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Background: Generic formulations are not necessarily identical to the original in terms of efficacy and adverse events. Generic docetaxel has been available in Canada since 2011., Objective: To compare the occurrence of grade III to IV adverse events between original docetaxel and a generic formulation in breast cancer patients., Methods: A consecutive series of 400 patients were assessed retrospectively: 200 who received the original docetaxel and 200 who received a generic formulation. Patients who received both formulations or received their chemotherapy outside our center were excluded. The primary outcome was the occurrence of grade III to IV adverse events related to docetaxel (febrile neutropenia, hand and foot syndrome, intestinal perforation, thrombotic event, and death)., Results: Three hundred-sixty-four patients were available for analysis (182/group). The use of a granulocyte colony-stimulating factor (G-CSF) was more frequent in the generic group (44.5% vs 28.8%), as well as treatment discontinuation (26.4% vs 14.8%). The occurrence of grade III to IV febrile neutropenia, hand and foot syndrome, intestinal perforation, thrombotic event, and docetaxel-related deaths were similar between the 2 formulations. However, grade IV febrile neutropenia was more frequent with the generic formulation (78.8% vs 56.3%). Limitations were the retrospective nature of the study and the variety of chemotherapy regimens., Conclusion: Adverse events occurrence was similar between the 2 formulations. However, febrile neutropenia was more serious with generic docetaxel, despite increased G-CSF use. Results suggest that the studied generic formulation may be safe, but more caution during treatments might be warranted, especially concerning febrile neutropenia events.

Objective: To systematically review the literature on generic antiepileptic drugs (AEDs), evaluate the efficacy and safety of generic AED substitution, and perform pharmacokinetic (PK) analysis using the American Academy of Neurology (AAN) scheme to classify evidence., Data Sources: PubMed and Cumulative Index to Nursing and Allied Health Literature searches from January 1, 1980, to October 15, 2010, were performed using the search terms anticonvulsant, antiepileptic drug, carbamazepine, divalproex, ethosuximide, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pheno-barbital, phenytoin, primidone, topiramate, valproate, valproic acid, and zonisamide; bioavailability, bioequivalence, bioequivalency, bioequivalent, and substitution; and generic., Study Selection and Data Extraction: Retrospective and prospective controlled studies of generic substitution of AEDs were included in the review. Non-English-language articles and uncontrolled clinical studies were excluded. Published articles were categorized using the AAN criteria for systematic reviews., Data Synthesis: We identified 156 articles. Of these, 20 met our inclusion criteria; 7 were retrospective studies, 6 were prospective studies in patients with epilepsy, and 7 were prospective studies in healthy subjects. All articles were rated Class I to Class III, using AAN criteria. The retrospective studies were categorized as Class III and showed a significant relationship between generic substitution and increased use of health care resources because of seizures or AED toxicity. Prospective studies were categorized as Class I, II, and III. Prospective studies in patients showed no differences between brand and generic drugs in PK parameters of bioequivalence. Three prospective studies in healthy subjects reported significant differences in maximum drug concentrations. Comparison of brand and generic drugs revealed no significant difference in seizure frequency; however, some prospective studies showed significant differences in PK parameters, primarily those not used for bioequivalence determinations., Conclusions: There is inconsistency between retrospective and prospective studies of generic AED substitution. The highest levels of evidence indicate that there should not be a problem with generic substitution, although some patients are more prone to problems with the generic products. Some evidence suggests that switches between multiple generic AED products in certain individuals may be problematic.

Many clinicians have expressed concerns about the bioequivalence of warfarin products, and data suggest that substituting warfarin products may increase the risk of major bleeding and thromboembolic complications. Anecdotal reports and some retrospective studies have reported differences in anticoagulation control after a warfarin product substitution. But the best available evidence-prospective, randomized, blinded clinical trials-has failed to validate these observations. Indeed, interpatient and intrapatient variability in anticoagulation control observed before and after warfarin product substitution is very similar. So, while differences in product standardization, bioavailability, and bioequivalence make a convenient explanation, the problem lies elsewhere. Perhaps poor communication, fractionated systems of care, and errors are the culprits.

