Annals of Pharmacotherapy

Campbell, Heather M; Boardman, Kathy D; Dodd, Melanie A; Raisch, Dennis W

doi: 10.1345/aph.1K074pmid: 17609233

Background:Prevention of cardiovascular disease (CVD) events by initiating an angiotensin-converting enzyme (ACE) inhibitor on diagnosis of type 2 diabetes may increase survival and decrease costs.Objective:To determine the incremental cost-effectiveness ratios of ACE inhibitor initiation in normoaIbuminuric, microalbuminuruc, and macroaIbuminuric patients with newly diagnosed type 2 diabetes.Methods:A cohort of patients with newly diagnosed type 2 diabetes was followed for 8 years in a Markov model. Clinical outcomes included CVD events, dialysis, all-cause mortality, and the composite endpoints of the 3 events. Probabilities and costs were obtained from the literature. One-way and two-way sensitivity analyses were conducted to test the robustness of the model.Results:Implementation of ACE inhibitor therapy on diagnosis of type 2 diabetes in normoalbuminuric and microalbuminuric patients is a dominant strategy (ie, more effective and less costly) across all outcomes. In macro-albuminuric patients, an additional $4,10 and $4.58 saves one life and avoids one composite endpoint, respectively; however, in these patients, not giving an ACE inhibitor is dominant for prevention of CVD events and dialysis. This is due to a 28.62% higher mortality rate in patients not receiving an ACE inhibitor. Thus, analysts of the composite endpoint shows that not giving an ACE inhibitor does not remain dominant. A limitation of our study is the inability to determine causality.Conclusions:If every newly diagnosed patient with type 2 diabetes in the US was prescribed an ACE inhibitor, our model shows that 68 314 CVD events would be averted, 46410 lives would be saved, and 48 people would be prevented from needing dialysis over 8 years. These findings suggest that ACE inhibitors prevent numerous events in patients with type 2 diabetes who are normoalbuminuric at diagnosis, in addition to those already identified as being at risk for CVD events.

Veronin, Michael A; Lee, Eunah; Lewis, E Neil

doi: 10.1345/aph.1H680pmid: 17595307

Background:Recently, there has been much debate in the US concerning drug importation from Canadian Internet pharmacies. The Food and Drug Administration and US drug manufacturers assert that drugs obtained from international markets via the Internet present a health risk to consumers from substandard products. The public's perception is that drugs from Canada are as safe as those from the US.Objective:To determine whether simvastatin tablets obtained via the Internet from Canadian generic manufacturers are comparable in blend uniformity, a major attribute of tablet quality, with the US innovator product.Methods:Generic simvastatin tablets from 4 Canadian Internet pharmacy Web sites and the US innovator product were obtained for pharmaceutical analysis, Tablet samples were analyzed using near-infrared spectroscopic imaging techniques, which are designed to detect formulation defects of drug products during the manufacturing process. Digital images were created, revealing the tablets’ internal structures.Results:The blend uniformity of the active pharmaceutical ingredient in the tablet samples from Canada was determined and compared with that of the US innovator product. Results indicated that there is little significant difference in blend uniformity among US innovator and Canadian generic tablets.Conclusions:Results of this study suggest comparable quality assurance manufacturing standards for the US innovator product and the Canadian generic drug products tested. These findings have clinical, legal, and economic implications that should be addressed by policy makers to safeguard consumers who choose to purchase Canadian-manufactured drugs via the Internet.

Smith, Scott R; Wahed, Abdus S; Kelley, Stephanie S; Conjeevaram, Hari S; Robuck, Patricia R; Fried, Michael W

doi: 10.1345/aph.1K024pmid: 17519299

Objective:To assess the validity of self-reported medication adherence provided by individuals in treatment for hepatitis C virus (HCV) infection with a regimen of peginterferon and ribavirin.Methods:Adherence was evaluated prospectively among 196 African American and 205 white subjects enrolled in Virahep-C (Viral Resistance to Antiviral Therapy of Chronic Hepatitis C), a treatment study for genotype 1 HCV infection. Adherence to the prescribed dose was measured by 2 methods: self-report questions administered during multiple clinic visits, using a touch screen computer; and recordings of bottle openings, using an electronic monitor placed inside the cap of prescription containers. Self-reported responses were compared with the electronic monitor data. Nonparametric tests were used to test the association between adherence measures at 4, 12, 24, 36, and 48 weeks of treatment.Results:The estimated proportion of participants who were adherent prior to a given visit ranged from 85% to 97% (ribavirin) and 97% to 100% (peginterferon) by self report and from 69% to 90% (ribavirin) and 64% to 100% (peginterferon) by electronic monitors. For ribavirin, the percentage of cases in which the 2 measurement methods agreed varied from 68% to 90%; peginterferon agreement was from 84% to 100%. Overall, adherence was higher for peginterferon than for ribavirin but decreased over time for both medications. Self-reported adherence was usually higher than that assessed by electronic measures, and the level of discrepancy increased during the course of treatment.Conclusions:Adherence to peginterferon and ribavirin decreased gradually during therapy but remained relatively high. Simple self-reported measures can be used to screen for nonadherence to HCV drug therapy, but should be considered as overestimation of the actual amounts taken.

