Off-label Drug Research Articles

Aligning quality of life and guidelines for off-label psychotropic drugs in adults with intellectual disabilities and challenging behaviour

Introduction Adults with intellectual disabilities have an increased vulnerability to mental health problems and challenging behaviour. In addition to psychotherapeutic or psychoeducational methods, off-label pharmacotherapy, is a commonly used treatment modality. Objective The aim of this study was to establish evidence-based guideline recommendations for the responsible prescription of off-label psychotropic drugs, in relation to Quality of Life (QoL). Method A list of guidelines was selected, and principles were established based on international literature, guideline review and expert evaluation. The Delphi method was used to achieve consensus about guideline recommendations among a 58-member international multidisciplinary expert Delphi panel. Thirty-three statements were rated on a 5-point Likert-scale, ranging from totally disagree to totally agree, in consecutive Delphi rounds. When at least 70% of the participants agreed (score equal or higher than 4), a statement was accepted . Statements without a consensus were adjusted between consecutive Delphi rounds based on feedback from the Delphi panel. Results Consensus was reached on 4 general:the importance of non-pharmaceutical treatments, comprehensive diagnostics and multidisciplinary treatment. Consensus was reached in 4 rounds on 29 statements. No consensus was reached on 4 statements concerning: freedom-restricting measures, the treatment plan, the evaluation of the treatment plan, and the informed consent. Conclusion The study led to recommendations and principles for the responsible prescription – aligned with the QoL perspective – of off-label psychotropic drugs for adults with intellectual disabilities and challenging behaviour. Extensive discussion is needed regarding the issues on which there was no consensus to furthering the ongoing development of this guideline.

Penggunaan obat off-label pada pasien anak di salah satu rumah sakit daerah Provinsi Nusa Tenggara Barat tahun 2017

Due to insufficient pharmacokinetic-pharmacodynamic data, off-label medication usage in children is commonly observed. It might result in Drug Related Problems (DRPs) that could lead to morbidity in youngsters. In one of West Nusa Tenggara Province's public hospitals, this study sought to gain a general understanding of pediatric patients between the ages of 4 and 14 who were using off-label medications. Retrospective descriptive methodology is used in this investigation. For each of the following categories: age, indication, contraindication, dosage, and method of administration, the percentage of off-label drug use was calculatedbased on medical records and literature reviews. Out of 302 medications prescribed to outpatients, 14 (4.63%) and 5 (1.65%) were off-label for the patient's age, and indication categories were determined.Regarding inpatients, out of 369 medicines, the categories for age, indication, and dose, respectively, indicated 7.85% (29), 1.08% (4), and 2.43% (9) off-labels. Both pediatric inpatient and outpatient patients were found to be using drugs off-label. To ascertain the impact of off-label pharmacological advantages on the efficacy of drug therapy, more research is required.

The Use of Off-label and Unlicensed Drugs for Neonates: A Report from a Teaching Hospital in Baghdad

Background: Neonates who are admitted to hospitals will need various drugs. The use of unlicensed or off-label drugs without scientific evidence makes this exposure unsafe. Aim of study: We aimed to assess the use of drugs for neonates based on the British National Formulary for Children and IBM Micromedex Neofax. Patients and methods: This is a descriptive study which reviewed the clinical files of enrolled neonates who have stayed in the hospital for more than 24 hours and received at least one drug. It was conducted in the neonatal care unit of the Children Welfare Teaching Hospital/ Medical City Complex in Baghdad during the period from 1st of January to 30th of June/2018. The data was entered on a predesigned format and analyzed by using the appropriate statistical methods. Results: A total number of 1079 neonates were admitted to the NCU during the study period, of whom 967 were included in the current study with 597 (61.7%) males and 370 (38.3%) females. There were 424 (43.8%) preterm, 496 (51.3%) term and post term neonates, and 47 (4.9%) neonates with unknown gestational age. Different classes of drugs were used with a total of 56 drugs, of which 33.9% were unlicensed and 66.1% were off-label. Accordingly, 42.5% of the neonates received unlicensed drugs and almost all patients received at least one off-label drug. Major risk factors for such use include mechanical ventilation, male sex and prolonged hospitalization. Conclusions: In hospitalized neonates, drugs were more frequently prescribed as an off-label rather than unlicensed. Almost all neonates were exposed to off-label formulations.

