Off-label use

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OFF LABEL USE OF MEDICINES IN CHILDREN

OFF LABEL USE OF MEDICINES IN CHILDREN

ABSTRACT: Although plenty of information relating to drug utilization among adults is available, the literature pertaining to children is scarce. The majority of drugs prescribed have not been tested in children and safety and efficacy of children‘s medicines are frequently supported by low quality of evidence. This is explained by the lack of clinical research in this population, caused by ethical, scientific and technical issues, besides commercial priorities. Therefore, most of the therapies prescribed to children are on an off- label or unlicensed basis. The off-label and unlicensed use of medicines is widespread and variable depending on the level of health care available, speciality concerned and patient characteristics. In the recent years, various laws and guidelines from the competent authorities have come up regulating the drug use and clinical research among children. This article reviews various pros and cons of the off- label use of medicines in children including various types, incidence rates, reasons, risks, consequences, management modalities, national and international guidelines related to the same.
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Off Label Use of Drug in Pediatrics: A Systematic Review

Off Label Use of Drug in Pediatrics: A Systematic Review

In the investigation of justification grounded in high quality for a prescription off label, the health professional must reconcile clinical experience from careful clinical observations and external evidence. It is essential, therefore, discern reliable sources of research, ethical and free from conflicts of interest, which excludes any information from the producer of medicines that have commercial interests in the product that often outshines the duty to inform correctly and scientifically. With the analysis of the articles that composed the present work clearly shows the high prevalence of off-label use and unlicesed of drugs in our midst, showing different prescribing habits in pediatrics and show classes of drugs that require regulation and incentives for research to guarantee safety and efficacy, thereby contributing to the promotion of rational use of medicines.
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Ethical and legal framework and regulation for off-label use: European perspective

Ethical and legal framework and regulation for off-label use: European perspective

took different paths to handle the problem and to moderate its negative effects. Due to the dependency of a country’s off- label situation on the national drug regulation (a drug may have a different authorization status in different countries) it is necessary for the different countries to find a national solution, especially in the areas of pharmaceutical law and health insurance law. Our overview shows that there are mainly two kinds of solutions which can be implemented as an interim arrangement. Firstly, a consensus list of accepted off-label uses, backed up by scientific evidence, would at least partly relieve the work of physicians in the field. Such a list could also be administered by the EMA with scientific support from the different European member states. The second solution, as practiced in France, is the evaluation and approval of specific off-label uses by an official expert group. Both solutions would have, from our point of view, the effect of helping physicians handle the ethical and legal paradoxes associated with the off-label use of drugs. At the same time, this would probably lead to a more safe and homogeneous medical supply for the concerned patients. For European citizens, a harmonized approach would presumably be of even greater value. Therefore, a discussion should be initi- ated at the European level to address which measures could be adopted to realize a direct improvement of the current off-label drug use situation.
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Off Label Use of Drugs and Devices in the Neuroendovascular Suite

Off Label Use of Drugs and Devices in the Neuroendovascular Suite

SUMMARY: The off-label use of drugs and devices in neuroendovascular procedures is common. Neurointerventionalists should be well aware of the level of evidence available in support of the off-label use of drugs and devices in their practice and some of the potential adverse events associated with them. These uses are categorized as I or II if they have been evaluated as primary or ancillary interventions in prospective trials/registries of neuroendovascular procedures and III if they were evaluated in case series. Category IV use is based on evaluation as primary or ancillary interventions in prospective trials/registries of non-neuroendovascular procedures. Physicians are allowed to use off-label drugs and procedures if there is strong evidence that they are beneficial for the patient. The neurointerventional professional societies agree that off-label use of drugs and devices is an important part of the specialty, but practicing providers should base their decisions on sound evidence when using such drugs and devices.
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OFF LABEL USE OF ANTIBACTERIALS IN A CONTEXT OF ANTIMICROBIAL RESISTANCE THREAT

OFF LABEL USE OF ANTIBACTERIALS IN A CONTEXT OF ANTIMICROBIAL RESISTANCE THREAT

In a prospective cohort [17], it has been found that adverse drug events are more frequent in situations where the use is not based on scientific evidence. Our data allow us to emphasize that use without this evidence is not uncommon, and AMD use control policies (antimicrobial stewardship program) must be formulated and conducted by specialists, including physicians, pharmacists, microbiologists, and nurses [4,5]. Pharmacists play a key role in drug use studies due to their expertise in the area of pharmaceutical care, such as minimizing toxicity and other adverse events, reducing the costs of health care for infections, limiting the selection of antimicrobial resistant strains and ensuring patient safety [4,28]. The off-label use was more frequently associated with males and the surgical and orthopedic clinic as a location of hospitalization. In Brazil, surgical site infections comprised 14%–16% of infections in hospitalized patients and are the second or third most frequent infection among all infections in health-care services [29,30], and the hospital is a reference in urgency and emergency and is accredited by the Ministry of Health for High Complexity Services in Traumatology and Orthopedics. Due to the experimental use, the prevalence of off- label prescription of extended-spectrum antimicrobials could be a reasonable indication for this association.
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Off-label use in germany - a current appraisal of gynaecologic university departments