Charrois, Theresa L; Hill, Richard L; Vu, Duc; Foster, Brian C; Boon, Heather S; Cramer, Kristie; Vohra, Sunita

doi: 10.1345/aph.1H463pmid: 17578882

Background:The majority of Canadians use natural health products (NHPs), most of which are purchased in pharmacies. Community pharmacists regularly field inquiries regarding NHPs. As such, pharmacists are ideally placed to answer questions about NHP use and interactions with other medications.Objective:To identify community pharmacists’ familiarity with NHPs and NHP-related adverse events (AEs) and their knowledge and ability to counsel on potential and known NHP–drug interactions.Methods:Survey questions were derived from a literature review of previous surveys, data collected from Health Canada, and in consultation with clinicians, pharmacists, policy-makers, and researchers. A convenience sample of 321 community pharmacists in Alberta and British Columbia were asked to participate.Results:We received responses from 132 pharmacists, resulting in a response rate of 41% (132/321). A total of 19% of the sample had previously reported an adverse event to Health Canada. When asked specifically about NHP–drug interactions/AEs, 47% of pharmacists stated that they had identified a potential interaction; however, only 2 of these reported it to Health Canada. Pharmacists were most familiar (76% of respondents) with the interaction between sertraline and St. John's wort and were least familiar with interactions between NHPs and antiretrovirals.Conclusions:This survey provides evidence to suggest that pharmacists encounter reportable NHP–drug interactions, yet rarely choose to report these events. The current lack of available data on NHP AEs makes it difficult to provide patients and healthcare providers with useful strategies for managing AEs and drug interactions. Changes to the current system of monitoring AEs due to NHPs and further education of healthcare professionals regarding NHP—drug interactions is required.

Spriet, Isabel; Goyens, Jo; Meersseman, Wouter; Wilmer, Alexander; Willems, Ludo; Paesschen, Wim Van

doi: 10.1345/aph.1K079pmid: 17609232

Background:Valproate and meropenem are frequently used in the intensive care unit to treat seizures and serious infections, respectively. Several case reports have described a remarkable interaction between the drugs when administered concurrently. The interaction leads to a significant drop in plasma concentrations of valproate within 24 hours and relapse of seizures in some patients.Objective:To evaluate a consecutive population of hospitalized patients who were simultaneously treated with meropenem and valproate and assess the effect on epileptic activity.Methods:A retrospective study of an 18 month period was performed to assess the extent and clinical impact of this interaction. To assess the relevance of the interaction, the time-relationship between the drop in plasma concentrations and relapse in seizure activity and/or deterioration of electroencephalogram recordings was determined. We investigated other contributing preconvulsive cofactors and concomitant antiepileptic treatment. Drug interaction probability scale (DIPS) scores were calculated.Results:Thirty-nine patients were treated simultaneously with valproate and meropenem. The pharmacokinetic interaction was observed in all 39 patients, with an average drop in valproate plasma concentrations of 66%, The decrease occurred within 24 hours, as shown in 19 patients who had daily plasma concentration monitoring, The clinical impact of the interaction could not be assessed in 19 (49%) patients due to death (n = 13) or incomplete charts (n = 6). In the remaining 20 (51%) patients, DIPS scores were calculated and clinical relevance was assessed. The interaction was considered to be probable in 16 patients and possible in 4, as calculated by the DIPS. The interaction contributed to electroclinical deterioration in 11 patients.Conclusions:The pharmacokinetic interaction between valproate and meropenem was present in all patients and led to a drop of valproate concentrations with an average of 66% within 24 hours. This interaction was clinically relevant with electroclinical deterioration in 55% of patients. To avoid patients’ possible neurologic deterioration, meropenem and valproate should not be administered together.