Use of off-label drugs in the neonatal intensive care unit in India

Background: Off-label use of drugs is widespread in pediatrics and almost all neonates hospitalized in NICU are affected by the use of off-label drugs regardless of gestational age and birth weight. This is because of the lack of regulation for medications in the neonatal population and the delays in updating drug instructions. This is mainly due to the ethical difficulty in the research and difficulties in conducting clinical trials in this vulnerable population. Hence, the study was planned to assess the extent of the use of off-label drugs in the NICU. Methods: An observational study was carried out in the NICU of a tertiary care center from May 2021 to Oct 2022 and case records of neonates admitted to the NICU were evaluated. Results: Among 1745 drug prescriptions in 360 neonates, 1208 (69.22%) were off-label. Anti-infectives were the most commonly used off-label class of drug, Piperacillin+tazobactam was the most commonly used off-label drug and most common reason for off-label prescriptions was indication and administration. It was found that 79.44% of neonates received at least one off-label drug. Conclusions: Off-label use of drugs, specifically anti-infective drugs, is common in NICUs of India as in other countries. So, more research should be done to generate evidence-based guidelines for the rational use of drugs in neonates.

Differential Diagnosis, Prevention, and Treatment of mpox (Monkeypox): A Review for Dermatologists.

The current 2022 mpox (monkeypox) outbreak has been officially recognized as a public health emergency. The mpox clinical symptoms include high fever, fatigue, chills, headache, swollen lymph nodes, muscle aches, and a disseminated painful rash. However, recent cases of mpox have shown a shift in clinical symptoms, with anogenital skin lesions emerging as the predominant feature. Due to the predominant skin manifestations of mpox, dermatologists could be crucial in detecting new mpox cases and educating frontline healthcare professionals about mpox. The mpox virus is continuously evolving and has several variants. Genome sequencing has revealed that the Clade IIb variant is responsible for the 2022 mpox outbreak. Mpox spread may occur through animal-to-human and human-to-human transmission; however, unlike coronavirus disease 2019 (COVID-19), long-range airborne transmission has not been reported. Healthcare professionals are at higher risk of becoming infected since they are usually in close contact with both the patients and potentially contaminated fomites (e.g., examination table, gowns, gloves). Both public and healthcare professionals should take preventive and avoidance measures to limit the spread. Mpox is usually self-limiting and may require only symptomatic treatment; however, it may cause severe complications in special populations such as immunocompromised individuals. For severe infection, clinicians may consider antiviral drugs (off-label), tecovirimat and brincidofovir, originally approved for smallpox treatment. Two smallpox vaccines, ACAM2000® and JYNNEOSTM, can be used as pre-exposure prophylaxis against mpox. JYNNEOSTM, which carries approval for mpox use, has less adverse effect potential than ACAM2000®, and may also be used as post-exposure prophylaxis, preferably within 4 days of exposure.

Korean Brain Tumor Society Consensus Review for the Practical Recommendations on Glioma Management in Korea.

Recent updates in genomic-integrated glioma classification have caused confusion in current clinical practice, as management protocols and health insurance systems are based on evidence from previous diagnostic classifications. The Korean Brain Tumor Society conducted an electronic questionnaire for society members, asking for their ideas on risk group categorization and preferred treatment for each individual diagnosis listed in the new World Health Organization (WHO) classification of gliomas. Additionally, the current off-label drug use (OLDU) protocols for glioma management approved by the Health Insurance Review and Assessment Service (HIRA) in Korea were investigated. A total of 24 responses were collected from 20 major institutes in Korea. A consensus was reached on the dichotomic definition of risk groups for glioma prognosis, using age, performance status, and extent of resection. In selecting management protocols, there was general consistency in decisions according to the WHO grade and the risk group, regardless of the individual diagnosis. As of December 2022, there were 22 OLDU protocols available for the management of gliomas in Korea. The consensus and available options described in this report will be temporarily helpful until there is an accumulation of evidence for effective management under the new classification system for gliomas.

