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Fenfluramine hydrochloride; Dravet syndrome; Medication administration support; Purified water; Dilution stability

LC/MS, liquid chromatography–mass spectrometry; UPLC/QTOF, ultra-performance liquid chromatography quadrupole time-of-flight; ESI, electrospray ionization; BPI, base peak intensity

Dravet syndrome, a refractory form of pediatric epilepsy that often manifests in infancy and exhibits strong resistance to drug therapy, has been designated an intractable disease by the government of Japan [1,2]. As it is characterized by frequent seizures of various types and is associated with serious comorbidities, it significantly impacts the quality of life of patients and their families.

Fenfluramine hydrochloride (Fintepla^®, Nippon Shinyaku Co., Ltd. 14 Kichijoin Nishinosho Monoguchi-cho, Minami-ku, Kyoto, A registered trademark of UCB, Inc.) a drug used to treat Dravet syndrome, has been approved and used in the United States, Europe, and Japan [3-7]. Fenfluramine hydrochloride is highly effective in treating the refractory epilepsy associated with Dravet syndrome, and its efficacy in treating Dravet syndrome has been reported [8].

As the amounts of fenfluramine hydrochloride required for newborns and children are extremely small, the rate of drug loss is higher when dosing children than when dosing adults. Typically, fenfluramine is administered orally at a dose of 0.2 mg/kg twice daily; however, because the oral solution has a concentration of 2.2 mg/mL, the preparation for pediatric patients involves very small volumes. Additionally, the high viscosity of the solution poses significant challenges during preparation and administration, making it difficult to ensure that the intended dose is accurately administered.

A patient hospitalized in our institution (Kameda General Hospital, Kamogawa, Japan) continued to exhibit uncontrolled seizures despite administration and titration of various medications, leading to the introduction of fenfluramine hydrochloride. In this case, because the patient had a gastrostomy tube owing to poor oral intake, viscosity became an issue. We therefore reevaluated the method of administration using a syringe and decided to administer the medication through the gastrostomy tube when oral intake was difficult. Furthermore, because fenfluramine hydrochloride is indicated to be taken without mixing with other beverages, foods, or medications [7], it is not recommended to collect the residual drug solution adhering to the oral administration pipette by diluting it with a small amount of water, leading to a dosage shortfall.

Various medications, including diazepam injection, phenytoin injection, and phenobarbital injection, undergo precipitation or compositional changes upon dilution [9-11]. However, the extent to which the stability of fenfluramine hydrochloride is affected by dilution in water remains unclear.

To address this and examine the potential clinical application of fenfluramine hydrochloride diluted in water, we used LC/MS to qualitatively examine its stability and composition under dilution and present a case study of a nine-year-old girl with Dravet syndrome administered fenfluramine hydrochloride.

Patient Selection and Ethical Approval

We selected a case involving a patient, admitted to Kameda General Hospital, who was prescribed fenfluramine hydrochloride for Dravet syndrome and presented challenges in medication management. Informed consent was obtained from the patient's legal representative regarding the inclusion of the case in this paper, and the associated ethical review was approved by the Research Ethics Committee at Kameda General Hospital (No. case25-002).

Laboratory Equipment

Liquid chromatography–mass spectrometry (LC/MS) analysis of fenfluramine hydrochloride(Fintepla^®, Nippon Shinyaku Co., Ltd. 14 Kichijoin Nishinosho Monoguchi-cho, Minami-ku, Kyoto, A registered trademark of UCB, Inc.) was performed using a Waters ACQUITY UPLC/QTOF system, with the following MS settings: detection mode, scan; ionization mode, positive ion; ionization method, ESI; and mass range, m/z 50–1200.

Fenfluramine Hydrochloride Measurement

For pretreatment, approximately 100 μL of fenfluramine hydrochloride oral solution was dissolved in 10 mL of methanol or purified water. For analysis, 10 μL of the solution was then diluted in 1 mL of methanol or purified water, respectively, achieving 10,000- fold dilution. We applied this dissolution method because using ethanol (which is listed in the interview form) caused the solution to become cloudy upon dissolution [12]. The solutions were kept at room temperature, in accordance with pharmaceutical storage guidelines, and analysis was conducted between 6.5 and 12 min.