Off-label use in germany - a current appraisal of gynaecologic university departments

Physicians desire the autonomy to prescribe drugs that match individual patient needs regardless of label, but they face difficulties staying abreast of rapidly evolving evidence. More education to legal status in using off-label drugs (actually only 17% engaged juris- tic advice) and cost coverage is necessary. the increas- ing consolidated medical findings and complexity of law as concentrated allocation-conflicts of the health care system will intensify the complexity of problems with the open questions of the off-label use in the fu- ture. to be a physician will require basic knowledge in social law and health care policy. a limitation of pure medicine won`t be possible, and would no longer be affordable in future [30].
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Implementation of Rotavirus Immunization in Philadelphia, Pennsylvania: High Levels of Vaccine Ineligibility and Off-Label Use

Implementation of Rotavirus Immunization in Philadelphia, Pennsylvania: High Levels of Vaccine Ineligibility and Off-Label Use

age limits of the PRV, may partially explain this phe- nomenon. The recommended age limits for PRV are novel in at least 2 aspects. First, few vaccines have an upper age limit for their initiation, and in the case of PRV, the upper limit (12 weeks) for initiation falls even earlier than the “on-time” benchmark for regular in- fancy immunizations such as DTaP (3 months [ie, 13 weeks]). Second, PRV is the only vaccine with age limits for recommended use counted in weeks. If this had been the primary source of confusion, however, one would expect that most of the off-label use would have oc- curred between the 12th and 13th week of age. Most off-label use of the first PRV dose occurred at the age of ⬎ 4 months (Fig 2), usually concurrently with a DTaP dose (generally not the first DTaP dose), which suggests a lack of knowledge about the guidelines for use of PRV by the providers. It is possible that unavailability of PRV in some practices during the early days of its implemen- tation in Philadelphia was responsible for a proportion of the off-label use, and this fraction of the off-label use could presumably disappear with unimpeded availability of PRV in the future. Because all Philadelphia hospital clinics are part of academic centers, it is likely that edu- cation and awareness of restrictions early in the imple- mentation of PRV explain the lesser amount of off-label use found for the hospital-based providers. In contrast to our finding that most DTaP doses were administered in private settings, the majority of PRV doses were given by hospital-based providers, which underscores the impor- tant role that academic centers can play in the imple- mentation of new vaccines in the community.
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Off-Label Use of Recombinant Factor VIIa in Pediatric Patients

Off-Label Use of Recombinant Factor VIIa in Pediatric Patients

This study describes the largest case series of off-label use of rFVIIa in pe- diatric patients that has been reported to date, from a well-designed, repre- sentative, and rigorously audited reg- istry. The main fi nding of the study was a signi fi cant reduction in blood product administration in the 24 hours after rFVIIa administration. The most frequent indication for rFVIIa use in our series was to control hemorrhage after cardiac and other surgical procedures. The occur- rence of TEAs was not associated with the dose or number of doses of rFVIIa. The reduction in blood product admini- stration is consistent with reports from observational studies that have demonstrated reduction in blood pro- duct requirements in pediatric patients treated with rFVIIa for uncontrolled hemorrhage 8,16,17 and studies in surgical
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Off-Label Use of Inhaled Nitric Oxide After Release of NIH Consensus Statement

Off-Label Use of Inhaled Nitric Oxide After Release of NIH Consensus Statement

these infants were treated at the same rate and average duration as the above PMG cohort (2.63%, 7.48 days per treated patient), the estimated total cost to US health care would be ∼ $153 million for off-label use. The accuracy of this estimate is uncertain, however, given that some hospitals pay for hourly usage of iNO, whereas others pay an up-front cost for

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Pediatric Off-label Use of Recombinant Factor VIIa

