Off-label drug use in paediatric haemato-oncology patients: financial implications and proposed solutions for Belgian patients.

Treatment of children with cancer requires access to and reimbursement of effective drugs. Children with haemato-oncological diseases are often treated according to established treatment recommendations or in the framework of late-phase clinical trials. These often involve the use of drugs authorised for adults but which, however, have been used for many years in paediatrics with no perspective of authorisation in children. In Belgium, medicines are predominantly reimbursed based on their authorised indication. As a consequence, many drugs used in paediatric haemato-oncology are used off-label, despite their status of 'standard of care'. As reimbursement is often not available, alternative ways for funding need to be explored, which causes a significant administrative burden for healthcare providers and emotional distress for the parents. Solutions to organise a systematic reimbursement of standard of care off-label used drugs are described.Conclusion: A number of structural solutions are proposed, and we hope that they might guide health authorities to provide a solution to the problem caused by the lack of reimbursement of some standard of care medicines for children with cancer. What is Known: • Off-label drug use is frequently observed in paediatric haemato-oncology and compromises-in some countries-reimbursement. What is New: • An estimation of the impact of non-reimbursed drugs in Belgium is provided. • Some solutions are presented to overcome this problem in Belgium.

Successful Treatment of Adenovirus Infection with Brincidofovir in an Immunocompromised Patient after Hematological Stem Cell Transplantation.

Immunocompromised patients, including hematopoietic stem cell transplantation (HSCT), HIV, and malnourished patients, are at increased risk for viral infections with high incidences of morbidity and mortality. In HSCT patients, the infection risk is increased until immune reconstitution is re-established. Therapy with standard of care antiviral drugs, for example Cidofovir, is expensive, requires prolonged administration, and has unfavorable toxicity profiles. Our case describes the successful use of Brincidofovir (CMX001), a lipid-conjugate of the nucleotide analog Cidofovir, in a 9-year-old post-HSCT girl with disseminated adenovirus infection. The increased efficacy of Brincidofovir (BCV) against multiple viral infections, limited toxicity, and oral-administered schedule opens options in different resource settings.

Drug shortages in a pediatric stem cell transplantation ward: Challenges and implications. A 5-year bilan.

This article describes the implications of shortages of pharmaceutical products used in conditioning and supportive care regimens of pediatric patients undergoing a hematopoietic stem cell transplantation in a tertiary care hospital. Between July 2011 and July 2016, a total of 84 individual shortages, affecting 22 different drugs (79.8% supportive care drugs; 20.2% chemotherapeutics) were detected with a mean duration of 85 days (SD 138) per individual drug shortage. Eighteen shortages were critical and very urgent. Sulfamethoxazol/trimethoprim, piperacillin/tazobactam, ranitidine, benzylpenicillin, ondansetron (supportive care) and methotrexate, melphalan (chemotherapeutics) had the longest supply disruptions. A variety of solutions could be identified including the purchase of a generic alternative (36.9%) for both oral and parenteral treatments (in a ratio 3:2). Urgent import from another (European) country was performed in 14 cases (16.7%). High impact solutions such as cohorting of patients and change of ongoing treatments (2.4%) were used for parenteral treatments only. Pharmaceutical modification was sometimes applied for oral treatments (2.4%). Due to persistent occurrence of these shortages, an efficient pharmacy workflow (electronic follow-up by end of 2016) and a multidisciplinary approach were needed.

[Pharmaceutical care for pediatric hemato-oncology and stem cell transplantation patients. Inventory of experiences and needs]. / Soins pharmaceuriques des traitements en onco-hématologie et de greffe de cellules souches en pédiatrie Inventaire des expériences et des besoins des pharmaciens et des étudiants en Flandre.

