Off-label Drug Use Research Articles

The genomic landscape of gene fusions across solid tumors and clinical outcome of targeted therapies: A real-world retrospective analysis.

3132 Background: Oncogenic gene fusions can be observed across numerous solid tumor types with therapies targeting fusion events emerging as important treatment modalities. The occurrence of rare fusion events and response to targeted therapy inclusive of off-label drug use has not been fully elucidated. We describe a real-world (RW) landscape of gene fusions in solid tumors and treatment outcomes of targeted therapies. Methods: Patients with solid tumors harboring a gene fusion or rearrangement were retrospectively identified through review of a clinical molecular database housing sequencing data on 6,800 patients from a single-center between 1/1/2015 – 12/31/2019. Patients who received targeted therapy for gene fusions were divided into three arms: off-label, on-label, and clinical trial use. Clinical characteristics were summarized using descriptive statistics. Overall survival (OS) and Progression free survival (PFS) between the three arms were compared using the Kaplan-Meier estimates. Results: A total of 336 (4.9%) patients had a fusion positive solid tumor with 197 (2.9%) having a fusion event predicted to be oncogenic and could be targeted with a drug. Thirty different cancer types had targetable fusions with the three most common types being lung adenocarcinoma (41%), glioblastoma (10.2%), and melanoma (7.1%). The most common observed targetable fusions included ALK (21.3%), RET (11.7%), ROS1 (9.1%), and FGFR2 (8.1%). A total of 71 patients received targeted therapy; 37 (52%) received therapies on-label, 20 (28%) off-label, and 14 (20%) on-trial (Table). The median PFS was 4 months for off-label, 16 months for on-label, and 9 months for on trial-therapy (p=0.02). The median OS was 8 months for off-label, 51 months for on-label, and 11 months for on-trial therapy (p=0.001). Seven out of twenty patients (35%) in the off-label group had PFS for at least 6 months. Three patients had a response for more than one year. However, higher toxicity related discontinuation rate was observed (30%, 8%, 7% for off-label, on-label, and on-trial, p=0.03). Conclusions: Off-label targeted therapy had shorter PFS and OS when compared to on-label therapy. However, 35% patients in the off-label group had at least 6 months PFS. Off-label therapy remained a valuable option for patients who were not candidate for clinical trials or with rare fusions. Further studies are needed to determine which patients are most likely to benefit from targeting gene fusion events.[Table: see text]

Factors associated with off-label (OL) drug use in oncology: The role of cost and financing in a universal healthcare system.

e18825 Background: In recent years, OL use in oncology has become widespread, with estimates ranging up to 50-75% of all prescriptions. Most OL use is not publicly reimbursed within universal healthcare systems. We aimed to characterize the financing sources of OL use and to identify predictors for forgoing such treatment. Methods: We studied 708 oncology OL prescription requests submitted for approval to the Institutional Drug Committee in Rabin Medical Center, a large tertiary center in Israel, between January 2016 and December 2018. We included only requests for patients that were alive for more than 60 days following prescription approval. For each indication we extracted the level of supporting evidence at the time of prescription (sufficient, limited, inadequate). We also examined patients’ disease and sociodemographic properties, treatment costs, and financing sources. We used univariable logistic regression to ascertain these variables’ effects on actual OL drug initiation. We then used multivariable logistic regression to explore predicting factors for drug initiation. Results: The median monthly cost of a planned OL treatment was ILS39,928 (approximately US$ 11,500). Approximately one third (31%) of the treatments did not have a financing source at the time of request approval. The primary financing sources were patient access plans (30%) and private health insurance (25%). Of 708 approved OL requests, only 583 (82.3%) treatments were initiated. The proportion of requests that were eventually initiated was higher in the metastatic versus adjuvant setting (84.9% vs. 76.5%; p= .008). The estimated median OS for metastatic patients was 9.9 months, significantly higher in patients that did initiate treatment versus patients that did not (10.4 vs. 7.2 months; p= .048). Although not significant, median costs of initiated treatments were higher compared to treatments that were not (ILS41,686 vs. ILS24,670). Prescriptions for the metastatic setting and immunotherapy as well as ones with sufficient evidence had higher odds for treatment initiation (OR = 1.73; p= .007, OR = 1.69; p= .013 and OR = 1.62; p= .016). Prescriptions with limited supporting evidence and with no planned financing source had lower odds for treatment initiation (OR = 0.59; p= .012, OR = 0.37; p< .0005). A multivariable logistic regression showed that if no financing plan was in place at the time of request, there was a 2.5 times higher likelihood of not initiating the treatment (OR = 2.5; p< .0005). Conclusions: While OL recommendation is widespread and institutional approval is granted, a substantial proportion of treatments are not initiated. Although cost was not associated with treatment initiation, having a planned financing source was a strong predictor for OL treatment initiation. This study elucidates the financing sources of OL treatments in a universal healthcare system and identifies access barriers.