Pediatric Off-label Use of Recombinant Factor VIIa

METHODS. This was a retrospective case series in a tertiary pediatric referral hospital. RESULTS. During 1999 –2006, 135 patients received recombinant factor VIIa for off- label use. The median number of doses was 2; the median dose was 88 ␮ g/kg. The most common diagnoses among patients receiving recombinant factor VIIa were disseminated intravascular coagulation/sepsis (28), surgical bleeding (19), proce- dural prophylaxis (16), and trauma (15). The median volume of blood products administered 24 hours before recombinant factor VIIa treatment was 29.7 vs 11.7 mL/kg 24 hours after treatment. Only 1 high-risk patient had significant bleeding after receiving prophylactic recombinant factor VIIa before an invasive procedure. Nonsurvivors had significantly increased incidence of multiple organ dysfunction syndrome (75%) compared with survivors (23%). The largest group of patients (n ⫽ 28) received recombinant factor VIIa for bleeding and/or coagulopathy because of disseminated intravascular coagulation; the mortality in this group was 26 (93%) of 28. Eleven patients received multiple doses of recombinant factor VIIa to treat bleeding complications after hematopoietic stem cell transplant, without improve- ment in blood use. Mortality in medical patients was 58% vs 16% in surgical patients. Three patients had significant thrombotic adverse events after receiving recombinant factor VIIa, resulting in 2 deaths and 1 leg amputation.
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Off-Label Use of Medical Devices in Children

Off-Label Use of Medical Devices in Children

Despite widespread therapeutic needs, the majority of medical and surgical devices used in children do not have approval or clearance from the Food and Drug Administration (FDA) for use in pediatric populations. The clinical need for devices to diagnose and treat diseases or conditions occurring in children has led to the widespread and necessary practice in pediatric medicine and surgery of using approved devices for “off-label” or “physician- directed” applications that are not included in FDA-approved labeling. This practice is common and often appropriate, even with the highest-risk (class III) devices. The legal and regulatory framework used by the FDA for devices is complex, and economic or market barriers to medical and surgical device development for children are signifi cant. Given the need for pediatric medical and surgical devices and the challenges to pediatric device development, off-label use is a necessary and appropriate part of care. In addition, because of the relatively uncommon nature of pediatric conditions, FDA clearance or approval often requires other regulatory pathways (eg, Humanitarian Device Exemption), which can cause confusion among pediatricians and payers about whether a specifi c use, even of an approved device, is considered experimental. This policy statement describes the appropriateness of off-label use of devices in children; the use of devices approved or cleared through the FDA regulatory processes, including through the Humanitarian Device Exemption; and the important need to increase pediatric device labeling information for all devices and especially those that pose the highest risk to children.
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Off-label use of orphan medicinal products: a Belgian qualitative study

Off-label use of orphan medicinal products: a Belgian qualitative study

Even though the extent of off-label use of OMPs appears to be significant; Kesselheim et al. found that in a sample of four top-selling orphan medicinal products, three orphan medicinal products were used more com- monly for non-orphan indications; the reasons behind off-label prescribing of medicinal products for rare disease patients are yet to be fully understood [6]. Therefore, the aim of this study was to map off-label use of OMPs in Belgium in terms of attitude towards off- label prescribing, factors influencing off-label prescrib- ing, disclosure of information towards the patient, reporting of off-label use, risks and consequences. This study is based on the work of five pharmacy students in the context of their Master theses at KU Leuven [9]. Mapping out these issues is a first step in achieving a more systematic approach for appropriate off-label prescribing.
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Off-Label Use of Drugs in Children

Off-Label Use of Drugs in Children

holds an investigational new drug application and that both takes re- sponsibility for and initiates a clinical investigation. The sponsor may be an individual or pharmaceutical company, governmental agency, academic in- stitution, private organization, or other organization. A sponsor does not ac- tually conduct the investigation unless the sponsor is a sponsor-investigator. A person other than an individual who uses 1 or more of his or her own em- ployees to conduct an investigation that he or she has initiated is considered to be a sponsor, not a sponsor-investigator. In this case, the employees are inves- tigators. Sponsor-investigators both initiate and conduct an investigation and direct the administration or dis- pensing of the investigational drug. The requirements applicable to a sponsor- investigator include both those applica- ble to an investigator and a sponsor. It is important to note that sponsors are not allowed to promote or even speak to off- label use. If a physician speaks on behalf of a sponsor, the same rule applies. It is acceptable to use drugs off label and to publish results related to off-label use, but it is not acceptable to receive re- muneration from the sponsor for these uses.
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OFF LABEL USE OF DRUGS AMONG CHILDREN AND ITS IMPLICATIONS IN A TERTIARY CARE HOSPITAL IN NORTH INDIA

