Efficacy and Safety of Naldemedine for Opioid-Induced Constipation in Children.

Background: Naldemedine, a peripherally acting opioid µ receptor antagonist, is effective for prevention of opioid-induced constipation (OIC); however, evidence on its use in children is limited. Objective: To evaluate the efficacy and safety of naldemedine in pediatric patients with OIC. Design, Setting/Subjects: Retrospective analysis of 32 pediatric patients with OIC treated with naldemedine in a single institution in Japan from June 2017 to March 2021. Measurements: Efficacy was evaluated in 13 evaluable patients with bowel movement (BM) response, defined as those with at least three BMs in the first 7 days after naldemedine initiation and an increase of at least one BM from baseline. Safety was evaluated by examining adverse events (AEs) based on the Common Terminology Criteria for AEs (v5.0). Results: BM response was recorded in 11 of the 13 patients (85%), and the number BMs per day significantly increased from 0.43 before naldemedine to 1.00 after naldemedine (p = 0.025). The most common AE was diarrhea, observed in 16 of the 32 patients (50%), and all instances were grade 1 or 2. In three of the 16 patients, naldemedine was discontinued owing to worsening diarrhea. Conclusions: In pediatric patients, naldemedine resulted in a high rate of BM response and increased the BM frequency, indicating its efficacy. In some patients, grade 2 diarrhea required naldemedine discontinuation, suggesting that it should be used with caution in pediatric patients. Further studies are warranted to determine the optimal naldemedine dose in pediatric patients.

Stability Study of Baclofen in an Oral Powder Form Compounded for Pediatric Patients in Japan.

Baclofen is used as a skeletal muscle relaxant for multiple sclerosis patients and pediatric patients with cerebral palsy and is prescribed to pediatric patients at 0.3 to 1.0 mg/kg/dose. Baclofen tablets, an oral drug, are usually administered as a powder in pediatric wards after a formulation change by the pharmacist. However, there is no information about stability and assurance of quality for compounded products. The purpose of this study was to design a 10 mg/g oral powder of baclofen and to investigate the stability and changes in the physical properties of this compounded product. A 10 mg/g baclofen powder was prepared by adding extra-fine crystal lactose hydrate to crushed and filtrated baclofen tablets and was stored in a polycarbonate amber bottle with desiccant or in a coated paper laminated with cellophane and polyethylene. The stability of baclofen at 25 ± 2 °C/60 ± 5%RH was tested for 120 days in 'bottle (closed)', 'bottle (in use)', and 'laminated' storage conditions. Baclofen concentrations ranged from 90.0% to 110.0% of the initial concentration under all storage conditions. No crystallographic or dissolution changes were observed after storage. This information can help with the management of baclofen compounded powder in pharmacies.

Stability of clonidine hydrochloride in an oral powder form compounded for pediatric patients in Japan.

BACKGROUND: Clonidine hydrochloride is used to treat sedative agent withdrawals, malignant hypertension, and anesthesia complications. Clonidine is also prescribed off-label to pediatric patients at a dose of 1 µg/kg. The commercially available enteral form of clonidine, Catapres® tablets, is often compounded into a powder form by pharmacists to achieve dosage adjustments for administration to pediatric patients. However, the stability and quality of compounded clonidine powder have not been verified. The objectives of this study were to formulate a 0.2 mg/g oral clonidine hydrochloride powder and assess the stability and physical properties of this compounded product in storage. METHODS: A 0.2 mg/g clonidine powder was prepared by adding lactose monohydrate to crushed and filtrated clonidine tablets. The powder was stored in polycarbonate amber bottles or coated paper packages laminated with cellophane and polyethylene. The stability of clonidine at 25 °C ± 2 °C and 60% ± 5% relative humidity was examined over a 120-d period in "bottle (closed)," "bottle (in use)," and "laminated paper" storage conditions. Drug dissolution and powder X-ray diffraction analysis were conducted to assess physicochemical stabilities. Validated liquid chromatography-diode array detection was used to detect and quantify clonidine and its degradation product, 2,6-dichloroaniline (2,6-DCA). RESULTS: Clonidine content was maintained between 90.0 and 110.0% of the initial contents in all packaging and storage conditions. After 120 d of storage, 2,6-DCA was not detected, and no crystallographic and dissolution changes were observed. CONCLUSIONS: Compounded clonidine powder stability was maintained for 120 d at 25 °C ± 2 °C and 60% ± 5% relative humidity. This information may contribute to the management of clonidine compounded powder in community and hospital pharmacies in Japan.

Stability of Hydrocortisone in Oral Powder Form Compounded for Pediatric Patients in Japan.

Hydrocortisone has been utilized in the management of adrenal insufficiency. For pediatric patients, the commercially available enteral form of hydrocortisone tablets (Cortoril®) is administered in powder form after being compounded by a pharmacist. However, the stability and quality of compounded hydrocortisone powder have not been verified. In this study, we formulated a 20 mg/g oral hydrocortisone powder by adding lactose monohydrate to crushed and filtered hydrocortisone tablets and assessed the stability and physical properties of this compounded product in polycarbonate amber bottles or coated paper packages laminated with cellophane and polyethylene. Stability was examined over 120 days in three storage conditions: closed bottle, in-use bottle, and laminated paper. Drug dissolution and powder X-ray diffraction analysis were conducted to assess its physicochemical stabilities. Validated liquid chromatography-diode array detection was used to detect and quantify hydrocortisone and its degradation products. Although impurity B (cortisone) and G (hydrocortisone-21-aldehyde) were found after 120 days of storage, no crystallographic and dissolution changes were noted. Hydrocortisone content was maintained between 90% and 110% of initial contents for 120 days at 25 ± 2 °C and 60 ± 5% relative humidity in all packaging conditions.

Retrospective survey of compounded medications for children in Japan.

Compounding of medications, such as crushing tablets and dispersing the contents of capsules, is a common practice in pharmacies and hospitals worldwide and is often done to provide age-appropriate formulations for oral use in pediatric patients. In the present study, a retrospective, descriptive, questionnaire-based survey was conducted to clarify the current status of drug compounding for pediatric patients in Japan. An electronic questionnaire was distributed to 740 hospitals in Japan with pediatric beds, and 208 (28.1%) of these hospitals responded. The total instances of compounding numbered 14,864 (9.6% of the total pediatric oral prescriptions) and comprised 266 active pharmaceutical ingredients (APIs), one-third of which (98 APIs) were compounded even though flexible dosage forms were available. The three most frequently compounded drugs were dantrolene sodium capsules (1152 prescriptions), ramelteon tablets (726 prescriptions), and hydrocortisone tablets (652 prescriptions), all of which were prescribed and administered in powder form. Although compounding of medications frequently varied by the patients' age, steroids such as prednisolone, dexamethasone, and hydrocortisone were commonly compounded in all age groups. To ensure the quality and safety of these compounded medications, developing a standard protocol for compounding methods is urgently needed in Japan.