Introduction Pharmacists can be faced with pediatric patients treated for a hemato-oncological condition or patients who underwent a hematopoietic stem cell transplantation [HSCT). This study aims to identify the roLe of the pharmacist and master in pharmacy students as well as their knowLedge of pharmaceutical care for this specific patient population. In addition, their experiences of basic education and expectations of continued education in pediatric hemato-oncology and HSCT are analyzed. Methods Pharmacists in Flanders and pharmacy students [Ghent University] were requested to complete and online survey with (1) general questions, (2) questions about knowledge by means of theoretical examples and practical cases and (3) questions about education (past and future) related to this topic. Results A total of 156 pharmacists and 67 students completed the survey. Results demonstrated that 22.0% of pharmacists and students already delivered medication to this particular patient group. A total of 98.2% [pharmacists and students] found that they had insufficient knowledge and experience to give optimal pharmaceutical advice. The pharmacist scored only 34.0% [average] in the general knowledge section, students 44.0%. Both pharmacists [68.6%] and students [79.0%] agreed that this topic should be included in the basic curriculum. The vas majority [91.0% pharmacists, 89.6% of students] were asking for courses on this theme by means of and evening session or an e-learning tool. Conclusion Although the role of pharmacists and students in this patient group can be confirmed, the results of the survey demonstrate a lack of knowledge among pharmacists and students about pediatric hemato-oncology and HSCT. There is interest in education in the basic curriculum and the vast majority of pharmacists are interested in continuing education.

[Stability of high-dose etoposide dilutions for use in hematopoietic stem cell transplantation conditioning regimens]. / Stabilité d'une dose élevée d'étoposide en dilution pour utilisation lors du conditionnement avant greffe de cellules souches.

High-dose etoposide is used in conditioning regimens for allogeneic stem cell transplantation. The limited stability of the drug induces barriers for its use for pharmacists, nurses and patients. When using a concentration of 10 mg/mL etoposide in physiologic saline, limitations can be overcome. This study provides stability data for etoposide in a high concentration that can be used in conditioning regimens. The solution was stable for 48h at 5°C, for 48h at 5°C followed by 8h at 25°C and for 24 h at 25°C.

[Acute lymphoblastic leukemia in children: history of drug therapy management]. / La leucémie aiguë lymphobtastique chez l'enfant: évolution de la pharmacothérapie.

The last forty years have witnessed major improvements in the survival of pediatric cancer patients with an evolution of acute tymphoblastic leukemia as an untreatable disease to acute lymphoblastic leukemia with a survival rate of more than 90%. This has become possible due to improvements in the various modalities of cancer therapy and supportive care. The aim of this commentary is to give an overview of the history of pharmacological treatment for children with acute Lymphoblastic leukemia.

Methemoglobinemia and hemolytic anemia after rasburicase administration in a child with leukemia.

CASE: We report a case of simultaneous methemoglobinemia and hemolytic anemia, probably related to the use of rasburicase, in a child starting treatment for acute lymphoblastic leukemia (ALL). In addition, the patient developed symptoms of pancreatitis. All complications resolved after 3 days of supportive therapy. CONCLUSION: Although usually well tolerated in pediatrics, physicians prescribing rasburicase should be aware of these possible life-threatening adverse reactions.

Basic principles for paediatric care: what ENT professionals should know.

Children undergoing medical or surgical treatment for ENT disorders should receive care from doctors familiar with the specificities of paediatric ENT pathology working in dedicated clinics where there are facilities for the activities that children usually indulge in and accommodation for parents. Many aspects of care for children with ENT problems involve a multidisciplinary team consisting of ENT surgeons working alongside a range of medical and paramedical professionals and nurses specifically trained in childcare, as well as in ENT nursing. Within this multidisciplinary approach, we will discuss some important aspects of the psychosocial approach and nursing, anaesthesia and pharmacotherapy that should be considered in order to raise the safety and quality of patient care in paediatric otorhinolaryngology.

Methemoglobinemia and hemolytic anemia after rasburicase administration in a child with leukemia.