Background: Substitution of generic warfarin for imprint warfarin (Coumadin; DuPont/Bristol-Myers Squibb) has been a controversial issue due to bioavailability and bioequivalence concerns., Objective: To assess the risk of thrombotic and hemorrhagic events following substitution of warfarin formulations in patients with atrial fibrillation (AF)., Methods: Historical cohort analysis was performed using a commercial insurance claims database. Adults with a diagnosis of AF between January 2003 and December 2007, with 16 or more months of continuous eligibility, a warfarin prescription within 30 days after index AF diagnosis, and at least 3 warfarin prescription fills during the follow-up period were included. Individuals with AF diagnosis or warfarin prescription during the pre-index period were excluded. Cox proportional hazard regression models controlling for sex and baseline comorbidities (Charlson comorbidity index, CCI) were used to evaluate the risks of thrombotic and hemorrhagic events following warfarin formulation switches., Results: Of 37,756 subjects included in the analysis (mean age 70.96 years, 42.3% females), 12,996 (34.4%) switched warfarin formulations, 20,292 (53.7%) used only 1 generic product, and 4468 (11.8%) used only Coumadin during follow-up. Compared with continued use of Coumadin, switching from that product to the generic formulation was associated with a significantly higher risk of thrombotic events (HR = 1.81; 95% CI 1.42 to 2.31). Similar findings were observed for switching from generic warfarin to Coumadin (HR = 1.76; 95% CI 1.35 to 2.30), and from 1 generic to another generic product (HR = 1.89; 95% CI 1.57 to 2.29). Similarly, switching from Coumadin to generic warfarin (HR = 1.51; 95% CI 1.17 to 1.93), generic warfarin to Coumadin (HR = 1.60; 95% CI 1.23 to 2.1), and from 1 generic to another generic product (HR = 1.74; 95% CI 1.45 to 2.11) were associated with significantly higher risk of hemorrhage than remaining on Coumadin., Conclusions: Switching warfarin formulations exposed patients with AF to a higher risk of bleeding events compared to remaining on a single product. Maintaining patients on a product with consistent bioavailability may optimize the risk-benefit balance of anticoagulation therapy.

Drug importation from Canada has been hotly debated for nearly a decade. Many believe that drug importation will bring needed competition and lower US drug prices. Opposition argues that the costs of ensuring product quality and safety, as well as added healthcare costs, will offset savings attained from imported pharmaceuticals. The US needs to become innovative and seek solutions that will provide effective, safe, and economical pharmaceuticals without placing a burden on other countries and without damaging the pharmaceutical research.

Background: Adverse reactions related to the upper gastrointestinal tract (UGIT) that are associated with generic alendronate formulations may differ from those associated with the brand drug., Objective: To test the hypothesis that adverse UGIT effects of alendronate formulations may differ between generic and brand products., Methods: We conducted a database health resource utilization analysis of UGIT outcomes in patients who started treatment with generic or brand alendronate formulations during 2001-2005. We included 6962 patients who were treated continuously for 3 months with 1 of 4 alendronate formulations: brand 10 mg/day (Merck, Sharpe & Dohme, n = 1418), generic A 10 mg/day (Teva, Israel, n = 650), generic B 10 mg/day (Unipharm, Israel, n = 628), and brand 70 mg/wk (n = 4266). In these patients, who had neither filled a prescription for alendronate nor had any gastrointestinal problems in the year preceding the study, we compared incidence rates of new use of gastric medications (H2-blockers, proton-pump inhibitors, or antacids), gastroenterology visits, endoscopies, and hospital admissions., Results: Incident rate ratios (IRR) for treatment discontinuation were higher with both daily generic products (IRR 1.3; 95% CI 1.04 to 1.63). Adherence (medication possession ratio [MPR] >80%) was better with brand 10 mg/day (IRR 1.19; 95% CI 1.11 to 1.27). All comparisons were adjusted for use of concurrent corticosteroids, nonsteroidal antiinflammatory drugs, and potassium supplements. Hospitalization rates (2.7-3.2%) were similar in all groups. New use of gastric medications (3.4-4.9%) was lower with brand 10 mg/day (IRR 0.71; 95% CI 0.53 to 0.95). Rates of UGIT endoscopy (n = 49) in patients receiving 10 mg were 0.6% (brand), 1.1% (generic A), and 1.6% (generic B), with generic B higher (IRR 2.88; 95% CI 1.14 to 7.29) in the entire cohort, but not among new users (n = 273) of gastric drugs (IRR 2.46; 95% CI 0.55 to 11.05). Endoscopic findings were normal in 22 patients, hiatal hernia with no mucosal lesion was present in 10 patients, and there was mild-to-moderate esophagitis or gastritis in 17 patients; there were no significant differences among the formulations., Conclusions: We found insufficient evidence to indicate major differences in UGIT adverse effects related to use of daily generic, as compared with brand, alendronates.

