Off-Label Use

BackgroundDespite their limited licensed indications, anti-interleukin-1 (anti-IL-1) agents are often used in clinical practice for an increasing number of auto-inflammatory diseases. We conducted a national cross-sectional observational study from January 2011 to January 2013 to record the off-label use of such agents in France. We aimed to estimate the off-label use of anti-IL-1 treatments in France, assess their efficacy in rare diseases, and increase the reporting of their possible side effects.MethodsPhysicians answered a questionnaire that covered patient and disease data, anti-IL-1 agent use, efficacy and adverse events. The study involved adult or paediatric patient who had received an anti-IL-1 agent after January 2005 in France.ResultsIn total, 189 patients from 38 centres were included. The main diseases were adult-onset Still's disease (AOSD) (35), gout (28), systemic juvenile idiopathic arthritis (27), cryopyrin-associated periodic syndrome (CAPS) (21), familial Mediterranean fever (14) and mevalonate kinase deficiency (12). The main off-label used agent was anakinra, used at least once for 185 patients, with canakinumab used for 25. Anakinra was effective in most patients (90%), with higher complete clinical response rates for Schnitzler's syndrome, gout, CAPS and AOSD. Overall, 58% of patients showed at least one adverse event, mainly minor injection-site reactions. The main reported serious adverse event was severe infection. Injection-site reactions and liver toxicity were significantly more frequent in children than adults. The main non-cutaneous adverse event was liver toxicity, significantly associated with treatment duration. Weight gain was reported in about 10% of patients and was associated with treatment duration and CAPS. Canakinumab was rarely used and showed better cutaneous tolerance than anakinra but similar rates of non-cutaneous and severe adverse events.ConclusionsAnakinra was well tolerated and effective in most patients with various inflammatory diseases. The main adverse events were mild injection-site reactions, especially in children. The survey allowed for collecting limited information on the off-label use of canakinumab.

PurposeTo evaluate the use of off-label and unlicensed medicines in a neonatal intensive care unit (NICU) of a teaching maternity hospital specialized in high risk pregnancy.MethodsA prospective cohort study was conducted between August 2015 and July 2016. All newborns admitted to the NICU who had at least one medication prescribed and a hospital stay longer than 24 hours were included. The classification of off-label and unlicensed drugs for the neonatal population was done according to the information of Food and Drug Administration.ResultsA total of 17421 medication items were analyzed in 3935 prescriptions of 220 newborns. The proportion of newborns exposed to off-label drugs was 96.4%, and to unlicensed medicines was 66.8%. About one-half (49.3%) of the medication items were off-label and 24.6% were unlicensed. The main reason for off-label and unlicensed classification was, respectively, frequency of administration and the administration of adaptations of pharmaceutical forms.ConclusionsAlthough there are actions to encourage the development of pharmacological studies with neonates, this study observed a high rate of prescription and exposure of newborns to off-label and unlicensed drugs in NICUs and pointed out areas of neonatal therapy that require scientific investment.

BackgroundThe treatment of aneurysmal bone cysts (ABCs) has evolved and less invasive methods have been tried. Denosumab is a monoclonal antibody which inhibits osteoclasts. It has been shown to be effective in giant cell tumour of bone (GCT) of bone and hence promises some effect also in ABC. We report on 6 patients treated with Denosumab and compare our results to the cases already published.MethodsData of 6 patients with ABCs and patients whose treatment included Denosumab were retrospectively analyzed. Denosumab was used at a dose of 120 mg on days 1, 8, 15 and 29, and every 4 weeks thereafter. In some of these patients the dose was reduced at the end of the treatment. Clinical and radiological responses were evaluated.ResultsIn 4 female and 2 male patients with a mean age of 17 years (range: 6-30 years) the lesions were located in the sacrum (2), in distal radius, distal femur, talus and pelvis. One of the sacral lesions healed after 12 months and has stayed stable for 3 years since. The second patient received 2 years of therapy with recalcification, but recurred 1 year later and is under renewed therapy. The pelvic lesion improved but recurred. This patient has a 13-years history of intermittent therapy including surgery, two pregnancies and remains in a stable situation. The lesion of the talus did not improve with Denosumab after surgery and was complicated by destruction of the ankle joint with osteoarthritis. Recurrent lesions of the distal femur and the distal radius, previously treated by curettage and bone grafting healed under Denosumab and have remained stable for 2 and 3 years, respectively. One case of severe hypercalcemia was observed in a 7-year old child 6 months after discontinuation of Denosumab.ConclusionDenosumab provides a treatment option for ABCs in anatomically critical locations. Adjuvant application might reduce the rate of local recurrence. In young patients, severe rebound hypercalcemia months after discontinuation of Denosumab may occur.

JAK inhibitors are used to treat various inflammatory skin diseases. However, systemic formulations are associated with an increased risk of major adverse events. Ruxolitinib 1.5% cream is a selective topical JAK1 and JAK2 inhibitor, which has recently been approved by EMA and MHRA for treating non-segmental vitiligo, while being FDA-approved for both vitiligo and atopic dermatitis. Recent literature has reported the off-label use of topical Ruxolitinib for several skin conditions, but data are mostly limited to single case reports and series and few prospective studies, with mixed results. We conducted a systematic review of the literature to investigate the potential efficacy of topical Ruxolitinib in various skin diseases in an off-label setting. The following keywords were used for searching the MEDLINE (Pubmed) and Scopus databases from inception to September 2024: "ruxolitinib cream and dermatology" and "topical ruxolitinib and dermatology". Reviews, articles not focusing on the main topic, books and book chapters, and articles with no English text were excluded. A total of 170 studies were screened, of which 112 fell within exclusion criteria and 58 were assessed for eligibility. Of these, 28 studies, published between 2012 and 2024, were selected. Ruxolitinib cream resulted in being used off-label mostly for treating lichenoid and granulomatous dermatoses, as well as alopecia areata. While for the former skin conditions, topical ruxolitinib proved to be effective and safe, results on efficacy in alopecia areata were controversial. Topical ruxolitinib might be a promising therapeutic option for lichenoid and granulomatous dermatoses. Noteworthily, despite the exciting results from the oral formulation, no consistent data were described for topical ruxolitinib in alopecia areata. Our review reported encouraging results for many inflammatory skin conditions that should be investigated in further studies.