Tsuruta, Ryosuke; Mizuno, Hidekazu; Kaneko, Tadashi; Oda, Yasutaka; Kaneda, Kotaro; Fujita, Motoki; Inoue, Takeshi; Kasaoka, Shunji; Maekawa, Tsuyoshi

doi: 10.1345/aph.1K010pmid: 17535843

Background:The Japanese Guidelines for the Diagnosis and Treatment of Deep-Seated Mycosis were established in 2003. Proven Candida infection (CI) is defined as at least one positive blood culture yielding a Candida species. Clinically documented CI requires documentation of more than 2 sites of colonization and a positive plasma β-O-glucan test. Possible CI is diagnosed by one of the above criteria in febrile, nonneutropenic critically ill patients.Objective:To assess the use of definitions of clinically documented and possible CI for guiding preemptive antifungal therapy in critically ill patients.Methods:The patients treated in our intensive care unit (ICU) for at least 48 hours between 2000 and 2004 were investigated. The administration of antifungal agents and ICU mortality were compared among proven, clinically documented, and possible CI groups for age, sex, APACHE II score, diagnosis, length of ICU stay, treatment, number of colonization sites, and plasma β-D-glucan level.Results:Six patients were diagnosed with proven CI, 25 were diagnosed with clinically documented CI, and 104 with possible CI. The patients with clinically documented CI were compared with those with possible CI, and statistically significant differences were found in the following variables: APACHE II score (p = 0.018), length of ICU stay (p < 0.01), use of ventilator (p = 0.027), tracheotomy (p = 0.027), number of colonization sites (p < 0.001), plasma β-D-glucan level (p < 0.001), and administration of antifungal agents (p < 0.001); incidence of mortality was not statistically significant (p = 0.33). The shorter length of ICU stay, use of ventilator, and continuous hemodiafiltration were risk factors for death after adjusting for APACHE II score, admission before/after 2003, antifungal therapy, and other factors. Although the frequency of the administration of preemptive antifungal therapy was higher after 2003 than before, the mortality rate did not differ significantly,Conclusions:The use of the definitions of clinically documented and possible CI may be beneficial for determining when it is appropriate to initiate preemptive antifungal therapy. However, use of the guidelines did not lead to prevention of possible CI proceeding to clinically documented CI or to improved mortality.

Chamberlin, Kevin W; Cottle, Mark; Neville, Rebecca; Tan, Jennifer

doi: 10.1345/aph.1H451pmid: 17595308

ObjectiveTo describe the pharmacology, safety and efficacy, and rationale for use of oral oxymorphone for the management of acute and chronic moderate-to-severe pain.Data SourcesA PubMed/MEDLINE search (1966-March 2007) was conducted using the following terms: oral oxymorphone, oxymorphone, EN 3202, EN 3203, Opana, and Opana ER. Manufacturer-provided data (package inserts) and abstracts presented at the American Pain Society meetings (2003–2006) were also reviewed.Study Selection and Data ExtractionHuman studies evaluating the safety and efficacy of oral oxymorphone in pain management were considered; animal and non–English-language data were excluded.Data SynthesisOral oxymorphone is a semisynthetic opioid agonist that is specific for the μ-opioid receptor and approved to treat both acute and chronic pain. Unlike other opioids, such as oxycodone, oxymorphone does not bind to the κ-opioid receptor. Due to extensive liver metabolism, oral oxymorphone is contraindicated in patients with moderate-to-severe hepatic impairment; however, no clinically significant CYP3A4, 2C9, or 2D6 mediated drug-drug interactions have been noted. Elderly patients may experience a 40% increase in plasma concentrations, while renally impaired patients may have a 57–65% increase in bioavailability. Food can increase the rate of absorption by as much as 50%, necessitating dosing either 1 hour before or 2 hours after a meal. Oxymorphone's primary adverse effects are similar to those of other opioids: nausea, vomiting, pruritus, pyrexia, and constipation.ConclusionsOxymorphone is an oral therapeutic option approved for the treatment of acute and chronic moderate-to-severe pain. Oxymorphone has a safety and efficacy profile similar to that of other commonly used pure opioids (morphine, oxycodone, hydromorphone). Like oxycodone and morphine, oxymorphone also has immediate-release and extended-re lease formulations. Since cost alone is not yet favorable for oxymorphone over oxycodone or morphine, further studies of comparative efficacy targeting potential advantages of oxymorphone over other opioids are necessary before considering it for addition to a formulary.