Use of off-label drugs and the prevalence of adverse reaction to drugs in the adult intensive care unit of a Brazilian public hospital

Objective: To Identify the occurrence of adverse reactions to medications (ADR) in patients using off-label prescriptions admitted in an adult intensive care unit (ICU). Methods: Cross-sectional and prospective study evaluated the use of off-label medications and the appearance of ADR in an adult clinical ICU of a Brazilian hospital from March to Aug/2018. The prescriptions were classified as label, off-label, and unlicensed, and the NARANJO algorithm assessed ADR occurrence. The suspected cases of ADR were separated into label and off-label. Results: The prevalence of off-label use was 73.0%, with 73.9% prescribed after admission to the ICU. Regarding the category of off-label use, 23.6% were due to the volume of the diluent. The predominant drug classification was systemic antimicrobials, accounting for 16.8%. The PHD represented 68.7% of the off-label medicines. Sixty suspected ADR were identified in 26 patients registered with suspected ADRs, from that 85.0% resulted from the use of off-label medications. The most prevalent reactions were classified as probable (81.7%), and diarrhoea was the most frequent symptom. There was a significant association between the use of off-label drugs, PHD prescriptions, and the occurrence of ADR (p <0.05).Conclusion: The findings showed that the event of ADR was higher among off-label drugs and PHD prescriptions.

Judicial and legislative practice and related suggestions on off-label drug use in China

BackgroundOff-label drug use exists widely in medical practice and is also an area which easily triggers controversy between patients and medical institutions. Previous studies have identified the reasons why off-label drug use long exists. However, there is no multidimensional analysis on real judicial precedents about off-label drug use. This study aimed to investigate the dispute points on off-label drug use based on real cases in China, and proposed suggestions based on newly-leased Physicians Law.MethodsOur study is a retrospective study with all the 35 judicial precedents on off-label drug use extracted from China Judgments Online from 2014 to 2019. This study mainly used the methods of statistical analysis, inferential analysis, exemplification, literature summarization and comparative analysis.ResultsAccording to the analysis of the 35 precedents of jurisdictions from 11 different aspects, it can be seen that the second-instance and retrial rates of this kind of cases are high, and the disputes between patients and medical institutions are fierce. In judicial practice of off-label drug use, medical institutions are determined whether to bear civil liability according to the constituent elements of medical tort liability: the rate of medical institutions’ bearing liability for off-label drug use is not high, and medical institutions are not directly identified as infringing acts and they don’t bear tort liability. The clear provisions about off-label drug use in Law of the People’s Republic of China on Physicians which was implemented in March 2022 confirm this at the legislative level.ConclusionsBy analyzing the current judicial practice of China’s off-label drug use cases, and summarizing the dispute points between medical institution and patients, the constituent elements of tort liability, and the rules of evidence etc., suggestions are proposed to further regulate off-label drug use and promote safe and rational drug use.

ИСПОЛЬЗОВАНИЕ ГУМАНИЗИРОВАННЫХ МОНОКЛОНАЛЬНЫХ АНТИТЕЛ OFF-LABEL В ПЕДИАТРИЧЕСКОЙ ПРАКТИКЕ

In recent years, the use of off-label drugs (the use of drugs for indications not approved by state regulatory bodies, and also not mentioned in the instructions for use) has become widespread in the pediatric population. For a long time, clinical trials in the pediatric population were considered difficult to conduct due to ethical issues, leading to frequent off-label drug use. Off-label drug use remains an important public health problem, especially in children with rare diseases or diseases not responding to standard treatment. The purpose of the review is to analyze foreign literature sources on the use of biological preparations outside the instructions. The use of drugs outside the instructions (off-label) is a topical issue in the clinical practice of doctors of various specialties, and this is especially in demand in pediatric practice. This is due to the fact that a registered drug may have a successful experience in adults, but at the same time not have official approval for use in children. The need to use drugs outside the instructions for use, as a rule, occurs in patients with severe, chronic, life-threatening pathology. Further studies analyzing their efficacy, safety, and cost-benefit ratio are needed to expand the use of biological therapy in the pediatric population.

