Off-label Indications Research Articles

An Evaluation of the Effectiveness of Risk Minimization Measures for Tigecycline in the European Union

Risk minimization measures (RMM) were implemented from February 2011 in the European Union to address risks of superinfection, off-label use and lack of efficacy associated with tigecycline. The objective of this study was to evaluate RMM effectiveness by describing prescription patterns among adults and children treated with any dose of tigecycline for any indication pre- and post-RMM implementation; incidence proportions of superinfection and lack of efficacy among adults treated with approved doses of tigecycline for complicated intra-abdominal infection and complicated skin and soft tissue infection were also evaluated. This was an observational, retrospective chart-abstraction study, including charts from 777 patients (399 pre-RMM, 378 post-RMM) at 13 sites across Austria, Germany, Italy, Greece and the United Kingdom (UK). Potential superinfection and lack of efficacy cases among those using tigecycline for on-label indication, age, dose, and duration were adjudicated. The distribution of indications for tigecycline was analyzed overall (i.e. across both study periods) and stratified by study period. Numbers and incidence proportions of superinfection and lack of efficacy cases (potential and adjudicated) were calculated overall and by study period. Off-label use (indication or age) decreased from 54.2% [95% confidence interval (95% CI): 49.0, 59.3%] pre-RMM to 35.7% (95% CI 30.4, 41.2%) post-RMM. Overall, 45.7% (95% CI 41.9, 49.5%) of patients were prescribed tigecycline off-label; the most commonly reported off-label indications were characterized as “other” (25.5%), hospital acquired pneumonia (8.2%), other pneumonia (6.3%), bacteremia (5.2%) and diabetic foot infection (1.5%). Across study periods, incidence proportions of definite or probable superinfection and lack of efficacy in adults treated for approved indications, authorized treatment doses and duration were 4.5% (95% CI 2.1, 8.4%) and 5.5% (95% CI 2.8, 9.7%), respectively. Off-label use of tigecycline decreased following RMM implementation. Overall incidence proportions of definite or probable superinfection and lack of efficacy were low. EU PAS register number: EUPAS3674

Off-label indications for antidepressants in primary care: descriptive study of prescriptions from an indication based electronic prescribing system

Objective To examine off-label indications for antidepressants in primary care and determine the level of scientific support for off-label prescribing.Design Descriptive study of antidepressant prescriptions written by primary care physicians...

Classics in Chemical Neuroscience: Haloperidol.

The discovery of haloperidol catalyzed a breakthrough in our understanding of the biochemical basis of schizophrenia, improved the treatment of psychosis, and facilitated deinstitutionalization. In doing so, it solidified the role for chemical neuroscience as a means to elucidate the molecular underpinnings of complex neuropsychiatric disorders. In this Review, we will cover aspects of haloperidol's synthesis, manufacturing, metabolism, pharmacology, approved and off-label indications, and adverse effects. We will also convey the fascinating history of this classic molecule and the influence that it has had on the evolution of neuropsychopharmacology and neuroscience.

Contrast echocardiography in daily clinical practice.

Ultrasound contrast agents have unique acoustic properties that enable them to enhance the cardiac blood flow and thus are used broadly in modern echocardiography laboratories for salvage of nondiagnostic studies, improving accuracy and reducing variability even in the presence of adequate image quality. Contrast echocardiography is also used as an adjunctive technique when unenhanced echocardiography falls short in the differentiation of cardiac structural abnormalities such as cardiac masses. Ultrasound contrast agents are pure intravascular tracers. Development of innovative ultrasound imaging techniques has led to myocardial perfusion imaging with contrast echocardiography. Although currently an off-label indication, it has been shown that perfusion imaging with contrast echocardiography adds incremental value to stress echocardiography in the detection of coronary artery disease. Moreover, it can be used for assessment of myocardial viability. In this paper we briefly discuss the basics of contrast echocardiography and its use in daily clinical practice.