Prospects of off-label (OL) drug use in oncology: Identifying predicting variables for registration and universal healthcare reimbursement.

e18842 Background: Many cancer drugs used OL, eventually complete clinical development and are registered and reimbursed, while others are not. We aimed to describe OL indications' registration and reimbursement prospects in a universal healthcare system and identify groups of treatments that remain OL longer. Methods: We studied 612 OL oncology prescription requests for 115 unique indications and 29 drugs. All requests were approved by the Institutional Drug Committee in Rabin Medical Center, a tertiary center in Israel, between January 2016 and December 2018. OL indications were not registered by the Israeli Ministry of Health (MOH) and were not included in the Israeli National List of Health Services (NLHS) for reimbursement at the time of prescription. Additionally, 459 requests for 100 indications were not approved by the FDA at the time of prescription. We explored the subsequent regulatory and reimbursement milestones in the timeline following each prescription. We identified three temporal events: FDA indication approval, MOH indication registration, and NLHS indication inclusion of reimbursement. We then defined three time-to-event variables from the OL prescription to each of the three milestones. We applied Kaplan-Meier analysis and multivariable Cox regression to identify drug and indication properties, which are predictors for registration and reimbursement. Results: With a median follow-up of 34.5 months, 10.4% of indications were eventually registered in Israel, and 6% were included in the NLHS. 7% of non-FDA approved indications were subsequently approved. For MOH registration, positive predictors were immunotherapy, sufficient evidence (ESMO-MCBS A-B, 5-4), and a patient access program at the time of prescription (HR = 21.99; p< .0005, HR = 3.4; p= .02 and HR = 2.73; p< .0005, respectively). Negative predictors were metastatic setting and lung and gastrointestinal (GI) cancers (HR = 0.42; p= .002, HR = 0.17; p= .001, and HR = 0.24; p= .043, respectively). For NLHS inclusion, positive predictors were immunotherapy, sufficient evidence, and an access program (HR = 9.03, HR = 6.24, and HR = 2.56, respectively, all p< .0005). Negative predictors were lung and GI cancers and orphan disease designation (HR = 0.07; p= .002, HR = 0.14; p= .021, and HR = 0.13; p= .009, respectively). For FDA approval, positive predictors were immunotherapy, sufficient evidence, and a patient access program (HR = 12.11; p< .0005, HR = 4.34; p= .002, and HR = 2.25; p= .001, respectively). Negative predictors were metastatic setting, lung cancer, and orphan disease (HR = 0.43; p= .003, HR = 0.25; p= .006, and HR = 0.08; p= .018, respectively). Conclusions: Few OL indications are subsequently approved and reimbursed, usually due to clinical futility and insufficient evidence. However, we identified factors related to lack of initiative for further clinical development and registration.

Ethical dimensions in randomized trials and off-label use of investigational drugs for COVID-19 treatment

Coronavirus disease 2019 (COVID-19) is a fast-developing viral pandemic spreading across the globe. Due to lack of availability of proven medicines against COVID-19, physicians have resorted to treatments through large trials of investigational drugs with poor evidence or those used for similar diseases. Large trials randomize 100–500+ patients at multiple hospitals in different countries to either receive these drugs or standard treatment. In order to expedite the process, some regulatory agencies had also given permission to use drugs approved for other diseases, despite a lack of evidence of efficacy in COVID-19. In this review, we highlight the potential ethical issues that should be addressed during the use of investigational drugs with little prior evidence as a treatment options during a pandemic. We discuss the impact of design of randomized clinical trials using LOTUS trial as an example and that of off-label use of drugs like chloroquine/hydroxychloroquine (CQ/HQ) on the safety of patients during COVID-19. We conclude that the adaptive randomized clinical trial designs offer a flexible and efficient approach, enabling patients to quickly switch to successful treatments, while minimizing the number of patients on standard of care. Randomized clinical trial design should consider blinding of investigators and only representative patients who can provide consent should be included. We also conclude the emergency approvals of drugs should be carefully issued and off-label use should be restricted in pandemics. Streamlined regulatory guidelines for emergency drug use in a pandemic can also help in providing benefit and minimizing harm to patients in the future.

