Safety and tolerability of cariprazine for the adjunctive treatment of major depressive disorder: a pooled analysis of phase 2b/phase 3 clinical trials.

To characterize the safety and tolerability of adjunctive cariprazine in patients with major depressive disorder (MDD) and inadequate response to monotherapy antidepressant treatment (ADT). Post hoc analyses evaluated pooled data from 2 fixed-dose phase 3 cariprazine studies (1.5 and 3 mg/d [approved doses for MDD]). In a separate safety analysis, cariprazine 0.1-4.5 mg/d was evaluated using data from the 2 fixed-dose trials plus 3 flexible-dose studies grouped by modal-daily dose. In the pooled phase 3 studies (placebo = 503, 1.5 mg/d = 502, 3 mg/d = 503), overall cariprazine-treated patients had high rates of study completion (90%). Patients had mostly mild/moderate treatment-emergent adverse events that caused premature discontinuation of 4.3%. Only akathisia, nausea, and insomnia occurred in ≥5% of cariprazine patients (any group) and at twice the rate of placebo; potential dose-dependent responses were observed for akathisia and insomnia. Cariprazine had a neutral metabolic profile, with mean weight increase of <1 kg. Modal-dose results were similar, and both analyses were consistent with the known safety profile of cariprazine across its approved indications. Adjunctive cariprazine therapy was safe and generally well tolerated in patients with MDD who had not obtained an adequate response to ADT monotherapy; no new safety signals were identified.

Cariprazine in Pediatric Patients with Autism Spectrum Disorder: Results of a Pharmacokinetic, Safety and Tolerability Study.

Objective: Cariprazine is a dopamine D3-preferring D3/D2 and serotonin 5-HT1A receptor partial agonist approved to treat adults with schizophrenia and manic/mixed or depressive episodes associated with bipolar I disorder. This study, which is the first to evaluate cariprazine in pediatric patients with autism spectrum disorder (ASD) (including children 5-9 years of age) using an oral solution formulation, evaluated the safety, tolerability, pharmacokinetics (PK), and exploratory efficacy of cariprazine and its two major active metabolites, desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR). Methods: This clinical pharmacology, open-label, multiple-dose study enrolled 25 pediatric patients from 5 to 17 years of age, who met the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria for ASD. All patients began treatment with cariprazine 0.5 mg once daily (QD) and underwent a titration over 7 days to maintenance doses of 1.5 or 3 mg QD for patients 13-17 years of age at Screening, 0.75 or 1.5 mg QD for patients 10-12 years of age at Screening, and 0.5 or 1.5 mg QD for patients 5-9 years of age at Screening. After 6 weeks total of dosing, there was a 6-week follow-up period. Study assessments included adverse events (AEs), safety parameters, noncompartmental PK parameters, and exploratory efficacy assessments, including the Aberrant Behavior Checklist-Irritability Subscale (ABC-I), Clinical Global Impressions (CGI-S), Caregiver Global Impressions (CgGI-S), Children's Yale-Brown Obsessive Compulsiveness Scale Modified for ASD (CYBOCS-ASD), Social Responsiveness Scale (SRS), and Vineland Adaptive Behavior Scale (VABS-III). Results: All AEs were mild or moderate in severity. Most frequent treatment-emergent adverse events (TEAEs) were increased weight, increased alanine aminotransferase, increased appetite, dizziness, agitation, and nasal congestion. Increases in weight were not considered clinically meaningful. Two subjects reported extrapyramidal symptom-related TEAEs that resolved without leading to discontinuation. Dose-normalized exposures of all analytes were modestly higher in pediatric patients from 5 to 9 years of age when compared to older patients. Consistent with previous studies, at steady state, the rank of exposure in plasma was DDCAR > cariprazine > DCAR. There was numerical improvement on all exploratory endpoints (ABC-I, CGI-S, CgGI-S, CYBOCS-ASD, SRS, and VABS-III). Conclusions: PK of cariprazine and its metabolites were characterized in pediatric patients with ASD at doses up to 3 mg QD (13-17 years) and 1.5 mg QD (5-12 years). Caripazine treatment was generally well tolerated and results from this study will inform the selection of appropriate pediatric doses for subsequent studies.

Environmental and Occupational Considerations of Anesthesia: A Narrative Review and Update.