Paediatric lung isolation

### Key points Lung isolation is required for a wide variety of pathology in paediatric patients. The varying size of the paediatric airway and size limitations of each lung isolation device poses a challenge to paediatric anaesthesiologists. The need for lung isolation includes: the prevention of contamination of one lung from the other due to haemorrhage or infection, the need to control the distribution of ventilation secondary to a bronchopulmonary fistula, a lung cyst or bullae, or severe hypoxaemia from unilateral lung disease. Extensive bronchopulmonary lavage may also necessitate lung isolation. Although lung isolation can assist in surgical exposure, in the paediatric population, surgical exposure for lung resections, mediastinal exposure, and thorascopy can often be accomplished by the CO2 pneumothorax and retraction of the operative lung without the need for lung isolation. This is most common in the young patient (<2 yr of age). Slinger1 teaches that there are the ‘ABCs’ of adult lung isolation: anatomy, bronchoscopy, and chest imaging. In paediatric lung isolation, there are still all the same ‘ABC’ considerations, with the addition of ‘D’—the varying diameter of the paediatric airway with age. ### Anatomy It has been long established that there are differences between the paediatric …

Avoiding Chlorhexidine Burns in Preterm Infants

Chlorhexidine is a skin antiseptic agent frequently used for off-label indications in NICUs. Changes to the safety labeling of chlorhexidine products for use in preterm infants were recently made because of the risk of severe chemical burns. We provide tips for a safer use of chlorhexidine to prevent injury in newborns and to help health care professionals protect themselves against burn injury claims.

Evaluation of patterns and predictors of off-label prescribing of antidepressants in psychiatry at a tertiary care hospital - An analytical cross-sectional study

Background: Off-label drug prescribing is commonly seen all medical fields including psychiatry. A regular auditing and publishing of off-label drug prescribing is important as it provides strong scientific evidence for the clinicians on the effectiveness and acceptability of these proposed treatments. Aims and Objective: To evaluate the pattern and predictors of off-label prescribing of antidepressants in psychiatry was taken up. Materials and Methods: After obtaining the permission from Institutional Ethics Committee, an analytical cross-sectional study was conducted among patients attending psychiatry outpatient department for 6 months. Demographic and drug data were noted and analyzed for off-label drug use as per Food Drug Administration approved indication. Chi-square test and Student’s t-test were used to compare the off-label and approved indication groups. Multivariate binary logistic regression model was used to determine the predictors of offlabel prescribing. Results: A total of 238 antidepressants were prescribed for 200 patients, of which 42.8% were used for off-label indication. Fluoxetine 44.1% and escitalopram 42.1% were the most frequently prescribed antidepressants in offlabel manner. The off label indications noted was somatoform disorder (12.5%), followed by generalized anxiety disorder (8.5%). There was significant causal association between off-label prescribing and number of antidepressant (odds ratio [OR] - 15.43, 95% confidence interval [CI] - 3.49-89.02, P < 0.05) and non-depressant use (OR - 74.37, 95% CI - 25.4-293.71, P ≤ 0.05). Conclusion: Off-label use of antidepressants was 42.8% in this study. A number of antidepressants and non-depressant uses were the significant predictors of off-label prescribing in our hospital.

Ciprofloxacin Use in Hospitalized Children: Approved or Off-label?

Objective:Fluoroquinolones are not routinely used as the first-line antimicrobial therapy in pediatrics. The American Academy of Pediatrics (AAP) and the United States Food and Drug Administration (FDA) approved fluoroquinolones on certain indications in children. The aim of this study was to evaluate to what extent and how ciprofloxacin is used on approved indication or as off-label. Besides, dose adequacy and treatment duration were assessed.Methods:In a 10-month observational study, all children receiving systemic ciprofloxacin were assessed. We classified ciprofloxacin prescription to an AAP/FDA or off-label indication. The off-label prescriptions were further categorized to justified and unjustified therapy subgroups. The AAP/FDA category and the justified subgroup constituted the appropriate prescriptions.Findings:During the study period, 32 patients were prescribed ciprofloxacin. In general, 37% (12) of prescriptions determined to be appropriate. Of the appropriate prescriptions, 7 were AAP/FDA-approved indications. Children with Crohn's disease with abdominal abscess and children with infectious bloody diarrhea constituted the off-label; justified therapy subgroup. Unjustified prescriptions mainly occurred in the presence of a suitable alternative antibiotic for ciprofloxacin. Mean ± SD of ciprofloxacin dose (mg/kg/day) and duration (days) were 21.25 ± 6.35 and 13.56 ± 8.48, respectively. Of the appropriate prescriptions, 41% were underdosed. Underdosing was more encountered in patients with cystic fibrosis. Duration of treatment of the appropriate prescriptions was determined to be appropriate.Conclusion:The majority of children were receiving ciprofloxacin off-label and in an inappropriate manner. This issue emphasizes that antimicrobial stewardship program on ciprofloxacin use in pediatric hospitals should be implemented. Further studies evaluating clinical and microbiological outcomes of these programs in children are needed.

