Impact of histamine-2 antagonist shortage on the incidence of hypersensitivity reactions to paclitaxel: a reconsideration of premedication protocols in France (PACLIREACT Study).

PURPOSE: An international shortage of ranitidine led to adjustments in premedication regimens for paclitaxel-based chemotherapy in early October 2019. In this study, we implemented and evaluated an anti-allergic protocol without histamine-2 antagonists (H2As) and aimed to assess the risk of hypersensitivity reactions (HSRs) to the different premedication regimens used. METHODS: We conducted a single-center observational retrospective study of paclitaxel administrations (7173 administrations in 831 patients). Between January 2019 and December 2020, all allergies reported were recorded. A mixed logistic regression model was implemented to predict the risk of allergy at each injection and to account for repeated administration per patient. RESULTS: A total of 27 HSRs occurred in 24 patients. No protective effect was observed for H2A when comparing paclitaxel injections with H2A premedication versus without H2A (OR = 1.12, p = 0.84). There was also no significant difference in risk of HSR for famotidine versus ranitidine (OR = 0.79, p = 0.78). However, the risk of HSRs was significantly lower for paclitaxel injections with corticosteroids than for those without (OR = 0.08, p = 0.03). In addition, the risk of HSR was significantly higher for the first, second, or third paclitaxel injections than for the subsequent injections (OR = 10.1, p < 0.001). CONCLUSION: We did not find substantial evidence of an increased risk of HSR due to the absence of H2A in the premedication protocols for paclitaxel. Thus, in contrary to the existing literature on paclitaxel, our findings support the use of a premedication protocol without H2A.

Successful administration of mitotane (O, p'-DDD) in pediatric oncology.

INTRODUCTION: Mitotane (o, p'-DDD) is a molecule that was developed many years ago for adrenal cortical carcinoma, but no suitable pediatric dosage form is available for administration to young children. Mitotane requires therapeutic drug monitoring because of its long half-life and difficulty in stabilizing plasma concentrations. Furthermore, Mitotane is a highly lipophilic drug that requires concurrent lipid administration. CASE REPORT: We present the case of a 3-year-old girl who was diagnosed with metastatic adrenal cortical carcinoma. Due to the difficulty in administering the tablets and the non-stabilized mitotane dosages, a nasogastric tube was inserted. An administration protocol based on dispersing the tablets in whole milk was established by the pharmacy team. This led to the stabilization of the disease for at least 1.5 years. MANAGEMENT AND OUTCOME: Mitotanemia is difficult to stabilize even when treatment is administered orally. To maintain biological efficacy, we propose an easily reproducible protocol. The efficacy was stabilized at a dosage of 1500 mg per day. Mitotanemia fluctuated between 14 mg/mL, and 20 mg/mL. The implementation of this protocol prevented treatment discontinuation. DISCUSSION: The administration of narrow therapeutic range drugs via a nasogastric tube is a challenge for healthcare teams, particularly in pediatric patients. Based on the findings of this clinical case, clinicians should consider future use of this protocol. The use of whole milk as a vehicle for mitotane is a simple, effective, and reproducible method to administer the drug to pediatric patients and can be used for other similar cases.

Long-term stability of ready-to-use 1-mg/mL midazolam solution.

PURPOSE: Midazolam is a benzodiazepine derivative commonly used in intensive care units to control sedation. Its use requires dilution of a 5-mg/mL commercial solution to a target concentration of 1 mg/mL. A study was conducted to evaluate the stability of diluted ready-to-use 1-mg/mL midazolam solutions over 365 days when stored in cyclic olefin copolymer vials or polypropylene syringes. METHODS: A specific stability-indicating high-performance liquid chromatography coupled with UV detection method was developed for midazolam hydrochloride and validated for selectivity, linearity, sensitivity, precision, and accuracy. Three storage conditions were tested: -20°C ± 5°C, 5°C ± 3°C, and 25°C ± 2°C at 60% ± 5% relative humidity. Half of the vials were stored upside down to test for the absence of interaction between midazolam and the stopper. Particle contamination, sterility, and pH were assessed. RESULTS: The limit of stability was set at 90% of the initial concentration. After 1 year's storage at -20°C and 5°C, concentrations remained superior to 90% under all storage conditions. At 25°C, stability was maintained up to day 90 in syringes (mean [SD], 92.71% [1.43%]) and to day 180 in upright and upside-down vials (92.12% [0.15%] and 91.57% [0.15%], respectively). No degradation products were apparent, no variations in pH values were detected, and containers retained their sterility and conformity with regard to any specific contamination during the study. CONCLUSION: The evaluated 1-mg/mL midazolam solution was stable over a 1-year period when stored at a refrigerated (5°C) or frozen (-20°C) temperature in both vials and syringes; with storage at 25°C, the stability duration was lower. The preparation of ready-to-use midazolam solutions by a hospital pharmacy is compatible with clinical practice and could help to decrease risks inherent in dilution in care units.