Abstract P4-01-40: Real World Data with Off-Label Insurance Approval of Trastuzumab Deruxtecan in Metastatic Breast Cancer

Abstract Background: Trastuzumab deruxtecan (T-DXd) improves outcomes in HER2-positive, and recently in HER2-low (IHC 1+ or IHC 2+/ISH-) previously treated metastatic breast cancer (MBC) patients. OncoHealth is a digital health care company that leverages managed care-trained, board-certified oncologists and oncology pharmacists to review the appropriateness of prior authorization (PA) requests for cancer treatment regimens. Our objective was to examine the rate of off-label PA approvals for T-DXd in MBC. Methods: We performed a retrospective cross-sectional study of T-DXd PA approvals by OncoHealth for MBC patients between 1/17/2020 – 6/21/2022. Using medical records and utilization management data, we assessed the prevalence of PA approvals for T-DXd in HER2-low and HER2-positive MBC patients according to PA support at the time of approval, whether on-label, off-label NCCN compendium supported, off-label acceptable scientific literature-only (LIT) supported, or approved by clinical justification if off-label/off-NCCN or LIT. Results: We identified 156 patients with MBC with a PA approval for T-DXd. The median patient age range was 60-69 years, 85% had visceral disease, 28% had brain metastases, 93.6% had HER2-positive MBC and remaining were HER2-low MBC. The median line of T-DXd therapy was 6 (range, 1-15) for HER2-low and 3 (range, 1-10) for HER2-positive MBC. All HER2-low T-DXd cases were supported by LIT and approved prior to NCCN guidelines incorporation in 6/21/2022. Among HER2-positive MBC patients, 25% (37/146) of PA approvals were off-label. Of these, 57% (21/37) were supported by NCCN, and the remaining 43% (16/37) were approved off-label/off-NCCN or LIT. The majority of the off-label/off-NCCN or LIT cases (10/16) were approved by clinical judgement based on 2nd line HER2-positive MBC abstract data from DESTINY-Breast03 presented at ESMO on 9/19/21. Conclusions: All off-label PA approvals for T-DXd in HER2-low MBC occurred prior to NCCN’s incorporation, expanding access. One quarter of all T-DXd approvals in HER2-positive MBC were off-label. Leveraging managed care, board-certified oncology clinicians with knowledge of the latest cancer therapies and use of additional coverage determination resources such as NCCN and acceptable scientific literature can help expedite and expand access to off-label anti-cancer drugs that may be beneficial for cancer patients. Table 1: T-DXd Authorization Approvals Citation Format: Laura R. Bobolts, Mark Mangurian, Shanthi Marur, Corey Wise, Melissa Pozotrigo, Hiywete Solomon, Nicole Hartung, Meera Ravindranathan, Rory Makielski, Shika Marur, Andrew Toler. Real World Data with Off-Label Insurance Approval of Trastuzumab Deruxtecan in Metastatic Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-40.