Use of recombinant human bone morphogenetic protein-2 in spine surgery.

Bone morphogenetic proteins are osteoinductive factors which have gained popularity in orthopaedic surgery and especially in spine surgery. The use of recombinant human bone morphogenetic protein-2 has been officially approved by the United States Food and Drug Administration only for single level anterior lumbar interbody fusion, nevertheless it is widely used by many surgeons with off-label indications. Despite advantages in bone formation, its use still remains a controversial issue and several complications have been described by authors who oppose their wide use.

A study on off-label and unlicensed drug use by community pharmacists: A report from resource-limited settings of South India

Introduction: Labeled uses of drug use are approved by the regulatory authorities based on preclinical and clinical data which confirms their safety and efficacy. From the community pharmacist perspective, the most common off-label use is due to physician's prescriptions and usage of over-the-counter (OTC) medications. In India, huge number of medicines is easily available for off-label use from the community pharmacists with or without prescriptions. Objectives: It is a preliminary study to evaluate and describe the off-label drug use by community pharmacists in resource-limited settings. Materials and Methods: It is a prospective cross-sectional study conducted among community pharmacies located in and around of Anantapur district, a rural part of Andhra Pradesh, South India. The data were collected through questionnaire-based semi-structured interview and/or asked the community pharmacists to complete on their own at the spot to avoid manipulation of data. The questionnaire is of two types: the first type evaluates pharmacist perspective on off-label indication for randomly selected drugs (frequent moving) and the second type evaluates dispensing practice of drugs for off-label use based on symptoms. Results: The present study results show that the frequency of off-label drug use is high among community pharmacists; moreover, they dispense the drugs without aware of off-label or inappropriate indication, sometimes as OTC medications. It is an acceptable fact that off-label or unlicensed drug use is not illegal but has plenty of safety and other issues. Conclusion: Thus, the present study provides a preliminary data to frame future educational and interventional programs to improve the rational use of drugs with regard to it.

Elucidating the Mechanism(s) Underlying Antipsychotic and Antidepressant-Mediated Fractures.

Mood spectrum disorders and medications used to treat these disorders, such as atypical antipsychotic drugs (AA), are associated with metabolic and endocrine side effects including obesity, dyslipidemia, hyperglycemia and increased risk of fractures. Antidepressant medications, including selective serotonin reuptake inhibitors (SSRI), have also been reported to increase fracture risk in some patients. The pharmacology underlying the increased risk of fractures is currently unknown. Possible mechanisms include alternations in dopaminergic and/or serotonergic signaling pathways. As these medications distribute to the bone marrow as well as to the brain, it is possible that drug-induced fractures are due to both centrally mediated effects as well as direct effects on bone turnover. Given the growing patient population that is prescribed these medications for both on- and off-label indications, understanding the level of risk and the mechanisms underlying drug-induced fractures is important for informing both prescribing and patient monitoring practices.

Doctors prescribe antidepressants for off-label indications without evidence

Doctors prescribe antidepressants for off-label indications without evidence

Off-label use of drugs in regional anesthesia: A need for setting up policies.

Off-label use of drugs in regional anesthesia: A need for setting up policies.

Proposed changes to the reimbursement of pharmaceuticals and medical devices in Poland and their impact on market access and the pharmaceutical industry

ABSTRACTIn Poland, two proposed amendments to the reimbursement act are currently in preparation; these are likely to substantially change the pricing and reimbursement landscape for both drugs and medical devices. Proposed changes include: alignment of medical device reimbursement with that of pharmaceuticals; relaxing the strict reimbursement criteria for ultra-orphan drugs; establishment of an additional funding category for vaccines; introduction of compassionate use, and a simplified reimbursement pathway for well-established off-label indications; appreciation of manufacturers’ innovation and research and development efforts by creating a dedicated innovation budget; introduction of a mechanism preventing excessive parallel import; prolonged duration of reimbursement decisions and reimbursement lists; and increased flexibility in defining drug programmes. Both amendments are still at a draft stage and many aspects of the new regulations remain unclear. Nonetheless, the overall direction of some of the changes is already evident and warrants discussion due to their high expected impact on pharmaceutical and device manufacturers. Here we evaluate the main changes proposed to the reimbursement of drugs, vaccines, and medical devices, and examine the impact they are likely to have on market access and pharmaceutical industry in Poland.