Advantages of everolimus therapeutic drug monitoring in oncology when drug-drug interaction is suspected: A case report.

INTRODUCTION: Drug interactions involving everolimus are fairly well known because of its common use, primarily as an immunosuppressant. Several recommendations regarding therapeutic drug monitoring are also available for the use of everolimus-based immunosuppression regimens. However, everolimus use in oncology differs substantially, particularly because of the high doses involved. Therapeutic drug monitoring, although sometimes necessary, is not recommended as a routine in oncology. Thus, it was deemed inapplicable due to the lack of clear recommendations. CASE REPORT: Here, we present a case where a patient was prescribed everolimus for renal cell carcinoma. The patient benefitted from a pharmaceutical consultation prior to treatment initiation, and a drug interaction with verapamil was suspected.Management and outcome: Therapeutic drug monitoring of everolimus was proposed. Based on the everolimus values reported in the literature, trough plasma concentration in the patient was greatly increased. The patient was then diagnosed with grade 4 oral mucositis, thereby requiring temporary suspension of everolimus treatment. Management of adverse effects was performed through multiple medicated mouthwashes. DISCUSSION: Therapeutic drug monitoring for everolimus is important for potential drug interactions or the occurrence of severe adverse events. In such cases, dose adjustments should be managed according to everolimus plasma concentrations. Clear oncological recommendations regarding plasma everolimus thresholds are required for a successful follow-up of the patient's condition and to ensure adequate response to treatment.

How to solve the problem of co-elution between two compounds in liquid chromatography through the first UV derivative spectrum. A trial on alternative plasticizers to di(2-ethylhexyl) phthalate.

To meet new regulations, alternative plasticizers to di(2-ethylhexyl) phthalate (DEHP) are now commonly used in the manufacturing of medical devices. These are: acetyl tri-n-butyl citrate (ATBC), bis (2-ethylhexyl)adipate (DEHA), dioctyl terephtalate (DEHT), di-isononylphtalate (DINP), diisononylcyclohexane-1.2-dicarboxylate (DINCH) and trioctyltrimellilate (TOTM). An HPLC-UV analysis was previously developed to characterize four of them. However, two compounds were systematically co-eluated: DEHP with DEHA and DEHT with DINP. The first derivative of UV spectra and photodiode array detection allow the quantification of DEHA and DINP. Moreover, for each plasticizer, maximum wavelength absorbance was chosen to be as specific as possible. Quantification ranged from 0.3 to 750µg/mL according to the plasticizer. The assays were validated by analysis of variance. Our method was validated by determining the following parameters: specificity, linearity, limits of detection and quantification. The relative biases were inferior to 5% for ATBC, DEHP, DEHA and DINCH and inferior to 10% for DEHT, DINP and TOTM. Plasticizers were extracted with tetrahydrofuran and methanol. The developed method was then used to determine the composition of plasticizers in several medical devices used in clinical service. The major plasticizers were quantified from 19% to 40% w/w, traces of DEHT were found in six medical devices and DEHP in five.

Identification and quantification by 1H nuclear magnetic resonance spectroscopy of seven plasticizers in PVC medical devices.