With an estimated worldwide volume of 266 million surgeries in 2015, the call for general inhalation anesthesia is considerable. However, widely used volatile anesthetics such as N2O and the highly fluorinated gases sevoflurane, desflurane, and isoflurane are greenhouse gases, ozone-depleting agents, or both. Because these agents undergo minimal metabolism in the body during clinical use and are primarily (≥95%) eliminated unchanged via exhalation, waste anesthetic gases (WAGs) in operating rooms and postanesthesia care units can pose a challenge for overall elimination and occupational exposure. The chemical properties and global warming impacts of these gases vary, with atmospheric lifetimes of 1-5 years for sevoflurane, 3-6 years for isoflurane, 9-21 years for desflurane, and 114 years for N2O. Additionally, the use of N2O as a carrier gas for the inhalation anesthetics and as a supplement to intravenous (IV) anesthetics further contributes to these impacts. At the same time, unscavenged WAGs can result in chronic occupational exposure of health care workers to potential associated adverse health effects. Few adverse effects associated with WAGs have been documented, however, when workplace exposure limits are implemented. Specific measures that can help reduce occupational exposure and the environmental impact of inhaled anesthetics include efficient ventilation and scavenging systems, regular monitoring of airborne concentrations of waste gases to remain below recommended limits, ensuring that anesthesia equipment is well maintained, avoiding desflurane and N2O if possible, and minimizing fresh gas flow rates (eg, use of low-flow anesthesia). One alternative to volatile anesthetics may be total intravenous anesthesia (TIVA). While TIVA is not associated with the risks of occupational exposure or atmospheric pollution that are inherent to volatile anesthetic gases, clinical considerations should be weighed in the choice of agent. Appropriate procedures for the disposal of IV anesthetics must be followed to minimize any potential for negative environmental effects. Overall, although their contributions are relatively low compared with those of other human-produced substances, inhaled anesthetics are intrinsically potent greenhouse gases and pose a risk to operating-room personnel if not properly managed and scavenged. Factors to reduce waste and minimize the future impact of these substances should be considered.

Validation of Waste Anaesthetic Gas Exposure Limits When Using a Closed Vaporizer Filling System: A Laboratory-Based Study.

INTRODUCTION: It is desirable to minimise exposure of personnel to halogenated inhaled anaesthetics in the operating room to avoid deleterious short-term and long-term health effects. The objective of this study was to determine whether, while filling anaesthetic vaporizers with sevoflurane using AbbVie's closed vaporizer filling system (Quik-Fil™), concentrations of sevoflurane in ambient air remained at or below recommended levels when measured at different operator heights. METHODS: Nine filling runs were conducted, with measurement heights of 95, 130, 140, 150, 160, and 185 cm. Within each 15-min run, five vaporizers were sequentially filled from bottles of sevoflurane with the closed valving system. Ambient-air sevoflurane concentration in the breathing zone was continuously measured once per second by using a MIRAN SapphIRe 205BXL portable ambient air analyser. RESULTS: The use of the closed filling system maintained a level of waste anaesthetic gas exposure that was well below (mean, 0.10 ppm; maximum, 0.16 ppm) the recommended short-term value of 20 ppm average for 15 min provided by the Swedish Work Environment Authority and also fell below the US limit of a time-weighted average of 2 ppm provided by the National Institute for Occupational Safety and Health. Exposure to sevoflurane appeared to be independent of the height at which the measurement was made. CONCLUSIONS: The presence of sevoflurane in the work environment while using the closed filling system maintains a level of waste anaesthetic gas exposure well below the recommended levels at all tested operator heights.

Investigation of possible aqueous phase formation during vaporization of sevoflurane.

BACKGROUND AND AIMS: Ultane® (sevoflurane; AbbVie Inc., North Chicago, IL, USA) has a dissolved water content of approximately 0.035% weight/weight (w/w). A previous report described formation of an aqueous layer in 4 of 13 sevoflurane vaporizers used in operating rooms. We investigated the conditions under which an aqueous layer could develop during vaporization of sevoflurane-water mixtures. MATERIAL AND METHODS: A temperature-controlled glass reactor was used to simulate a vaporizer. In four experiments, the vaporization of different sevoflurane-water mixtures was monitored over approximately 3-4 days. Samples were removed at regular intervals for analysis of water content. For confirmation, one experiment was replicated in a Tec 7 vaporizer. RESULTS: Saturation of sevoflurane with water occurred at 0.11%-0.13% w/w at an ambient temperature; at greater water concentrations a separate aqueous phase was initially present. The sevoflurane-water azeotrope contained approximately 1.2% w/w water at 25°C. When the initial water content was <1.2% w/w (0.11%-1.03% w/w), vaporization resulted in a single phase of drier sevoflurane (final water concentration 0.02%-0.08% w/w). When the starting water concentration exceeded the azeotropic concentration (5.0% w/w), vaporization increased the water content, reaching 13% w/w at 71 h. Results under the low initial water condition were similar in the Tec 7 vaporizer. CONCLUSIONS: An increase in water concentration following vaporization of sevoflurane can only occur when the starting water content is higher than the azeotropic concentration and therefore cannot originate from the dissolved water present in the marketed product because the water concentration in Ultane® is 34 times lower than the azeotropic concentration.

A clinical review of inhalation anesthesia with sevoflurane: from early research to emerging topics.

A large number of studies during the past two decades have demonstrated the efficacy and safety of sevoflurane across patient populations. Clinical researchers have also investigated the effects of sevoflurane, its hemodynamic characteristics, its potential protective effects on several organ systems, and the incidence of delirium and cognitive deficiency. This review examines the clinical profiles of sevoflurane and other anesthetic agents, and focuses upon emerging topics such as organ protection, postoperative cognitive deficiency and delirium, and novel ways to improve postanesthesia outcomes.