CASE: We report a case of simultaneous methemoglobinemia and hemolytic anemia, probably related to the use of rasburicase, in a child starting treatment for acute lymphoblastic leukemia (ALL). In addition, the patient developed symptoms of pancreatitis. All complications resolved after 3 days of supportive therapy. CONCLUSION: Although usually well tolerated in pediatrics, physicians prescribing rasburicase should be aware of these possible life-threatening adverse reactions.

Highly effective treatment with tacrolimus ointment in an adolescent with oral graft-versus-host disease.

CASE: We report a case of acute oral graft-versus-host disease in an adolescent, which was successfully treated with tacrolimus 0.1% ointment. CONCLUSION: Although tacrolimus ointment is not licensed for the indication of oral GvHD, this case report provides preliminary evidence for a potential effectiveness of using tacrolimus in case of failure when GvHD is resistant.

Clinical pharmacy in a multidisciplinar team for chronic pain in adults.

The aim of this study was to evaluate the role and the impact of a clinical pharmacist as a member of a multidisciplinary pain team. Although physicians have a good knowledge of pharmacotherapy in the field of pain medication, pharmacy interventions were necessary to enhance the quality of prescribing. On a population of 93 patients, a total of 120 interventions were recorded. The different types of interventions included: provision of information (10.0%), clinical intervention (89.2%) and the provision of a specific product (0.8%). Out of the 107 clinical interventions, a total of 95.3 % interventions were accepted by the physicians. The results highlight the clinical importance of the pharmacy in optimizing drug therapy for adult patients with chronic pain.

Vulvovaginal candidiasis in a Flemish patient population.

Increased resistance to fluconazole has been reported in oral, oesophageal and urinary Candida isolates, but this has not been observed commonly in genital tract isolates. The rate of isolation of Candida spp. and their susceptibility to amphotericin B, flucytosine and azoles were determined in a number of clinical practices in the city of Ghent, Belgium. Patients with symptomatic vulvovaginal candidiasis (VVC) were treated with fluconazole, and the mycological and clinical outcomes were evaluated. Isolates were identified as Candida albicans (78.6%), Candida guilliermondii (17.3%), Candida glabrata (2.6%) and Candida dubliniensis (1.3%). The rates of mycological and clinical cures were 79.5% and 100%, respectively. Women with recurrent VVC were infected more frequently by non-albicans Candida spp., but no association was found between the use of antifungal agents and the presence of non-albicans spp. In-vitro resistance to fluconazole was not detected, even among subsequent Candida isolates from nine patients for whom mycological cure was not achieved.

Detection of single cells of Cryptococcus neoformans in clinical samples by solid-phase cytometry.

A method based on solid-phase cytometry for the detection and enumeration of single cells of Cryptococcus neoformans in serum and cerebrospinal fluid is described. Both viable and nonviable cells are detected by using fluorescence viability labeling and immunofluorescence. This 30-min procedure has a detection limit of 3 to 6 cells per ml.

Evaluation of human albumin use in a university hospital in Belgium.

UNLABELLED: In 1996-1997, a drug use evaluation (DUE) of human albumin was conducted in the Ghent University Hospital (Belgium) to determine the pattern and appropriateness of the albumin use. The DUE was followed by permanent review of the albumin consumption. This paper describes how the DUE was carried out and how the albumin use in our hospital changed over time. METHOD: The study was based on criteria for indications and end of treatment, accepted by consensus of the physicians prescribing albumin. Albumin treatment episodes were classified as appropriate or inappropriate according to these criteria. RESULTS: For 115 treatment episodes in 90 patients, the researchers found 21 (18.3%) deviations from the developed criteria. After analysis, half out of them were considered as minor. Most deviations involved starting treatment too early (n = 17). Follow-up results indicated that the overall consumption of albumin dropped by 50.1% from 1994 to 1999, while the consumption of colloid solutions during the same period remained stable. CONCLUSION: A good compliance with internally developed criteria for indications and end of treatment with human albumin was observed. Discussion with the clinicians involved led to the development of stricter criteria and a continuous decrease in albumin consumption.