Medical devices are generally made of polyvinyl chloride plasticized by six authorized plasticizers as alternatives to di-(2-ethylhexyl)-phthalate (DEHP) classified as reprotoxic class 1b. These are acetyl tri-n-butyl citrate (ATBC), di-(2-ethylhexy) adipate (DEHA), di-(2-ethylhexyl) terephthalate (DEHT), di-isononyl cyclohexane-1,2-dicarboxylate (DINCH), di-isononyl phthalate (DINP), and tri-octyl trimellitate (TOTM). The main objective of this study was to propose a new method using 1H NMR spectroscopy to determine and quantify these seven plasticizers in PVC sheets, standard infusion tubings, and commercially available medical devices. Two techniques were compared: dissolution in deuterated tetrahydrofuran and extraction by deuterated chloroform. Plasticizer 1H NMR spectra were very similar in both deuterated solvents; dissolution and extraction provided similar results. The sensitivity of this method enabled us to detect and quantify the presence of minor plasticizers in PVC. In nine commercially available samples, the major plasticizer was identified and quantified by 1H NMR. In six samples, one, two, or three minor plasticizers were identified and also quantified. DEHP was detected in only one tubing. NMR is therefore very convenient for studying plasticizers contained in medical devices. Only small quantities of solvents and sample are required. It is not necessary to dilute samples to enter a quantification range, and it is sufficiently sensitive to detect contaminants.

Stability of 10 mg/mL cefuroxime solution for intracameral injection in commonly used polypropylene syringes and new ready-to-use cyclic olefin copolymer sterile vials using the LC-UV stability-indicating method.

CONTEXT: Injecting intracameral cefuroxime has been found beneficial in reducing the risk of postoperative endophthalmitis but its use has been limited through a lack of approved marketing and of ready-to-use single-units as well as the problem of aseptic compounding. OBJECTIVE: Our aim was to assess a new automated primary packaging system which should ensure a higher level of sterility, thanks to its closed, sterile, ready-to-use polymer vial called "Crystal® vial". The chemical stability of a 10 mg/mL cefuroxime solution was compared in 1 mL Crystal® vials and 1 mL Luer-lock polypropylene syringes (actual reference) to eliminate any potential and specific interactions with its cyclic olefin copolymer (COC) body and elastomer stopper. METHODS: Cefuroxime solution was introduced into vials and syringes and stored at -20 °C, +5 °C and +25°C/60% Relative Humidity. Cefuroxime concentration and the relative amount of the main degradation product (descarbamoyl-cefuroxime) were both determined by an HPLC/UV method indicating stability. Solutions were considered steady if the concentration remained at over 90% of the initial value. In the adapted storage conditions, the evolution of osmolality, pH and sterility was assessed. RESULTS: Stability profiles were identical between vials and syringes in all storage and temperature conditions. The solution was stable (cefuroxime concentration, pH and osmolality) and still sterile for 365 days at -20°C. The concentration fell below 90% after 21 days at +5 °C and after 16 h at +25°C/60%s relative humidity. CONCLUSIONS: The COC and thermoplastic elastomer of the vials had no impact on the degradation process confirming its possible use for a ready-to-use cefuroxime solution single-unit dose.

In vitro comparison of two changeover methods for vasoactive drug infusion pumps: quick-change versus automated relay.

This study aimed to compare in vitro two syringe changeover techniques to determine which was better at minimising variations in norepinephrine (NE) delivery: the manual quick-change or automated technique. NE concentration was measured continuously using a UV spectrophotometer, and infusion flow rate was monitored by an infusion pump tester. Syringe changeovers were made with either of the two techniques studied. Relays induced disturbances in drug delivery. The temporary increase in NE mass flow rate was significantly higher with manual relays than with automated ones. The automated relay offered a better control of the amounts of NE administered than the quick-change technique.

Quantification of five plasticizers used in PVC tubing through high performance liquid chromatographic-UV detection.

Searching for alternatives to di-(2-ethylhexyl)-phthalate, a plasticizer that has been widely used in the manufacturing of PVC medical devices, has become a major challenge since a European regulation underlined some clinical risks. The aim of this study is to develop an HPLC-UV method to quantify the currently used alternative plasticizers to DEHP. Five plasticizers, acetyl tributyl citrate, di-(2-ethylhexyl)-phthalate, di-(ethylhexyl)-terephthalate, di-isononyl-1,2-cyclohexane-dicarboxylate, and trioctyl trimellitate, were separated on a C8 stationary phase (2.6 µm, 100 mm × 4.6mm) under gradient elution in 13 min. They were detected at 221 nm leading to a quantification threshold from 0.3 to 750 µg/mL as a function of the plasticizer. Within-day and between-day precisions were inferior to 0.9% and 18%, respectively. The assays were validated according to the accuracy profile method. Plasticizers were extracted from PVC-tubing by dissolving PVC in THF then precipitating it in methanol with a yield of over 90% for each plasticizer. This assay could feasibly be used to quantify plasticizers in PVC medical devices.