OFF LABEL USE OF DRUGS AMONG CHILDREN AND ITS IMPLICATIONS IN A TERTIARY CARE HOSPITAL IN NORTH INDIA

and 7(39%) did not receive any off-label drug. In this 60% of the total 120 patients had received atleast one off-label drug which is similar to the frequency of off-label use in patients with adverse drug reaction. An increased risk of adverse drug events could not be established on the basis of these findings from this study. Unexpectedly, this was in contrast to other studies where incidence of off-label drug was more among those patients who experienced an adverse drug reaction as reported in a study from Europe. [38] Among the serious adverse events 2 were associated with off-label use of drugs on the basis of dose and 2 were observed with onlabel drugs. This indicates that serious adverse events may be more common with off-label use of drugs as off-label drugs were prescribed in lesser number compared to onlabel drugs. The results from this study could not establish the association of adverse drug reaction nor could it disapprove the association. The reason could be small sample size of the study and difference in the demographic and diagnostic profile of the patients. In most of the studies which have shown a higher incidence of adverse drug reaction with off-label use had off-label use for a different indication while in our study the most common reason for off-label use was for a different dose and age. [39]
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The Off-Label Use of Consumer Credit Ratings

The Off-Label Use of Consumer Credit Ratings

The increasing versatility of credit ratings is yet another sign of the growing role of finance in modern life (Deutschmann 2011). Financialization, the term often used to describe the way society becomes dominated by finance, spawned a large literature devoted to documenting the swelling of the relative size of the financial industry (Krippner 2011), the increasing influence of financial mar- kets in the governance of non-finance companies (Fligstein 1990, 2008; Dob- bin and Zorn 2005), and the various ways households become directly depend- ent on the financial world, either by means of indebtedness or by investing their savings in financial instruments (Sullivan et al. 2000; Hyman 2011; Harrington 2008; Keister 2000; Frank 2000). All of these, at different levels, testify to the expansion of finance, the pushing of its boundaries to encompass larger and larger segments of the social world. Throughout this expansion, finance lays claims to new territories by redefining old problems as those of the flow of money that then must be addressed by the logic and tools of finance. As finan- cialization is moving forward, many of its instruments, developed in the specif- ic context of a particular financial transaction come to be utilized for novel purposes, outside their original context. In this paper, I will focus on credit ratings, a tool developed for credit transactions. When credit ratings are used in new ways outside the context of credit granting, I call it off-label use.
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Off-label use and harmful potential of drugs in a NICU in Brazil: A descriptive study

Off-label use and harmful potential of drugs in a NICU in Brazil: A descriptive study

This paper presents a detailed analysis of drug use in a NICU in Brazil, and it is a pioneer study in the country in this aspect. While the number of observations of clinical records considered here is high, it has limitations in terms of the external validity. Primarily, because of the descriptive methodology of a wide range of newborn categories, diseases and drugs. Also, due to the retro- spective character of the study, an important amount of clinical files were excluded due to incomplete data. Finally, it is based on a single NICU; even though a reference facility in the public health system in the Federal District, and covering a large population with a general profile of attendance. The conditions that led to hospitalization were similar to those seen in other NICUs in Brazil [14] and in other countries [16, 30], among which jaundice, sepsis, anemia and hyaline membrane disease were the most prevalent [31]. The length of hospital stay and the number of drugs were greater than found in other studies [16, 30], but lower than reported in preterm neonates admitted to an NICU in Germany (11.1 drugs/patient) [2], and in the USA (11.8 drugs/ patient) [32].
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PRE- AND POST-MARKETING PHARMACOVIGILANCE: THE MYTHS OF THE PLACEBO EFFECTS AND OF THE OFF-LABEL USE OF DRUGS