LC/MS findings

The BPI chromatograms of both the purified water-diluted and methanol-diluted fenfluramine hydrochloride oral solutions exhibit a peak (Peak 1) corresponding to the main component both immediately after dilution and after 24 h (Figure 1). No changes were observed between these time-points in peak shape or retention time or in the main component (Figures 2 and 3), or in the mass spectrum pattern of Peak 1 (Figure 4). Based on the composition calculation results for Peak 1, the ion C₁₂H₁₆NF₃ was identified as the main component of fenfluramine hydrochloride (Figure 5). This molecular formula corresponds (without the salt) to (2RS)-N-ethyl-1-[3-(trifluoro-methyl) phenyl] propan-2- amine monohydrochloride (molecular formula C₁₂H₁₆NF₃N·HCl), as described in the package insert for fenfluramine hydrochloride [7].

Figure 1: BPI chromatogram after diluting fenfluramine hydrochloride in methanol or purified water. For preparation, 100 μL fenfluramine hydrochloride was dissolved in 10 mL of methanol or pure water. Ten microliters of this solution were then diluted in 1 mL of methanol or pure water, achieving 10,000 - fold dilution. UPLC/QTOF analysis was performed using a Waters ACQUITY UPLC/QTOF system (Waters, Milford, MA, USA) in scan mode with electrospray ionization in positive ion mode over a mass range of m/z 50–1200.

Figure 2: BPI chromatogram after diluting fenfluramine hydrochloride in methanol and purified water (enlarged spectrum). For preparation, 100 μL fenfluramine hydrochloride was dissolved in 10 mL of methanol or pure water. Ten microliters of this solution were then diluted in 1 mL of methanol or pure water, achieving 10,000 - fold dilution. UPLC/QTOF analysis was performed using a Waters ACQUITY UPLC/QTOF system (Waters, Milford, MA, USA) in scan mode with electrospray ionization in positive ion mode over a mass range of m/z 50–1200.

Figure 3: BPI chromatogram after diluting fenfluramine hydrochloride in methanol or purified water (enlarged spectrum). For preparation, 100 μL fenfluramine hydrochloride was dissolved in 10 mL of methanol or pure water. Ten microliters of this solution were then diluted in 1 mL of methanol or pure water, achieving 10,000 - fold dilution. UPLC/QTOF analysis was performed using a Waters ACQUITY UPLC/QTOF system (Waters, Milford, MA, USA) in scan mode with electrospray ionization in positive ion mode over a mass range of m/z 50–1200.

Figure 4: Mass spectra of Peak 1 immediately following and 24 h after dilution with purified water. UPLC/QTOF analysis was performed using a Waters ACQUITY UPLC/QTOF system (Waters, Milford, MA, USA) in scan mode with electrospray ionization in positive ion mode over a mass range of m/z 50–1200.

Figure 5: Composition calculation results for Peak 1. UPLC/QTOF analysis was performed using a Waters ACQUITY UPLC/QTOF system (Waters, Milford, MA, USA) in scan mode with electrospray ionization in positive ion mode over a mass range of m/z 50–1200.

Case Study

A nine-year-old girl with Dravet syndrome (identical mutation in both sisters; no genetic mutations in the parents) underwent gastrostomy, 18 months prior to admission, because of difficulty with oral feeding. Eight months after gastrostomy, she was admitted for treatment because she continued to experience cluster seizures. After admission, attempts were made to control the seizures by increasing the dose of potassium bromide; however, as seizure control remained inadequate, the family requested initiation of fenfluramine hydrochloride treatment. After initiation, in Step 1, fenfluramine hydrochloride was administered at 0.2 mg/kg/d (0.6 mL twice daily) for one week, but issues related to viscosity arose during the first week. In Step 2, the dose was increased to 0.3 mg/kg/d (0.9 mL twice daily). After gathering information related to medication administration, the outpatient pharmacy explained the method of administration (i.e., via syringe) to the patient’s family: the drug should be administered orally, and if that were not possible, via the gastrostomy tube; and the drug should be administered alone, before meals. Five months later, a seizure episode occurred, and the dose was increased to 0.4 mg/kg/d (1.2 mL twice daily) as Step 3. At the time of writing, the patient is being managed at this dose, and treatment is progressing smoothly. Any residual medication left in the syringe after fenfluramine hydrochloride administration was collected using water and administered.

