

Queuing Theory and Customer Satisfaction: A Review of Terminology, Trends, and Applications to Pharmacy Practice

471.31 and

Evaluating equivalence and noninferiority trials

378.51, respectively. For those patients whose therapy was changed to an ACE inhibitor/CCB combination and who were continuous users, the average AWP was

Antipsychotic Medication Utilization Trends Among Texas Veterans: 1997–2002

598.47 per year (

Physician Specialty Associated With Antipsychotic Prescribing for Youths in the Texas Medicaid Program

492.05 AMP). Once the change from monotherapy to an ACE inhibitor/CCB combination occurred in continuous users, AWP costs per member per month increased by approximately