Less explored off-label indications of dexmedetomidine.

Less explored off-label indications of dexmedetomidine.

Off-label use of tumour necrosis factor-alpha inhibitors and anakinra at an Australian tertiary hospital.

Tumour necrosis factor-alpha inhibitors (anti-TNFα) and anakinra are monoclonal antibodies against pro-inflammatory cytokines overexpressed in many systemic inflammatory diseases. In Australia, they are registered for the treatment of several rheumatological, gastroenterological and dermatological indications. Despite increasing observational evidence for their use in off-label indications, there is a paucity of outcome research from the Australian hospital sector. To describe the off-label use of anti-TNFα and anakinra at a tertiary referral hospital in Queensland, Australia and consideration of a drug register to inform future clinical decision-making. We performed an in-depth retrospective chart audit of off-label treatment with anti-TNFα or anakinra at the Royal Brisbane and Women's Hospital from mid-2010 to mid-2014, linking demographic, phenotypic, pathology and outcome data with these drugs. Off-label use was identified in 10 patients. The most frequent indications were sarcoidosis and dermatological conditions. Three patients required sequential therapy with a second anti-TNFα (total responses = 13). Complete response occurred in 46%, partial response in 38% and primary non-response in 8%. Response was unable to be determined in 8%. We recorded 14 adverse events (infections most common). This study suggests that anti-TNFα may be beneficial for some off-label indications (e.g. sarcoidosis). However, the observational design of this study (and pre-existing research) limits the ability to infer causality and generalise results. We propose the creation of a mandatory drug register to monitor off-label use. Whilst comparative efficacy cannot be established without a matched placebo arm, a register would enable some reporting on effectiveness in rare diseases and identify infrequent but serious adverse events.

Technical Considerations for Filler and Neuromodulator Refinements.

Background: The toolbox for cosmetic practitioners is growing at an unprecedented rate. There are novel products every year and expanding off-label indications for neurotoxin and soft-tissue filler applications. Consequently, aesthetic physicians are increasingly challenged by the task of selecting the most appropriate products and techniques to achieve optimal patient outcomes. Methods: We employed a PubMed literature search of facial injectables from the past 10 years (2005-2015), with emphasis on those articles embracing evidence-based medicine. We evaluated the scientific background of every product and the physicochemical properties that make each one ideal for specific indications. The 2 senior authors provide commentary regarding their clinical experience with specific technical refinements of neuromodulators and soft-tissue fillers. Results: Neurotoxins and fillers are characterized by unique physical characteristics that distinguish each product. This results in subtle but important differences in their clinical applications. Specific indications and recommendations for the use of the various neurotoxins and soft-tissue fillers are reviewed. The discussion highlights refinements in combination treatments and product physical modifications, according to specific treatment zones. Conclusions: The field of facial aesthetics has evolved dramatically, mostly secondary to our increased understanding of 3-dimensional structural volume restoration. Our work reviews Food and Drug Administration-approved injectables. In addition, we describe how to modify products to fulfill specific indications such as treatment of the mid face, décolletage, hands, and periorbital regions. Although we cannot directly evaluate the duration or exact physical properties of blended products, we argue that "product customization" is safe and provides natural results with excellent patient outcomes.

Prasugrel Use Following PCI and Associated Patient Outcomes: Insights From the National VA CART Program.

Prasugrel is more effective than clopidogrel in preventing thrombotic complications after percutaneous coronary intervention (PCI) among patients with acute coronary syndromes (ACS), but it increases the risk of bleeding in subgroups of patients. There is limited data on whether prasugrel use in routine practice is targeted to clinical settings with greatest anticipated patient benefit. In a national cohort of 11 617 veterans who underwent PCI between 2010 and 2013 at Veterans Administration hospitals nationwide, we assessed overall trends in the use of prasugrel and the frequency of prasugrel use in patients with contraindications (prior transient ischemic attack or cerebrovascular accident), higher bleeding risk (age ≥75 or weight <60 kg), and nonindicated settings (non-acute coronary syndrome [non-ACS]). We then evaluated the association between prasugrel use and 1-year risk-adjusted mortality, myocardial infarction, and major bleeding rates. Overall, 1040 (9.0%) patients who received prasugrel after PCI were included. Prasugrel was infrequently used in contraindicated (2.4%) or higher-bleeding-risk (1.8%) settings. Additionally, 35.8% of patients received prasugrel in settings that lack evidence of clinical benefit (ie, non-ACS). Compared with clopidogrel, there were no significant differences in risk-adjusted mortality, myocardial infarction, or major bleeding outcomes with prasugrel therapy at 1-year follow-up. Prasugrel use after PCI in the Veterans Administration is low and prasugrel was rarely used in contraindicated or high-bleeding-risk settings. However, a third of patients received prasugrel for off-label non-ACS indications that lack efficacy data.