Off-Label Use and Safety of Drug Use in Vascular Anomalies

Background: Off-label drug use is associated with an increased risk of adverse drug reactions. It is common in pediatrics and in rare diseases, which are two characteristics applying to vascular anomalies (VA). Objectives: The aim of this work was to quantify off-label drug use in VA and assess its safety. Methods: A review was conducted to extract a list of drugs used in VA management. A drug was considered to have significant safety concerns if a black box warning was present or if a serious adverse drug reaction (SADR) was reported in at least 1% of the patients (SADR is defined as a noxious and unintended response to a drug that occurs at any dose and results in hospitalization, prolongation of existing hospitalization, congenital malformation, persistent or significant disability or incapacity, life-threatening condition, or death). The labelling status and safety of each drug was assessed based on the product monograph, Micromedex, and the FDA data. Results: We found that 98.9% of the inventoried drugs were used off-label or unlicensed for VA management. Only the oral solution of propranolol hydrochloride (Hemangeol®) for the treatment of infantile hemangiomas is approved. Significant safety issues concerned 73% of the drugs and were more frequent among systemic than locally delivered drugs. Conclusions: Off-label drug use in VA is the rule and not the exception. Significant safety concerns are common. It is necessary to carefully weigh risk and benefits for every patient when using systemic and local treatments carrying safety concerns. Patients should be openly informed and involved in the decision-making process.

Pharmacotherapy for Frontotemporal Dementia.

Frontotemporal dementia is a heterogeneous spectrum of neurodegenerative disorders. The neuropathological inclusions are tau proteins, TAR DNA binding protein 43 kDa-TDP-43, or fused in sarcoma-ubiquitinated inclusions. Genetically, several autosomal mutations account for the heritability of the disorder. Phenotypically, frontotemporal dementia can present with a behavioral variant or a language variant called primary progressive aphasia. To date, there are no approved symptomatic or disease-modifying treatments for frontotemporal dementia. Currently used therapies are supported by low-level of evidence (mostly uncontrolled) studies. The off-label use of drugs is also limited by their side-effect profile including an increased risk of confusion, parkinsonian symptoms, and risk of mortality. Emerging disease-modifying treatments currently target the progranulin and the expansion on chromosome 9 open reading frame 72 genes as well as tau deposits. Advancing our understanding of the pathophysiology of the disease and improving the design of future clinical trials are much needed to optimize the chances to obtain positive outcomes.

AAP Publications Reaffirmed or Retired

Policy Statement. Point-of-care ultrasonography by pediatric emergency medicine physicians. Pediatrics . 2015;135(4). Available at: www.pediatrics.org/cgi/content/full/135/4/e1097. Reaffirmed September 2019 Technical Report. Point-of-care ultrasonography by pediatric emergency medicine physicians. Pediatrics . 2015;135(4). Available at: www.pediatrics.org/cgi/content/full/135/4/e1113. Reaffirmed September 2019 Policy Statement. Consumption of raw or unpasteurized milk and milk products by pregnant women and children. Pediatrics . 2014;133(1):175–179. Available at: https://pediatrics.aappublications.org/content/133/1/175. Reaffirmed November 2019 Policy Statement. Off-label drug use in children. Pediatrics . 2014;133(3):563–567. Available at: https://pediatrics.aappublications.org/content/133/3/563. Reaffirmed November 2020 Technical report. Prevention of … Corresponding author; email: jshaw{at}aap.org

Off-label use of drugs administered by enteral feeding tubes in an Intensive Care Unit in Fortaleza, Brazil