Bruce, Susan P; Boyce, Eric G

doi: 10.1345/aph.1K057pmid: 17609234

Objective:To review and update the pharmacology, pharmacokinetics, safety, precautions, efficacy, and use of abatacept for rheumatoid arthritis (RA).Data Sources:Studies and abstracts were identified through MEDLINE, International Pharmaceutical Abstracts, Cochrane databases, and Science Citation Index (1990–April 2007). Key search terms included abatacept, CTLA4–Ig, and BMS 1888667. Information available only in abstract form was retrieved from national and international rheumatology associations. Additional data were obtained from the manufacturer.Study Selection and Data Extraction:All available animal and human studies describing the pharmacology of abatacept and human studies describing the pharmacokinetics, pharmacodynamics, efficacy, safety, adverse events, and precautions of abatacept were included.Data Synthesis:Abatacept significantly improves the signs and symptoms of moderate-to-severe RA in patients who experienced an Inadequate response to methotrexate or antitumor necrosis factor-α inhibitors. By month 12, approximately 50% of patients achieved remission (defined as a disease activity score <2.6) that was maintained until at least 24 months of therapy. The most common adverse events include headache, upper respiratory tract infections, nausea, and nasopharyngitis. Rare but serious adverse events include serious infections and malignancy.Conclusions:Abatacept has documented efficacy and safety in patients with inadequate responses to methotrexate and antitumor necrosis factor agents in both short- and long-term studies. Additional clinical trial and postmarketing evidence is necessary to understand the long-term safety, efficacy, economics, and rote of abatacept in clinical practice.

Waksman, Javier C; Brody, Aaron; Phillips, Scott D

doi: 10.1345/aph.1H341pmid: 17609238

Objective:To assess possible cardiovascular risks associated with use of nonselective nonsteroidal antiinflammatory drugs (NSAIDs).Data Sources:Medline and Embase were searched from January 1985 through April 2007 and relevant studies were retrieved.Study Selection and Data Extraction:Peer-reviewed, prospective, double-blind, case–control, and cohort-design studies published in the English language literature were considered eligible for review. Previous meta-analyses and systematic reviews were also analyzed. In total, 17 case–control studies; 9 cohort studies; 1 prospective, double-blind study; 3 meta-analyses; and 1 systematic review of observational studies were identified.Data Synthesis:Three studies were prospective and the remainder consisted of observational, retrospective studies, with most reporting acute fatal or nonfatal myocardial infarction as the cardiovascular endpoint. Among the nonselective NSAIDs, diclofenac appears to pose the highest risk for cardiovascular toxicity; other agents trend toward a neutral effect with respect to cardiovascular risk. Although the data are suggestive, it remains unclear whether naproxen provides protective cardiovascular effects among patients on chronic therapy.Conclusions:Currently available data are insufficient for defining evidence-based clinical guidelines for the use of NSAIDs, and the need for additional research, specifically randomized controlled trials, is evident. Diclofenac demonstrates a significant risk while naproxen appears to pose the lowest, albeit nonsignificant, risk for cardiovascular morbidity. Although the current clinical evidence may not warrant recommending naproxen as the preferred NSAID treatment, it may be prudent to avoid diclofenac for patients with cardiovascular risk factors requiring NSAID treatment.

Feig, Denice S; Briggs, Gerald G; Koren, Gideon

doi: 10.1345/aph.1K045pmid: 17535842

Objective:To provide information on the use of oral antidiabetic agents in pregnancy and breast-feeding.Data Sources:Primary articles were identified by a MEDLINE search (1966–March 2007) using the MeSH headings: pregnancy in diabetics, pregnancy, polycystic ovary syndrome, hypoglycemic agents, glipizide, glyburide, metformin, rosiglitazone, pioglitazone, clinical trial, controlled clinical trial, multicenter study, randomized controlled trial, case–control studies, and cohort studies.Study Selection and Data Extraction:All studies using oral antidiabetic agents in pregnancy were evaluated and relevant data were included in the discussion.Data Synthesis:Studies of glyburide and glipizide have found little or no transfer of these drugs across the placenta, whereas metformin and rosiglitazone cross readily. Animal studies have found no evidence to suggest that glyburide, glipizide, metformin, or rosiglitazone are teratogenic. In gestational diabetes, glyburide was safe and efficacious; however, 16–19% of women failed to achieve optimal glucose control. No developmental toxicity in infants was observed when metformin was used before and throughout pregnancy in women with polycystic ovarian syndrome (PCOS). Some of the studies involving patients with type 2 diabetes had methodological problems. A randomized controlled trial using metformin for gestational diabetes in the third trimester is underway. The human information is inadequate to evaluate the risk of glipizide or the thiazolidinediones in pregnancy. In breast milk, 3 studies measured nonsignificant amounts of metformin and one study was unable to detect either glyburide or glipizide.Conclusions:Neither glyburide nor metformin has caused developmental toxicity in humans. Glyburide has been used for the treatment of gestational diabetes, and metformin has been used in women with PCOS who eventually became pregnant. Additional trials are needed to better define the benefits and risks of oral antidiabetic agents in pregnancy. Metformin, glyburide, and glipizide appear to be compatible with breast-feeding.