Clozapine Rechallenge After Major Adverse Effects: Clinical Guidelines Based on 259 Cases.

BACKGROUND: Clozapine is widely prescribed for treatment-refractory schizophrenia, but its use is limited by many potentially life-threatening adverse effects. The risk of rechallenge after these complications has never been comprehensively assessed in controlled studies. Thus, clinical guidelines must rely on the published case reports. The number of such reports is likely to increase over time, and updated analyses of larger samples are needed, as they may lead to changes in clinical guidelines. STUDY QUESTIONS: How safe is the clozapine rechallenge after life-threatening adverse effects? STUDY DESIGN: The published case reports of clozapine rechallenge were identified in a MEDLINE search. We added 121 cases reported from 2012 through 2017 to the 138 cases reported from 1972 through 2011 analyzed by us in a previous publication. The 95% confidence intervals (CIs) of the successful rechallenge rate were calculated for each adverse effect with at least 5 published case reports. The rechallenge was considered a valid clinical option when the lower end of the CI range was at least 50%. RESULTS: A successful outcome was documented in 128/203 patients rechallenged after neutropenia (63.0%, CI, 56.0%-69.6%), 3/17 after agranulocytosis (17.7%, CI, 4.7%-44.2%), 11/17 after myocarditis (64.7%, CI, 38.6%-84.7%), and 7/7 after neuroleptic malignant syndrome (100%, CI, 56.1%-100%). Among the 15 patients with other clozapine-induced adverse effects, the rechallenge was successful in those with eosinophilia, cardiac complications other than myocarditis (QTc prolongation, pericarditis, cardiomyopathy, and atrial flutter), and gastrointestinal hypomotility. The rechallenge failed in patients who had developed pancreatitis or renal insufficiency. CONCLUSION: Clozapine rechallenge is a reasonable clinical option after return to baseline for patients who had developed neutropenia and neuroleptic malignant syndrome, but not after agranulocytosis or myocarditis. Data are insufficient to formulate rechallenge guidelines for any other clozapine-related adverse effects.

Liquid chromatography-mass spectrometry method for the determination of venlafaxine in human plasma and application to a pharmacokinetic study.

A sensitive and selective liquid chromatographic-mass spectrometric (LC-MS) method for the determination of venlafaxine in human plasma has been developed. Samples were prepared using liquid-liquid extraction and analyzed on a C(18) column interfaced with a triple quadrupole mass spectrometer. Positive electrospray ionization was employed as the ionization source. The mobile phase was methanol-water containing 10 mmol/L ammonium acetate, pH 7.9 adjusted with aqueous ammonia (80:20, v/v) at the flow rate of 1.0 mL/min. The analyte and internal standard clozapine were both detected by use of selected ion monitoring mode. The method was linear in the concentration range of 1.0-200.0 ng/mL. The lower limit of quantification (LLOQ) was 1.0 ng/mL. The intra- and inter-day relative standard deviation across three validation runs over the entire concentration range was less than 10.1%. The accuracy determined at three concentrations (5.0, 50.0 and 150.0 ng/mL for venlafaxine) was within +/-10.0% in terms of relative error (RE). The method was successfully applied for the evaluation of pharmacokinetic profiles of venlafaxine capsule in 20 healthy volunteers. The results show AUC, T(max), C(max) and T(1/2) between the testing formulation and reference formulation have no significant difference (p > 0.05). Relative bioavailability was 103.4 +/- 14.1%.

Case reports of the reemergence of psychotic symptoms after conversion from brand-name clozapine to a generic formulation.

BACKGROUND: The use of generic drugs has resulted in considerable cost savings; however, whether all generics are truly bioequivalent to their brand-name counterparts is questionable. Although the efficacy of clozapine in the management of treatment-resistant schizophrenia has been well established, reports of relapse after conversion to a generic formulation are becoming more common. OBJECTIVE: This article presents 7 case studies of patients in a long-term residential care facility who experienced a relapse of psychotic symptoms when the pharmacy inadvertently switched their therapy from brand-name clozapine to a generic formulation. Neither patients, physicians, nor staff of the facility were aware of this switch. Possible reasons for the apparent increased risk of relapse in some patients switched to the generic formulation of clozapine are explored, with reference to US Food and Drug Administration bioequivalence standards and reports. RESULTS: All 7 patients, whose condition had been well stabilized with brand-name clozapine, experienced a rapid and profound deterioration after the switch to the generic formulation. Five patients required hospitalization. All patients responded well when brand-name clozapine was reinstated. CONCLUSION: The findings suggest that brand-name clozapine and the generic formulation may display important clinical differences, and a comparable therapeutic response may not be achievable despite adequate monitoring. Large, controlled, prospective trials are needed to clarify the potential for treatment failure with the use of generic clozapine.

United States Food and Drug Administration requirements for approval of generic drug products.

As generic products become more available for the treatment of psychiatric disorders, clinicians must stay abreast of the U.S. Food and Drug Administration (FDA) requirements for the approval of generic drug products. The FDA declares that pharmaceutical equivalents only are therapeutically equivalent, and pharmacokinetic data are all that is usually required to determine therapeutic equivalence. The rationale behind the overall concept of bioequivalence is that if 2 pharmaceutical equivalents provide identical plasma concentration-time profiles in humans, there is no evidence to demonstrate that the 2 identical dosage forms will exhibit a difference in safety and efficacy. This article reviews current terminology used in abbreviated new drug applications for generic products, typical bioequivalence study designs, and FDA bioequivalence guidance for clozapine.

Pharmacoeconomics of the new antipsychotics for the treatment of schizophrenia.

Inevitably, the greater availability of more costly antipsychotic medications has resulted in attempts to regulate the use of these agents. Early objections over the cost of treatment with clozapine or risperidone have in part been mollified by preliminary statistics on the cost effectiveness of these agents. However, this issue is complex and requires careful consideration of pharmacoeconomic principles in the development and clinical distribution of novel antipsychotics. Future cost-effectiveness studies need to consider a balance of public and private perspectives. These studies should be conducted in several settings, preferably also within the context of broader, multimodal treatment intervention strategies.