Objective: To analyze the prescription profile of drugs administered through enteral feeding tubes in an adult intensive care unit and gather recommendations for their safe administration. Methods: This is a descriptive and retrospective study conducted with adult critical clinical patients of a university hospital in Fortaleza-Ceará from March to May 2018. We performed analyses of patients’ medical records and prescriptions regarding drugs, pharmaceutical presentations and the possibility of administration through enteral tubes. Results: 489 prescriptions containing 1914 items were evaluated, from which 16.6% (n = 318) through tubes. Medicines for the cardiovascular system (34.6%), nervous system (27.4%) and digestive system and metabolism (15.1%) were the most predominant, with an average of 5.8 (DP: 4.2) different per patient. Regarding the pharmaceutical presentation, oral solids were frequently prescribed via enteral tube (67.9%), especially risperidone (8.8%), carvedilol (8.3%) and amiodarone (7.9%). There were contraindications for administration through tubes in 21.6% of solid oral formulations, while there were alternative standardized pharmaceutical forms in the hospital for 43.1%. In addition, substitution for liquid preparations from the market were possible in 43.1%. Among those to which there were no alternative formulations, drugs targeting the cardiovascular system prevailed (52.2%). A table with guidelines for the proper administration of the prescribed solid medications was elaborated then. Conclusion: Solid oral medications were frequently prescribed through enteral tubes, especially those for the cardiovascular system without alternative formulations, which shows the need for guidelines to promote the safety of this process.

Association of Supporting Trial Evidence and Reimbursement for Off-Label Use of Cancer Drugs

In many health systems, access to off-label drug use is controlled through reimbursement restrictions by health insurers, especially for expensive cancer drugs. To determine whether evidence from randomized clinical trials is associated with reimbursement decisions for requested off-label use of anticancer drugs in the Swiss health system. This cross-sectional study used reimbursement requests from routinely collected health records of 5809 patients with drug treatment for cancer between January 2015 and July 2018 in 3 major cancer centers, covering cancer care of approximately 5% of the Swiss population, to identify off-label drug use. For each off-label use indication with 3 or more requests, randomized clinical trial evidence on treatment benefits was systematically identified for overall survival (OS) or progression-free survival (PFS). Data were analyzed from August 2018 to December 2020. Available randomized clinical trial evidence on benefits for OS or PFS for requested off-label use indications. The main outcome was the association between evidence for treatment benefit (expressed as improved OS or PFS) and reimbursement in multivariable regression models. Among 3046 patients with cancer, 695 off-label use reimbursement requests in 303 different indications were made for 598 patients (median [interquartile range] age, 64 [53-73] years; 420 [60%] men). Off-label use was intended as first-line treatment in 311 requests (45%). Reimbursement was accepted in 446 requests (64%). For 71 indications, including 431 requests for 376 patients, there were 3 or more requests. Of these, 246 requests (57%) had no supporting evidence for OS or PFS benefit. Reimbursement was granted in 162 of 246 requests without supporting evidence (66%). Of 117 requests supported by OS benefit, 79 (67%) were reimbursed, and of 68 requests supported by PFS benefit alone, 54 (79%) were reimbursed. Evidence of OS benefit from randomized clinical trials was not associated with a higher chance of reimbursement (odds ratio, 0.76, 95% CI, 0.45-1.27). These findings suggest that in a health care system enabling access to off-label use, it was frequently intended as a first-line treatment in cancer care. Availability of randomized clinical trial evidence showing survival benefit was not associated with reimbursement decisions for off-label anticancer drug treatment in Switzerland. A transparent process with criteria considering clinical evidence is needed for evidence-based reimbursement decisions to ensure fair access to cancer treatments.

Off-label drug use and the risk of medication errors in critically ill neonates: A conceptual pilot study.

Off-label drug (OLD) use is common in neonates. There is a dearth of information associating the OLD use and the risk of medication errors in critically ill neonates. Hence, the present study was carried out. Drug prescriptions in neonates admitted to the intensive care unit of a tertiary care hospital between September 2018 and June 2019 were evaluated. Details on their demographics, reason for admission in intensive care unit, drug-related information and serum creatinine were extracted. United States Food and Drug Administration approved drug labels were compared. World Health Organization (WHO) anatomy, therapeutic and chemical (ATC) classification was used for drug categorization. We assessed the risk of medication errors in the adult population using a validated tool: medication risk score (MERIS). One hundred and seventy-one neonates with 2394 prescriptions were included in this study. Seventy one percent of the neonates in the present study received at least one OLD/unlicensed prescription item. A trend in increased numbers of OLD/unlicensed drug use in more premature and lower birth weight neonates were observed. Medication risk score was significantly higher in neonates receiving OLD/unlicensed drugs compared to those with only labelled drugs. Very and extreme pre-term (along with very low and extremely low birth weight) neonates were at higher risk of medication errors compared to others. Presence of OLD/unlicensed prescribed items is associated with a potentially increased risk of medication errors by an odds ratio of 20.4 compared to labelled drugs. Significant proportions of critically ill neonates received at least one OLD/unlicensed drug and such use was associated with potentially increased risk of medication errors.