PRE- AND POST-MARKETING PHARMACOVIGILANCE: THE MYTHS OF THE PLACEBO EFFECTS AND OF THE OFF-LABEL USE OF DRUGS

The difficulties in accepting the current practice, that can however be improved, of the degree of quality of biological and clinical experiments, which is accepted to be independent of the peer review process (unfortunately rarely conducted in a double-blind fashion), have been discussed repeatedly [26]. The problem of the selection of "normal volunteers" for human studies, "a perfect allegory of our time", is also an object of destructing, suicidal mirth [27]. The question can easily be extended to the experimenters, who are sometimes surreptitiously recruited by the sponsors, specialist practitioners, belonging to the traditional bandwagon of the never too faithful. Here we merely note that the reviews that allow registered drugs to be kept in use, a necessary process, especially in the period immediately following release for sale, which is an increasingly globalised affair (Cf.: PPM-PV in phases IIIa and IVa) – are too often postponed, so much so as to be not systematically performed. The same American regulatory transparency, reduced by back-staging, can be unreliable [28]; in addition, professional observational alarms, ignored unless that are raised by well-established statisticians [29], with data that do not reach the required level of significance, either favourable or adverse, that are not reused to avoid waste, not only of a financial nature [30]; "innovative" products that are proved to be neither new nor useful [31]; general qualities of poor research [32], too often highlighted with great delay or supported with cost motives that belong to the myth of faceless, evanescent "distributed responsibility" [33]. Groups of ethics experimenters are formed that can be modified with changes in the political climate (from neuroethics [34], but also [23, 22, 1] and, below, [38] to neuro marketing it is a short distance), with influences that are far from invisible if sought attentively even if sporadically, with recruitment of well-paid direct and indirect financial promoters, whose independence cannot seriously be sustained (Cf: "inherent counting and accountability"). The free-market system of industrialised countries, a subject of PTS economics, has far from shied away from capitalists, as considered essential by Rajan & Zingales [35], which is shocking when riches can be made from pain and sickness. Here unfortunately the available documentation is shameful, and that facts can still be learnt should not be reassuring [36], because this is already part of the intolerably cynical multiple models of experienced games.
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Off-label use of common predictive biomarkers in gastrointestinal malignancies: a critical appraisal

Off-label use of common predictive biomarkers in gastrointestinal malignancies: a critical appraisal

The use of immunohistochemistry (IHC) as a companion diagnostic is an increasingly important part of the case workup by pathologists and is often central to clinical decision making. New predictive molecular markers are constantly sought for to improve treatment stratification parallel to drug development. Unfortunately, official biomarker guidelines lag behind, and pathologists are often left hesitating when medical oncologists request off- labelled biomarker testing. We performed a literature review of five commonly requested off-label IHC predictive biomarkers in gastrointestinal tract (GIT) malignancies: HER2, mismatch repair (MMR), PD-L1, BRAF V600E and ROS1. We found that HER2 amplification is rare and poorly associated to IHC overexpression in extracolonic and
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A review of the off-label use of selamectin (Stronghold®/Revolution®) in dogs and cats

A review of the off-label use of selamectin (Stronghold®/Revolution®) in dogs and cats

Eight cats naturally infested with the harvest mite Neo- trombicula autumnalis were treated with selamectin at 6 mg/kg and two days later the clinical signs associated with the infection had subsided and all mites were dead [24]. Demodex spp. are tiny, "cigar-shaped" mites which live in the hair follicles and sebaceous glands of mammals. Most infections are not associated with any clinical disease and it is not until much larger than normal populations infest the host, probably due to genetic characteristics or immu- nodeficiency of the host or to concomitant disease, that clinical manifestation of the infestation occurs [25]. In localised infestations on dogs, circumscribed areas of ery- thema and alopecia appear typically around eyes, mouth and on the forelegs; infestations which remain thus local- ised may self-cure [25] making it difficult to evaluate time efficacy of a product against localised infestations. How- ever, the infestation may become persistent and general- ised, with the hair becoming sparse over multiple areas of the body or feet, and in these cases the response to treat- ment may be poor. Attempts have been made to treat the generalised form of canine demodicosis with selamectin, applied both as recommended on the label and more fre- quently than recommended, applied to the recommended application site or directly to the visible lesions, but with- out success [26]. No improvement was seen in a Japanese Chin with generalised demodicosis which had previously proved unresponsive to ivermectin therapy when treated with selamectin once daily for two weeks at 30 mg/kg [27].
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An online survey of Australian physicians reported practice with the off-label use of nebulised frusemide

An online survey of Australian physicians reported practice with the off-label use of nebulised frusemide

The survey ascertained the basic demographics related to medical specialty, highest palliative care qualification and length of time working in palliative care. Respondents were then asked if they had prescribed nebulised frusemide in the previous 12 months. For those who had prescribed nebulised frusemide, they were asked a series of questions relating to their opinion of efficacy and prescribing practice of nebulised frusemide. To establish in more detail the use and perceived efficacy of nebulised frusemide, those who had prescribed nebulised frusemide were given the option to describe (basic demographics, diagnosis, co- morbidities, treatments previously used for breathlessness, and any agents co-prescribed and the impression of the efficacy) for two cases where they had prescribed nebulised frusemide. If respondents had not prescribed nebulised frusemide in the previous 12 months, they were asked the main reason why they had not prescribed it. Ethics approval was received from Curtin University (SON&M 12-2010). Data are reported as number (percentage) unless otherwise specified.
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