Background: Substitution of generic warfarin for Coumadin presents safety concerns due to warfarin's narrow therapeutic index and because a prior generic formulation was removed from the US market after it was associated with adverse events., Objective: To determine whether a health maintenance organization (HMO) can add generic warfarin to its formulary without adversely affecting warfarin management or increasing adverse events., Design: In a prospective, observational study, an HMO that formerly dispensed only Coumadin added a generic warfarin preparation (Barr Laboratories, Pomona, NY) to its formulary., Setting: An anticoagulation service (ACS) affiliated with an HMO that was based in St. Louis, MO., Participants: The cohort consisted of 182 enrollees in the ACS as of May 1, 1999. At the start of the study, these participants were taking Coumadin; by October 31, 2000, all had switched to Barr warfarin., Measurements and Main Results: We collected data 8 months prior to and 10 months after the introduction of generic warfarin for the following endpoints: international normalized ratio (INR) control, frequency of INR monitoring, number of dose changes, and rate of thrombotic and hemorrhagic events. Statistical process control charts were used to differentiate between random variation in the endpoints and changes due to different warfarin formulations, and we used the Wilcoxon signed-rank test to look for a change in any endpoint after patients changed to generic warfarin. No significant differences were found in any endpoint., Conclusions: Substitution of Barr warfarin for Coumadin did not significantly affect INR control, warfarin management, or adverse events. Our findings suggest that HMOs can safely substitute at least 1 generic formulation of warfarin without extra monitoring.

Objective: To evaluate safety and dosage requirements when patients taking brand-name clozapine (Clozaril, Novartis Pharmaceuticals) are converted to generic clozapine (Zenith Goldline)., Methods: In November 1999, patients at Colorado Mental Health Institute at Pueblo taking Clozaril were changed to generic clozapine. Seventeen patients had been prescribed Clozaril for three years and were included in the study. Drug dosage, white blood cell (WBC) count values, and adverse drug reaction reports were compared. Data regarding patients on the brand-name product were evaluated retrospectively for the months of November, December, January, and February during the years 1996/1997, 1997/1998, and 1998/1999. These data were compared with those from the same patients after switching to generic clozapine for the same months in 1999/2000. A one-year comparison of brand-name (1998/1999) with generic drug (1999/2000) was also performed. Statistical analysis included a standard test comparing WBC values and a Brown-Forsythe test for comparing dosages., Results: There were no differences between the values obtained for the brand-name and generic products. WBC counts for the three-year data resulted in a p value of 0.9992. There was no difference when comparing the samples one year prior to switching and after the switch (p = 0.9991). There was no difference in dosages at three years or one year (p = 0.9999 and p = 0.9993, respectively). No adverse events were noted with the generic product., Conclusions: No differences were found between the brand-name and generic clozapine groups with regard to WBC count, dosage, and adverse events. The conversion to the generic product is projected to save the pharmacy $90,000 annually.

Objective: We report two cases of lost seizure control associated with the generic substitution of carbamazepine, review pertinent literature, and discuss the impact of this substitution on patient care., Data Sources: Case studies, abstracts, and research publications identified in MEDLINE and bibliographic review., Data Extraction: One author reviewed cases supplied by the other authors and abstracted information from published literature sources., Data Synthesis: The first case describes a 15-year-old boy who received valproic acid and carbamazepine for partial seizures. A change in government program policies caused him to receive generic carbamazepine. This resulted in loss of seizure control and a decrease in his serum carbamazepine concentration from 12.4 to 6.7 micrograms/mL. When his carbamazepine concentration returned to previous levels, seizure control was not reestablished. A second case involves a 21-year-old woman who substituted generic carbamazepine because of financial problems. After being seizure-free for at least five years on phenobarbital and carbamazepine, she experienced seizures related to the product change. Her carbamazepine concentration decreased from 11.8 to 8.5 micrograms/mL; she also became pregnant at that time. Seizure control was not reestablished. At least three other studies do not support these observations, but the tightly controlled conditions in these studies may not have simulated actual clinical practice., Conclusions: When generic substitution of carbamazepine is required, serum concentrations should be carefully monitored. The extra care required may negate the financial advantages of the substitution.