Features of patients that died for COVID-19 in a hospital in the south of Mexico: A observational cohort study.

Due to the wide spread of SARS-CoV2 around the world, the risk of death in individuals with metabolic comorbidities has dangerously increased. Mexico has a high number of infected individuals and deaths by COVID-19 as well as an important burden of metabolic diseases; nevertheless, reports about features of Mexican individuals with COVID-19 are scarce. The aim of this study was to evaluate demographic features, clinical characteristics and the pharmacological treatment of individuals who died by COVID-19 in the south of Mexico. We performed an observational study including the information of 185 deceased individuals with confirmed diagnoses of COVID-19. Data were retrieved from medical records. Categorical data were expressed as proportions (%) and numerical data were expressed as mean ± standard deviation. Comorbidities and overlapping symptoms were plotted as Venn diagrams. Drug clusters were plotted as dendrograms. The mean age was 59.53 years. There was a male predominance (60.1%). The mean hospital stay was 4.75 ± 4.43 days. The most frequent symptoms were dyspnea (88.77%), fever (71.42%) and dry cough (64.28%). Present comorbidities included diabetes (60.63%), hypertension (59.57%) and obesity (43.61%). The main drugs used for treating COVID-19 were azithromycin (60.6%), hydroxychloroquine (53.0%) and oseltamivir (27.3%). Mexican individuals who died of COVID-19 had shorter hospital stays, higher frequency of shortness of breath, and higher prevalence of diabetes than individuals from other countries. Also, there was a high frequency of off-label use of drugs for their treatment.

Off-label pediatric medicines in Spain

Since 2009, the use of off-label and unlicensed drugs has been regulated in Spain. In pediatrics, this exceptional use is more common than in other medical specialties. It varies from 10% to 90% of all prescriptions in children. This variability is due to differences in methodology, classification and sources of information used, and also to the different pediatrics subspecialties. In addition, the knowledge of several pediatricians on this issue is limited and more than half do not comply with the law, in many cases due to ignorance. However, the use of off-label and unlicensed drugs is legal and necessary. The Medicines Committee of the Spanish Association of Pediatrics (CM-AEP) considers that it is necessary to improve the existing information on medicines in the pediatric population. Therefore, the CM-AEP works out a document where suggestions and actions are proposed to achieve it, because children’s health deserves it.

Both Chloroquine and Lopinavir/Ritonavir Are Ineffective for COVID-19 Treatment and Combined Worsen the Pathology: A Single-Center Experience with Severely Ill Patients

The off-label use of antiviral and antimalarial drugs has been considered by many researchers as a fast and relatively safe alternative to provide therapeutic options to treat COVID-19, but the assessment of such drug-specific effectiveness in this regard is far from complete. Especially, the current body of knowledge about COVID-19 therapeutics needs more data regarding drug effectiveness and safety in the severely ill patients with comorbidities. In the present article, we retrospectively analyze data from 61 patients that received treatment with chloroquine, lopinavir/ritonavir, both drugs administered together, or a standard treatment with no antiviral drugs, and the study was carried in severely ill patients. We found that either drug is ineffective at treating COVID-19, as they are not able to reduce hospitalization length, mortality, C-reactive protein (CRP), lactate dehydrogenase (LDH), d-Dimer, or ferritin, or to enhance gasometric parameters, lymphocytes, total leukocytes, and neutrophil levels, whereas both drugs administered together decrease circulating lymphocytes, increase LDH and ferritin levels, and more importantly, enhance mortality. In this way, our results show that both drugs are ineffective and even potentially harmful alternatives against SARS-CoV-2.

