Iatrogenic clozapine intoxication after hospital admission: A case-based rationale for an inpatient pharmacy clozapine monitoring service.

BACKGROUND: Clozapine must be retitrated after 2 consecutive days or more of missed doses owing to the risk of severe hypotension, bradycardia, and cardiac arrest. However, other important adverse events such as somnolence, sialorrhea, or respiratory depression can occur without severe cardiovascular sequalae. These other unintended consequences are not well characterized in the literature. Three cases are reported, highlighting the concerns for continuing clozapine without retitration after periods of not taking the medication. Implications are discussed as well as how pharmacists can collaborate with other disciplines to mitigate safety risks associated with clozapine for hospitalized patients. CASE SUMMARIES: The first case highlights the importance of medication reconciliation and verifying adherence before clozapine continuation in the hospital. Waiting for collateral information and missing one dose are safer than unknowingly resuming clozapine. The second case suggests that it may be safer to consider patients with unexplained worsening psychiatric symptoms as nonadherent and even partially reduced clozapine doses after nonadherence may be unsafe. The final case demonstrates the importance assessing comedications (e.g., warfarin, phenytoin) that have available therapeutic drug monitoring to suggest nonadherence. Each case resulted in significant adverse events requiring transfer to a higher level of care or prolonged hospitalization. PRACTICE IMPLICATIONS: Continuation of psychiatric medications when a patient is admitted to the hospital is important to prevent worsening of symptoms. However, assessment of clozapine adherence and confidence in that assessment is crucial to prevent clozapine intoxication, severe hypotension, and even death. Pharmacists are uniquely positioned to assess clozapine adherence and ensure patient safety. A hospital-based service was created at a 2000-bed academic medical center to improve transitions of care when patients are admitted with clozapine. The process was created in collaboration with the psychiatric consultation service. Through this process, pharmacists also complete appropriate hematologic monitoring and ongoing clinical monitoring for adverse events.

Clozapine-induced cardiomyopathy and myocarditis monitoring: A systematic review.

The use of clozapine requires monitoring the absolute neutrophil count because of the risk of agranulocytosis, but other potentially fatal adverse events associated with clozapine (specifically, myocarditis and cardiomyopathy) do not have mandatory procedures. We performed a systematic review of English-language articles to synthesize an evidence-based approach for myocarditis and cardiomyopathy monitoring. Articles published from January 1988 through February 2017 were identified through a search of Ovid MEDLINE, Ovid Embase, Ovid Cochrane Database of Systematic Reviews, Web of Science, Scopus, and Google Scholar. Selected articles were required to relate to myocarditis or cardiomyopathy in humans from exposure to clozapine. A total of 144 articles were included. Recommendations varied widely. Some authors recommended baseline laboratory monitoring, with or without follow-up testing, for C-reactive protein, creatine kinase MB, and troponin. Electrocardiography was commonly recommended, and echocardiography was less commonly recommended. The expense of monitoring was a consideration. A unanimous recommendation was to stop the use of clozapine and seek a cardiovascular consultation if myocarditis or cardiomyopathy is suspected. Although there is general agreement on which tests to perform for confirming myocarditis and cardiomyopathy, preemptive screening for these clozapine-induced conditions is controversial, and cost and barriers for the use of clozapine are concerns. For asymptomatic patients receiving clozapine, testing could include baseline electrocardiography, echocardiography as part of a cardiac consultation if patients have cardiac disease or risk factors, and monitoring of C-reactive protein and troponin as indicated.

IV fosphenytoin in obese patients: Dosing strategies, safety, and efficacy.

BACKGROUND: Previous studies evaluated the disposition of IV phenytoin loading doses and found that obese patients had increased drug distribution into excess body weight, larger volumes of distribution, and longer half-lives when compared to their nonobese counterparts. We assess the safety and efficacy of fosphenytoin loading doses in patients with different body mass indices (BMIs). METHODS: A retrospective chart review was conducted in 410 patients who received fosphenytoin. Patients were divided into 2 groups: BMI <30 (nonobese) and BMI ≥30 (obese). Patient demographics, fosphenytoin dose administered in mg/kg body weight, renal and liver function tests, fosphenytoin drug levels, and pre- and post-fosphenytoin administration vital signs were collected to assess for adverse events. Necessity of additional antiepileptic loading doses was used as a surrogate for clinical efficacy. RESULTS: The median dose of fosphenytoin administered was 19 mg/kg (interquartile range 15-20). The most frequently encountered adverse event was hypotension, which occurred in 39% of the cohort. Using a Bonferroni adjustment for multiple comparisons, there were no differences in adverse events between the 2 groups. The need for additional antiepileptic loading doses was not different between the 2 groups (p = 0.07). CONCLUSIONS: The incidence of adverse events and the need for repeat loading antiepileptic medications was similar between the 2 groups. From our findings, the patients in our study did not receive empiric loading dose adjustments and the current method of loading fosphenytoin achieves similar outcomes, regardless of the patient's BMI.

Reduction in adverse symptoms as blood pressure becomes controlled.

STUDY OBJECTIVES: To evaluate trends in adverse symptoms as blood pressure becomes controlled, and to determine if these symptoms are influenced by social support and self-efficacy. DESIGN: Secondary analysis from a randomized controlled study of physician-pharmacist collaboration to improve blood pressure control. SETTING: Five university-affiliated primary care clinics. PATIENTS: A total of 179 patients (aged 21-85 yrs) with uncontrolled primary hypertension who were taking no antihypertensive drugs or up to three antihypertensive drugs at baseline were randomized to the intervention group, in which pharmacists were involved in their care, or to the control group, who received usual care from their physicians. Of these patients, 160 completed the study: 92 were in the intervention group, and 68 were in the control group. INTERVENTION: In both groups, patient-reported symptoms suggestive of adverse drug reactions (ADRs) were recorded at each study visit with use of a structured ADR questionnaire. Social support and self-efficacy questionnaires were also administered at each study visit. MEASUREMENTS AND MAIN RESULTS: Patients' ADR scores decreased significantly from baseline to the end of the study in both the control (from a mean of 26.5 to 18.4) and intervention (from 29.9 to 22.7) groups (p<0.0001 for both comparisons), although no significant difference was noted between groups. The mean +/- SD number of antihypertensive drugs/patient increased in both the intervention (from 1.5 +/- 1.0 to 2.4 +/- 0.9 drugs) and control (from 1.4 +/- 1.0 to 1.9 +/- 1.0 drugs) groups; however, the difference between groups was significant only at the end of the study. Additional analyses were performed on self-efficacy and social support to determine a potential reason for the reduction in ADR scores despite an increase in drug use. Improvements in self-efficacy and social support scores were significantly and independently associated with improvement in ADR score (p<0.05). CONCLUSIONS: In both groups, ADR scores improved despite an increase in antihypertensive drug use. Improvements in social support and, to a lesser extent, self-efficacy were associated with improvements in ADR scores. Patients should not expect an increase in distressful symptoms as their blood pressure becomes controlled with antihypertensive drugs, especially when adequate social support is available.