EARLY ONSET AGGRESSIVE BEHAVIOR INDUCED BY PERAMPANEL IN THE TREATMENT OF CHRONIC INSOMNIA: A CASE REPORT

IntroductionChronic insomnia, resistant to different treatments (pharmacological, sleep hygiene and cognitive-behavioral therapy) remains one of the greatest challenges in our daily practice as psychiatrists. The pharmacological options include benzodiazepines and their analogues (zolpidem, zopiclone, etc.). However, when trying to treat chronic insomnia the use of off-label drugs, including antidepressants with sedative action (such as trazodone), antipsychotics or antiepiletic drugs, is not uncommon.Perampanel is a non-competitive AMPA receptor antagonist, marketed for the treatment of partial onset epilepsy and primary generalized tonic-clonic seizures. It has been used in the treatment of chronic insomnia with positive results and it has shown to improve the quality of sleep in a recent observational retrospective cohort study.The most frequent adverse effects of Perampanel include dizziness and drowsiness. Perampanel can also cause psychiatric and behavioral adverse effects, aggression and irritability in up to 10% of patients, as well as depression, and suicidal ideation, with higher rates in patients with psychiatric history.ObjectivesTo draw attention to possible adverse effects of Perampanel and to add knowledge to improve the treatment for chronic insomnia.MethodsCase report and non-systematic literature review of the current data.ResultsA 33 year old woman with Anorexia Nervosa was admitted to the psychiatric hospitalization unit due to suicidal ideation and a history of chronic insomnia. Perampanel was started at a dose of 2mg/day, progressively titrated to 6mg/day, following patient’s informed consent. A week after the initiation of treatment, her sleep pattern had improved but she became aggressive, showed low tolerability to minor frustrations and suffered from an intensification of suicidal ideation. She became extremely hostile to the personnel, had severe tantrums and deliberate self injurious behavior. Perampanel was discontinued and in less than a week her aggressive behavior succumbed. Although she was not re-exposed to Perampanel the symptoms she presented are considered a very likely adverse drug reaction. Levomepromazine 20mg/day and Lormetazepam 0.5mg/day were reinstated as a treatment for insomnia.ConclusionsPsychiatric comorbidity is known to be a risk factor for behavioral adverse effects of Perampanel. Therefore Perampanel as a treatment for chronic insomnia needs a careful individual benefit-risk assessment and monitoring for adverse effects.Disclosure of InterestNone Declared

Old Drugs, New Indications (Review)

Introduction. The drug can be used in the treatment of one disease and for the prevention and treatment of another pathological process. This is possible due to the repurposing of medicines. Creating drugs from scratch takes a long time to develop and implement, which leads to large financial costs, and also has a high dropout rate of candidate substances and requires significant financial costs. The main advantage of repurposing instead of creating new drug is relatively low financial costs and a significant reduction in the first two phases of clinical trials.Text. Drug repurposing is based on pharmacology, pharmacokinetics, pharmacodynamics, pharmaceuticals and clinical trials, where the first two phases are significantly reduced compared to the creation of a completely new. There are examples of successful repurposing and negative side effects with off-label drug use, which is unsafe but the best solution for orphan diseases. A targeted search for the possibility of repurposing drugs using an automatic procedure is being carried out, where a large number of chemical compounds are tested for activity or affinity for receptors and enzymes – high-throughput screening. Computer design has become widespread, which or repurposing "in silico", where information about the drug is used: targets, chemical structures, metabolic pathways, side effects, followed by the construction of appropriate models. Machine learning (ML) algorithms: Bayes classifier, logistic regression, support vector machine, decision tree, random forest and others are successfully used in biochemical pharmaceutical, toxicological research. But the most promising development of reprofiling is associated with the use of deep neural networks (DNN). Using deep learning, DNN were found to outperform other algorithms for drug development and toxicity prediction.Conclusion. Currently, interest in drug repurposing has grown markedly. A search for the keywords «drug repurposing» showed 2,422 articles on the problem of new uses for drugs that already exist in medicine.

Rapid Whole Genome Sequencing Diagnoses and Guides Treatment in Critically Ill Children in Belgium in Less than 40 Hours.