Relationship between adverse drug reactions and unlicensed/off-label drug use in hospitalized children (EREMI): A study protocol

To date, few studies have shown a significant association between off-label drug use and adverse drug reactions (ADRs). The main aims of this study is to evaluate the relationship between adverse drug reactions and unlicensed or off-label drugs in hospitalized children and to provide more information on prescribing practice, the amplitude, consequences of unlicensed or off-label drug use in pediatric inpatients. In this multicenter prospective study started from 2013, we use the French summaries of product characteristics in Theriaque (a prescription products guide) as a primary reference source for determining pediatric drug labeling. The detection of ADRs is carried out spontaneously by health professionals and actively by research groups using a trigger tool and patients' electronic health records. The causality between suspected ADRs and medication is evaluated using the Naranjo and the French methods of imputability independently by pharmacovigilance center. All suspected ADRs are submitted for a second evaluation by an independent pharmacovigilance experts. For our best knowledge, EREMI is the first large multicenter prospective and objective study in France with an active ADRs monitoring and independent ADRs validation. This study identifies the risk factors that could be used to adjust preventive actions in children's care, guides future research in the field and increases the awareness of physicians in off-label drug use and in detecting and declaring ADRs. As data are obtained through extraction of information from hospital database and medical records, there is likely to be some under-reporting of items or missing data. In this study the field specialists detect all adverse events, experts in pharmacovigilance centers assess them and finally only the ADRs assessed by the independent committee are confirmed. Although we recruit a high number of patients, this observational study is subject to different confounders.

AAP Publications Reaffirmed or Retired

Policy Statement. Point-of-care ultrasonography by pediatric emergency medicine physicians. Pediatrics. 2015;135(4). Available at: www.pediatrics.org/cgi/content/full/135/4/e1097. Reaffirmed September 2019Technical Report. Point-of-care ultrasonography by pediatric emergency medicine physicians. Pediatrics. 2015;135(4). Available at: www.pediatrics.org/cgi/content/full/135/4/e1113. Reaffirmed September 2019Policy Statement. Consumption of raw or unpasteurized milk and milk products by pregnant women and children. Pediatrics. 2014;133(1):175–179. Available at: https://pediatrics.aappublications.org/content/133/1/175. Reaffirmed November 2019Policy Statement. Off-label drug use in children. Pediatrics. 2014;133(3):563–567. Available at: https://pediatrics.aappublications.org/content/133/3/563. Reaffirmed November 2020Technical report. Prevention of drowning. Pediatrics. 2010;126(1):e253–e262. Available at: https://pediatrics.aappublications.org/content/126/1/e253. Reaffirmed February 2019Clinical report. Child sex trafficking and commercial sexual exploitation: health care needs of victims. Pediatrics. 2015;135(3):566–574. Available at: https://pediatrics.aappublications.org/content/135/3/566. Reaffirmed October 2020Clinical report. Management of food allergy in the school setting. Pediatrics. 2010;126(6):1232–1239. Available at: https://pediatrics.aappublications.org/content/126/6/1232. Reaffirmed October 2020Policy statement. HIV testing and prophylaxis to prevent mother-to-child transmission in the United States. Pediatrics. 2008;122(5):1127–1134. Available at: https://pediatrics.aappublications.org/content/122/5/1127. Reaffirmed October 2020Clinical report. Suicide and suicide attempts in adolescents. Pediatrics. 2016;138(1):e20161420. Available at: https://pediatrics.aappublications.org/content/138/1/e20161420. Reaffirmed October 2020Technical report. SIDS and other sleep‐related infant deaths: expansion of recommendations for a safe infant sleeping environment. Pediatrics. 2011;128(5):e1341–e1367. Available at: http://pediatrics.aappublications.org/content/128/5/e1341. Reaffirmed October 2020Policy statement. SIDS and other sleep‐related infant deaths: expansion of recommendations for a safe infant sleeping environment. Pediatrics. 2011;128(5):1030–1039. Available at: http://pediatrics.aappublications.org/content/128/5/1030. Reaffirmed October 2020Policy statement. Pediatrician-family-patient relationships: managing the boundaries. Pediatrics. 2009;124(6):1685–1688. Available at: https://pediatrics.aappublications.org/content/124/6/1685. Reaffirmed October 2020Clinical report: Attention-deficit/hyperactivity disorder and substance abuse. Pediatrics. 2014;134(1):e293–e301. Available at: https://pediatrics.aappublications.org/content/134/1/e293.full. Reaffirmed October 2020Clinical report: Health supervision for children with sickle cell disease. Pediatrics. 2002;109(3):526–535. Available at: https://pediatrics.aappublications.org/content/109/3/526. Reaffirmed September 2020Policy statement. Postnatal corticosteroids to prevent or treat chronic lung disease following preterm birth Pediatrics. 2010;126(4):800–808. Available at: https://pediatrics.aappublications.org/content/126/4/800. Reaffirmed September 2020Policy statement. Children’s Health Insurance Program (CHIP): accomplishments, challenges, and policy recommendations. Pediatrics. 2013;133(3):e784–e793. Available at: https://pediatrics.aappublications.org/content/133/3/e784. Reaffirmed August 2020Policy statement. Guiding principles for pediatric hospital medicine programs. Pediatrics. 2013;132(4):782–786. Available at: https://pediatrics.aappublications.org/content/132/4/782. Retired August 2020