This study examines the effects of dilution in purified water or methanol on the chemical stability of fenfluramine hydrochloride, which requires administration without mixing with other beverages, foods, or medications. Based on LC/MS analysis, Peak 1 (which presumably indicates fenfluramine hydrochloride) was stably detected under all dilution conditions, and no new peaks or significant fluctuations in peak intensity were observed either immediately after dilution or 24 h later. This suggests that fenfluramine hydrochloride is relatively stable under dilution and that diluting it in purified water in clinical settings is unlikely to significantly impact its stability. This stability is based on the fact that the drug, being a hydrochloride salt, is generally more stable than the free base form [13]. Further, its skeleton comprises an aromatic ring, a trifluoromethyl group, and a saturated alkylamine; therefore, it lacks an ester or amide structure that is prone to hydrolysis, and it does not break down easily upon hydrolysis [14]. Moreover, the strong electron-withdrawing properties of the trifluoromethyl group contribute to its chemical stability [15].

In clinical practice, water or warm water are generally recommended for administering medication, and similar administration conditions are applied as standards in clinical trials [12]. Here, owing to the characteristics of LC/MS analysis, we set extremely low concentration conditions (10,000-fold dilution), which are not typically encountered in clinical settings, and chemical stability may be maintained even at this dilution. This suggests an even lower risk of compositional change under the lower dilution ratios typically used during actual administration. These findings suggest that small residual amounts of the drug solution, such as those left in the container after administration, remain stable and clinically effective when diluted using a small amount of water and subsequently administered.

In the case presented here, the patient was diagnosed with Dravet syndrome and treated with fenfluramine hydrochloride. As oral intake was temporarily difficult, a gastrostomy tube was inserted. When residual medication remained in the syringe after administration, the option of diluting the residue in water and injecting this solution via the gastrostomy tube was considered as a last resort. Even when oral administration was used, the patient was given a little water to dilute the residual drug remaining in her mouth, thus helping her to swallow the residue, and the clinical course remained favorable. These findings strongly indicate that diluting fenfluramine hydrochloride with water does not affect the stability of its active ingredient and that this strategy is likely to be feasible in clinical practice.

This study has several methodological limitations. First, LC/MS was not conducted under conditions simulating actual administration. Owing to the technical constraints of LC/MS, the concentration of the drug analyzed was lower than that used in clinical practice. Alternative analytical methods are required to analyze it at clinically relevant concentrations. Second, because this drug is highly viscous, the possibility of drug residues remaining in administration devices poses a practical challenge. This study did not examine the influence of device material and shape on the residual amount, and verifying device designs that reduce the residue requires future research. Third, the test results were obtained using purified water, and the potential for variation owing to the effects of mineral water or other liquids used in clinical settings was not examined.

These results suggest that fenfluramine hydrochloride maintains high chemical stability when diluted in water and confirm its compatibility with standard administration procedures in clinical settings. However, unresolved issues, including the presence of residues in administration devices and the need to evaluate chemical stability within the clinical concentration range, remain to be addressed. Addressing such issues will help to establish more appropriate and practical administration methods.

These findings provide a reference that can be used in medication counseling when dispensing fenfluramine hydrochloride, potentially helping to reduce dosage variability and symptom instability caused by administration techniques. The finding that residual medication in the syringe can be recovered with a small amount of water will help to improve reproducibility in practice and ensure dosing accuracy. Standardizing these methods may reduce the burden on caregivers, who are responsible for the daily preparation and administration of medications for children, and simultaneously improve treatment adherence.

These findings reveal that fenfluramine hydrochloride was diluted with water, no significant changes were observed in the LC/MS signals corresponding to the active ingredient within 24 hours after dilution, suggest that recovering the residual drug from administration devices using a small amount of water may help to ensure accurate dosing. Although the dilution factor used here was higher than that used in clinical practice, the drug remained stability even at this extremely low concentration. These findings on the stability of diluted fenfluramine hydrochloride support practical improvements in its administration methods. Future studies to verify these findings should apply clinically relevant concentrations and quantitative methods.

Author contributions

Manuscript preparation: Masanori Suzuki. Concept and design: Masanori Suzuki, Takashi Tomita; Acquisition, analysis, or interpretation of data: Nana Tomioka, Masanori Suzuki, and Takashi Tomita. All of the authors have reviewed the final version and have agreed to be accountable for all aspects of this work.

Availability of data and materials

All data generated or analyzed in this study are included in the published article.

Competing interests

The authors declare that they have no competing interests.

Funding

Not applicable.

Acknowledgements

We would like to thank TOSHIBA NANOANALYSIS (Kanagawa, Japan) for conducting the experiments and Editage (www.editage.jp) for the English language editing.

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