Rapid Whole Genome Sequencing (rWGS) represents a valuable exploration in critically ill pediatric patients. Early diagnosis allows care to be adjusted. We evaluated the feasibility, turnaround time (TAT), yield, and utility of rWGS in Belgium. Twenty-one unrelated critically ill patients were recruited from the neonatal intensive care units, the pediatric intensive care unit, and the neuropediatric unit, and offered rWGS as a first tier test. Libraries were prepared in the laboratory of human genetics of the University of Liège using Illumina DNA PCR-free protocol. Sequencing was performed on a NovaSeq 6000 in trio for 19 and in duo for two probands. The TAT was calculated from the sample reception to the validation of results. Clinical utility data were provided by treating physicians. A definite diagnosis was reached in twelve (57.5%) patients in 39.80 h on average (range: 37.05-43.7). An unsuspected diagnosis was identified in seven patients. rWGS guided care adjustments in diagnosed patients, including a gene therapy, an off-label drug trial and two condition-specific treatments. We successfully implemented the fastest rWGS platform in Europe and obtained one of the highest rWGS yields. This study establishes the path for a nationwide semi-centered rWGS network in Belgium.

Rectal use of levetiracetam: best practice report for a stepwise approach for sustainable off-label decision making and treatment

Off-label drug use is common practice in palliative care. It may pose a risk to the patient and benefit should outweigh harm. A decision and documentation aid for off-label use was developed to support practitioners in clinical practice off-label use. Using the example of the rectal administration of levetiracetam in three patient cases, the utilisation and benefits of the decision and documentation aid are presented and discussed. The rectal administration of levetiracetam clearly is an experimental treatment approach with little underlying evidence. To support and document the decision-making process for or against such an off-label use in clinical practice, it is helpful to have a structured approach in order to make this data comprehensible for a later point in time. Off-label use may be a permissible treatment alternative without underlying evidence, provided it takes place in a well-planned and well-monitored therapeutic setting and the benefits outweigh the potential risks.

Efficacy and safety of repeated low-dose rituximab therapy in relapsing-remitting multiple sclerosis: A retrospective case series study.

Rituximab (RTX) is an extensively used off-label drug for multiple sclerosis (MS), whereas the induction and maintenance regimens vary widely among studies. Few data are available on efficacy and safety of repeated low-dose RTX therapy in MS patients. This study aimed to evaluate the efficacy and safety of repeated low-dose RTX therapy for relapsing-remitting MS (RRMS), the most common form of MS affecting approximately 85% of patients. Nine RRMS patients were enrolled and the medical records were retrospectively reviewed. RTX at 100mg per week for three consecutive weeks was used as induction therapy. Maintenance therapy was reinfusions of RTX at 100mg every 6 months during the first year, followed by 100mg every 6 to 12 months. Main outcome measures included annualized relapse rate (ARR), expanded disability status scale (EDSS) score, and T2 lesion burden on MRI for evaluating the efficacy of low-dose RTX regimen. Meanwhile, adverse events (AEs) were recorded to assess the safety of repeated RTX infusions. All patients were females with an average onset age of 25.4±6.7 years. The median disease duration before the first RTX infusion was 56 (range, 3-108) months and the median follow-up period was 30 (range, 15-40) months. No relapses were recorded in all patients after RTX therapy. Repeated low-dose RTX therapy resulted in a dramatic reduction of median ARR (pre-RTX vs post-RTX, 1.1vs 0, p=0.012), median EDSS score (2.0vs 0, p=0.007), and the number of T2 lesions on MRI (35.6±18.0vs 29.4±18.1, p=0.001). A total of 35 episodes of AEs occurred during repeated low-dose RTX therapy, and all of them were mild and transient. Repeated low-dose RTX therapy is cost-effective for RRMS patients and shows a good safety profile. It may be a promising option for those having no access or poor response to first-line disease-modified drugs (DMDs), particularly in low- or middle-income countries.