Emulsions with alkyl polyglucosides as carriers for off-label topical spironolactone – safety and stability evaluation

Androgens play an important role in the pathogenesis of acne. Being an anti-androgen drug with many side effects, spironolactone has recently been used in dermatology as a topical therapy for acne. Off-label drug use in dermatology is common, although those drugs are basically available as compounded formulations; the choice of a proper vehicle is often neglected in that case. Alkyl polyglucosides (APGs) are a FDA certified class of polyethylene glycol (PEG)-free surfactants produced from the renewable resources. Following the preformulation tests, two different APG emulsifiers were used in this study to stabilize emulsions as carriers for topical spironolactone. Assessment of the physical stability of emulsions per se and after incorporation of 5% of spironolactone was performed using polarization microscopy, electrical conductivity and pH measurements. The skin irritation profile and moisturizing potential was assessed in vivo on human volunteers. APG-based emulsions per se and with 5% of spironolactone showed acceptable skin irritation profiles and significant potential for skin hydration, which is important in acne treatment. Good physical stability and satisfying preliminary safety profile of all investigated samples were also obtained showing that moisturizing APG-based emulsions could be promoted as vehicles for off-label topical spironolactone.

Off-label use of ivermectin for COVID-19: Are there any neuropsychiatric effects to be aware of?

Sir, The COVID-19 pandemic has challenged the health systems and medical providers around the world. This emergency has led to the off-label use of different drugs in the treatment of this new disease, such as ivermectin. Nonetheless, the use of ivermectin is still controversial. The repurposing of drugs for the treatment of COVID-19 is a potential good strategy if their effectiveness and safety have been established. The aim of this mini-commentary is to discuss the evidence regarding the use of ivermectin and its effects on behavioral and neurological functioning. Although there are many reports about the effects of ivermectin on animals, we aimed to summarize the evidence to provide guidance to physicians who prescribe ivermectin. This commentary is a summary of available case reports and case series about the use of ivermectin and the occurrence of neuropsychiatric symptoms, retrieved from a PubMed and Web of Science search. The keywords employed were: “neurological symptoms of ivermectin use,” “motor symptoms of ivermectin use,” “behavioral symptoms of ivermectin use,” “affective symptoms of ivermectin use,” and “psychiatric symptoms of ivermectin use.” Ivermectin is an antiparasitic drug with multiple uses in human, as well animal healthcare. It acts on the chloride-dependent channels of glutamate and γ-aminobutyric acid, interrupting neurotransmission in nematodes and arthropods. Its use in animals has shown neurological effects. In mammals, blindness and ivermectin-induced retinopathy have been reported at doses of approximately 22 mg.[1] In humans, there have been reports of serious neurological adverse events (ataxia, tremor, convulsive disorder, confusional state, amnesia, encephalopathy, and coma) observed with the use of ivermectin in the treatment of onchocerciasis (dose range: 3–24 mg).[2] These adverse effects may not be entirely explained by the concomitant loiasis infections (with supportive evidence on the presence of ivermectin in the encephalic tissue in one case, and the recurrence of symptoms on repeated exposure in three cases).[2] Furthermore, secondary delirium has been reported (dose: 12 mg)[3] as well as psychotic episodes (dose: 6 mg)[4] associated with ivermectin use in combination with albendazole. A case of encephalitis has also been reported due to the weekly use of 12 mg of ivermectin for 6 months, with resolution of the encephalitis after hospitalization of the patient and suspension of the drug.[5] This effect could be due to drug interactions and severity of the disease itself. There is scarce literature on the neurological and behavioral effects of ivermectin use in humans. The off-label use of this drug in the treatment of COVID-19 might encourage more research about the therapeutic and side effects of this agent, above all on behavioral, psychological, and neurological factors of patients. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