Comparison of chromogenic and fluorogenic membrane filtration methods for detection of four Candida species.

CHROMagar Candida medium was inoculated with a variety of clinical samples (n = 282) by using membrane filtration instead of swabbing or streaking. This modified CHROMagar procedure increased the ability to detect yeast by 16.7%. Compared to an enzymatic two-step membrane filtration method with fluorogenic substrates, it yielded similar recovery but was slower.

Repeated isolation of Cryptococcus laurentii from the oropharynx of an immunocompromized patient.

Cryptococcus laurentii is one of the non-neoformans cryptococci that have rarely been isolated from humans. We report a case of repeated colonization of the oropharynx by Cr. laurentii in a patient with erythroleukaemia. The isolate was identified by phenotypic and genotypic tests and showed resistance to fluconazole.

Development of a flow-through enzyme immunoassay and application in screening green coffee samples for ochratoxin A with confirmation by high-performance liquid chromatography.

A flow-through enzyme immunoassay has been developed for the screening of green coffee bean samples for ochratoxin A (OA) and was later used in a survey on OA in green coffee from different countries. The test has a sensitivity of 8 ng/g, and calculated recoveries ranged from 70 to 89% and from 86 to 95% for spiked and naturally contaminated samples, respectively. There were no significant differences in within-day and between-day assay performance (P > 0.05). Green coffee samples (15 Arabica and 7 Robusta) received from an international coffee trader were analyzed for intrinsic fungal contamination, screened for OA, and subsequently confirmed by high-performance liquid chromatography (HPLC). All 22 samples were contaminated by fungal species of the genus Aspergillus, while Penicillium species were isolated from a mere 13.6% of the total number of samples. Isolates were tested for their ability to produce OA, and only 3.9% were positive. There was no correlation between occurrence of OA-producing isolates and levels of OA in contaminated samples. Results of the screening procedure showed that 4 of the 22 samples were contaminated with 8 ng/g or higher. The HPLC method confirmed that the OA levels ranged from 27 to 168 ng/g. A fifth sample, which was shown to be negative during screening, had an OA concentration of 4 ng/g. There were no false negatives or positives recorded, and the flow-through enzyme immunoassay results correlated with those obtained by HPLC.

Colonization of a voice prosthesis by Cryptococcus neoformans.

Tracheoesophageal voice prostheses in laryngectomized patients commonly deteriorate due to the presence of yeasts, particularly Candida species. We describe the first case of colonization of such a device by Cryptococcus neoformans in a patient with a history of glottic carcinoma. The isolate showed an identical genomic pattern with C. neoformans from pigeon excreta in the patient's environment.

The mucosal toxicity of different benzalkonium chloride analogues evaluated with an alternative test using slugs.

PURPOSE: The objective of this study was to evaluate the mucosal toxicity of different benzalkonium chloride (BAC) analogues using slugs as the alternative test organism. METHODS: The effect of different BAC analogues on the mucosal tissue of slugs was determined from the protein, lactate dehydrogenase, and alkaline phosphatase released from the foot mucosa after treatment. Additionally, mucus production and reduction in body weight of the slugs were measured. The eye irritation potency of the molecules was evaluated with the Bovine Corneal Opacity and Permeability (BCOP) assay. The antimicrobial activity of the different BAC analogues was also assessed. RESULTS: All BAC analogues induced severe damage to the mucosal epithelium of the slugs, and the irritation increased with decreasing alkyl chain length: BAC-C16 < BAC-C14 < BAC-C12 approximately BAC-mix. A similar ranking was obtained with the BCOP assay for eye irritation. The relative order of activities among the three BAC analogues was the same, i.e., BAC-C14 > or = BAC-C16 > BAC-C12. The BAC-C14 exhibited higher activity than the BAC-mix. CONCLUSIONS: The toxicity and activity of BAC analogues depend on the alkyl chain length. The use of BAC-C14 as a conservative agent in pharmaceutical preparations instead of the BAC-mix should be considered.