Off-label pharmacological treatment of obesity: a systematic review of clinical studies

Introduction: There are 2.0 billion overweight and obese people in the world, and Brazil ranks fifth in the world. The World Health Organization (WHO) advises that the use of drugs to combat obesity is indicated for patients who have a body mass index (BMI) above 30 kg/m2 or when the BMI is 25 kg/m2 associated with comorbidities. that permeate excess weight. A variety of drug classes approved for other indications have been used off-label in an attempt to promote weight loss. Objective: It was to list and present the main off-label drugs for obesity in adults, as well as to show the scientific evidence of clinical studies. Methods: The present study followed a concise systematic review (PRISMA) model. The literary search process was carried out from July 2022 to September 2022 and was developed based on Scopus, PubMed, Science Direct, Scielo, and Google Scholar, using scientific articles from 2002 to 2022. The low quality of evidence was attributed to reports of cases, editorials, and brief communications, according to the GRADE instrument. The risk of bias was analyzed according to the Cochrane instrument using the Funnel Plot. Results and Conclusion: We found 98 studies that underwent eligibility analysis, and then 15 of the 12 total studies were selected. Most studies showed homogeneity in their results, with I2 =96.5% >50%. The Funnel Plot showed a symmetrical behavior, not suggesting a significant risk of bias in the studies. Off-label prescribing is very common among physicians who treat obesity. However, randomized controlled studies should be increasingly encouraged and increased to clearly present the scientific evidence and, thus, propose a scientific formalism for the safe and effective use of off-label anti-obesity drugs. Physicians, however, have adopted a more pragmatic approach, giving much greater credibility to shared clinical experience, particularly in situations where favorable outcomes have been consistently observed over decades. International medical bodies do not recommend the off-label use of drugs approved for the exclusive use of weight loss. In Brazil, the Brazilian Association for the Study of Obesity and Metabolic Syndrome (ABESO) recommends that drugs approved for the treatment of obesity be prescribed preferentially over off-label treatments. In addition, the patient must be well informed and aware that the drug is not approved by Anvisa for this indication or chronic use.

A 2023 Update on Managing Insomnia in Primary Care: Insights From an Expert Consensus Group.

Objective: To evaluate the status of management of insomnia disorder, describe gaps in current recognition and treatment, identify current guidance for optimal management, and develop up-to-date educational recommendations for primary care providers.Participants: Four insomnia experts representing primary care, psychiatry, and clinical research were selected based on clinical expertise, educational qualifications, and research experience. A patient with insomnia was also included.Consensus Process: The Insomnia Working Group met in March 2022 to review data on available therapies (including medications approved since publication of current guidelines) and share current best practices for evidence-based multimodal treatment of insomnia disorder.Conclusions: Insomnia is highly prevalent but underdiagnosed and undertreated. It is increasingly recognized as a distinct disorder, not merely a symptom arising secondary to another medical or psychiatric illness. The subtypes of sleep disturbance-reports of difficulty falling or staying asleep, insufficient sleep duration, early waking-and the presence of next-day impairment and common comorbid conditions require a targeted, individualized approach to therapy. Challenges exist in treating insomnia with commonly used on- and off-label drugs, including low-dose antidepressants, benzodiazepines, and benzodiazepine receptor agonists because of the risk of adverse effects, including impaired next-day functioning. The dual orexin receptor antagonists have a novel mechanistic target and offer an alternative pharmacologic choice. Optimal outcomes for insomnia require a comprehensive approach that includes lifestyle and behavioral strategies to mitigate maladaptive thoughts and behaviors related to sleep and selection of pharmacotherapy based on individual patient complaints and characteristics.

A Survey of Off-label and Unlicensed Antibiotic and Respiratory Medications Prescribed for Toddler Patients

Background: Many medications are unlicensed for use in toddlers and many drugs are prescribed as off-label in this age group. Different studies showed high prevalence of prescribing such medications in children. Prescribing off-labeled or unlicensed drugs can cause adverse drug events (ADEs) and harm to the patients. To evaluate the rate of off-label and unlicensed drugs prescribed for toddlers.
 Methods: Out-patient prescriptions within the electronic database from a main governmental health insurance company in Tehran, Iran were evaluated for off-label and unlicensed drugs in a two-month period (November-December 2019).
 Results: 5358 prescriptions for toddlers reached to the insurance database, of these, 461 prescriptions were randomly selected. Three hundred and fifty prescriptions contained antibiotics and/or respiratory medications, from them, 183 (52.3%) had at least one off-labeled or unlicensed medication.
 Conclusion: Our study showed high rates of off-label and/or unlicensed medication use in pediatric population.