Adverse drug reactions to off label use of drugs in spontaneously reported cases at a tertiary care hospital

Background: Off-label prescribing is the prescription of medication in a manner different from that approved by the Food and drug administration (FDA). This term implies that the drug is given either for different indication, different dose, different dosage form, different route, or different age group as compared to the approval criteria. The safety data of drugs used for labeled use cannot be applied to safety of drugs during off-label use. Aim and Objective: The aim of the study was to analyze the pattern of adverse drug reactions (ADR) occurring during off label use from the spontaneously reported ADR cases at the pharmacovigilance unit of a tertiary care hospital. Materials and Methods: The spontaneously reported ADR cases at a tertiary care hospital ADR monitoring center were analyzed for off label use using the NFI-2016 and updates on www.cdsco.nic.in website. Results: 82 ADRs occurred due to off-label use of drugs in 77 patients, these patients had received 433 medicines of which 231 were off label drugs. Off label drug use was maximum for systemically used anti-infective (152 drugs, 65.80%) and was associated with 75 ADRs (59.52%). Non-recommended co-administration of drugs was associated with maximum number of ADRs (23.01%). Most commonly affected organ system was skin and subcutaneous tissue (38.8%) and rash was the commonly occurring ADR. Conclusion: Safety is always the main concern while prescribing drugs. Off-label use of drugs is associated with ADR and caution should be administered while prescribing. ADR monitoring is needed to reduce ADRs associated with off label use.

The evolving role and utility of off-label drug use in multiple myeloma.

The treatment landscape for multiple myeloma (MM) has dramatically changed over the last three decades, moving from no US Food and Drug Administration approvals and two active drug classes to over 19 drug approvals and at least eight different active classes. The advances seen in MM therapy have relied on both a structured approach to obtaining new labels and cautious off-label drug use. Although there are country and regional differences in drug approval processes, many of the basic principles behind off-label drug use in MM can be summarized into four main categories: 1) use of a therapy prior to the current approval regulations; 2) widespread use of a therapy following the release of promising clinical trial results but prior to drug approval; 3) use of a cheap therapy supported by clinical safety and efficacy data but without commercial backing; and 4) niche therapies for small well-defined patient populations where large clinical trials with sufficient power may be difficult to perform. This review takes a historical approach to discuss how off-label drug use has helped to shape the current treatment approach for MM.

Prescription of off-label and unlicensed drugs for preterm infants in a neonatal intensive care unit.

ObjectiveTo evaluate the use of off-label and unlicensed medications in preterm infants hospitalized in a neonatal intensive care unit.MethodsThis nonconcurrent cohort study included preterm infants admitted to 3 neonatal intensive care units in 2016 and 2017 who were followed up during the neonatal period. The type and number of medications used were recorded for the entire period and classified based on the Anatomical Therapeutic Chemical. Descriptive and bivariate data analyses were performed to assess associations between the number of drugs used (total, off-label and unlicensed) and the explanatory variables of interest.ResultsFour hundred preterm infants received 16,143 prescriptions for 86 different pharmaceuticals; 51.9% of these medications were classified as off-label and 23.5% as unlicensed. The most prescribed drugs were gentamicin and ampicillin (17.5% and 15.5% among off-label, respectively) and caffeine (75.5% among unlicensed). The results indicated significant associations between the use of off-label drugs and lower gestational age, low birth weight, lower 5-minute Apgar score, advanced resuscitation maneuver in the delivery room and death. The prescription of unlicensed drugs was associated with lower gestational age, low birth weight and 5-minute Apgar score below 7.ConclusionNeonates admitted to neonatal intensive care units are highly exposed to off-label and unlicensed medications. Further studies are needed to achieve greater safety and quality of drug therapy used in neonatology.