Self-reported indications for antidepressant use in a population-based cohort of middle-aged and elderly.

Background Population-based studies investigating indications for antidepressant prescribing mostly rely on diagnoses from general practitioners. However, diagnostic codes might be incomplete and drugs may be prescribed ‘off-label’ for indications not investigated in clinical trials. Objective We aimed to study indications for antidepressant use based on self-report. Also, we studied the presence of depressive symptoms associated with the self-reported indications. Setting Our study population of antidepressant users was selected based on interview data between 1997 and 2013 from the prospective population-based Rotterdam Study cohort (age >45 years). Method Antidepressant use, self-reported indication for use, and presence of depressive symptoms (Center for Epidemiological Studies Depression Scale) were based on interview. Self-reported indications were categorized by the researchers into officially approved, clinically-accepted and commonly mentioned off-label indications. Main outcome measures A score of 16 and higher on the Center for Epidemiological Studies Depression Scale was considered as indicator for clinically-relevant depressive symptoms. Results The majority of 914 antidepressant users reported ‘depression’ (52.4 %) as indication for treatment. Furthermore, anxiety, stress and sleep disorders were reported in selective serotonin reuptake inhibitor and other antidepressant users (ranging from 5.9 to 13.3 %). The indication ‘pain’ was commonly mentioned by tricyclic antidepressant users (19.0 %). Indications were statistically significantly associated with higher depressive symptom scores when compared to non-users (n = 10,979). Conclusions Depression was the main indication for antidepressant treatment. However, our findings suggest that antidepressants are also used for off-label indications, subthreshold disorders and complex situations, which were all associated with clinically-relevant depressive symptoms in the middle-aged and elderly population.

R05 - Off-label drugs use in home care: a non evidence-based established practice

Background: Advanced cancer patients (pts) experience many different symptoms and the use of drugs in off-label indications, doses, formulations and administration route is a common practice in this setting. Drugs mixture (DM) solutions by continuous administration are frequently utilized. However, evidence-based data on the use of off-label drugs in this patients subset is scarce. Patients and methods: A retrospecitive analysis of 484 consecutive assistential pathways provided by our Home Care Service from July 2010 to April 2016 was performed. Elastomeric pumps (5 days - 2 ml/h) with drugs diluited in 0.9% NaCl without protection from light were used. Infusions were administreted subcutaneously (sc) or by a central venous (iv) access. Analysis was performed on: treated symptoms, drugs, doses and concentrations, solution transparency, adminitration route, infusion duration, clinical response, adverse events (AEs), compliance and treatment acceptability, device proper functioning and treatment interruptions. Results: 226 pts/484 pathways (47%) treated with DM infusions were identified, M/F 121/105, median age 70 yrs (range 21-92), treated symptoms were pain (50%), nausea/vomiting (20%), dyspnea/agitation (20%), dysphagia/mucositis (18%). Most of pts had >1 symptom. Infused drugs included morphine, midazolam, dexamethasone, ranitidine, metoclopramide, scopolamine, alizapride, haloperidol, furosemide and ketorolac. The median number of drugs in the DM was 3 (range 1-6). The administration route was sc in 174 pts (77%), iv in 52 pts (23%). Median/mean infusion duration was 5/9.6 days (range 0-64). Symptom control was archieved within 72 hours in 69% of pts. No AEs related to the infusion devices were observed. Compliance was good in 92% of pts, poor/inadequate in 8%. 4 elastomeric pumps malfunctions were observed: 1 human error, 1 device obstruction due to furosemide flocculation, 2 unexplained. Also, 2 pts required sc infusion interruption due to fluid accumulation near the injection site. Conclusions: This retroscpective analysis showed efficacy and tolerability of DM administration by elastomeric pumps in the home care setting. Treatment compliance were high. No AEs were observed, pump malfuncion and therapy discontinuation were rare. However, there are still many open questions about the off-label use of drugs in this setting. Prospective trials are strongly suggested.