Off-Label Uses of Ranibizumab and Aflibercept for Age-Related Macular Degeneration in Turkey.

To evaluate the clinical and demographic aspects of off-label drug use applications for age-related macular degeneration (AMD) in Turkey. Applications for off-label drug use in the treatment of AMD to the Turkish Medicines and Medical Devices Agency (TITCK) in 2018 were retrospectively analyzed. Demographic characteristics, requested drugs, previous treatment regimens, and reasons for applications were evaluated. The mean age of the patients (n = 209) was 64.9 ± 15.7 years, of which 48.8% were male and 51.2% were female. Ranibizumab (n = 113) comprised 54.1% and aflibercept (n = 96) 45.9% of off-label use applications. No application was made for bevacizumab. The most frequent reasons for application were switchback (49.3%), nonreimbursement of indicated drugs in cases under 50 years of age (24.4%), and failure to complete the loading dose (14.4%). Ranibizumab was the most requested off-label drug for AMD. There was no application for off-label bevacizumab since its use does not require approval from TITCK. In Turkey, new rules were established for the reimbursement of intravitreal drugs for AMD in 2019. Three doses of intravitreal bevacizumab were required initially for aflibercept and ranibizumab to be covered for reimbursement. There is not enough data in the English literature regarding the off-label use of ranibizumab and aflibercept for AMD. This study provides information about drug regulations and the off-label treatment options preferred by physicians for AMD in Turkey.

A 15 Year Evolution of Dichloroacetate-Based Metabolic Cancer Therapy: A Review with Case Reports

Despite Otto Warburg’s discovery of aerobic glycolysis in cancer cells in the 1920’s, the potential for developing therapeutics that targeted cancer cell metabolism was essentially ignored until 2007 when a groundbreaking publication was released from a group of Canadian researchers. Bonnet et al. (who paradoxically were not specialized in oncology) discovered that the generic drug dichloroacetate sodium (“DCA”) could reverse the Warburg phenotype in cancer cells in vitro and in vivo resulting in natural cancer cell suicide and tumour shrinkage in rats. This phenomenon was previously thought to be impossible as it was believed that mitochondria in malignant cells were permanently altered and unable to trigger apoptosis. Despite the fact that no large clinical trial of DCA as a cancer therapy was ever completed, a small number of doctors in North America and Europe rapidly translated this new knowledge into clinical cancer protocols through independent observational research and creative thinking. Since off-label drug use is permitted in most jurisdictions, clinicians initially began to use DCA in patients who had failed all conventional therapies. Over the years, further novel anti-cancer mechanisms of DCA were discovered such as angiogenesis inhibition, immune activation and cancer stem cell targeting. Around 2011, the work of Seyfried (USA) began to illuminate the importance of glutamine inhibition and suggested that a multi-energetic targeted approach was superior to glycolysis inhibition alone. A collaborative effort of the authors incorporating Seyfried’s concepts resulted in the creation of a new metabolic protocol named “MOMENTUM” (Metabolic, Oncologic, Multi-ENergetic Targeted, Universal, Modified). In this protocol, glucose and glutamine metabolism were targeted simultaneously with a combination of multiple natural and pharmacologic agents administered intravenously. Surprising preliminary clinical results in several difficult cancer cases confirmed that metabolic multi-targeted methods are extremely promising, and more so than metabolic monotherapy. Life threatening side effects of this approach to cancer management are virtually non-existent and therapy costs are manageable. A disappointing absence of industry funding for large clinical trials has not curtailed the development of the metabolic approach as a clinically viable methodology, proving that unadulterated medical science can conquer the ongoing push for multibillion-dollar economic reward.