Off-label Drug Use Research Articles

Drugs supply and pharmaceutical care management practices at a designated hospital during the COVID-19 epidemic.

The coronavirus disease-19 (COVID-19) is caused by the novel severe acute respiratory syndrome coronavirus that was first detected at the end of December 2019. The epidemic has affected various regions of China in different degrees. As the situations evolve, the COVID-19 had been confirmed in many countries, and made a assessment that it can be characterized as a pandemic by the World Health Organization on March 11, 2020. Drugs are the main treatment of COVID-19 patients. Pharmaceutical service offers drug safety ensurance for COVID-19 patients.According to COVID-19 prevention and control policy and requirements, combined with series of diagnosis and treatment plans, pharmacists in the first provincial-level COVID-19 diagnosis and treatment unit in Jilin Province in Northeast China have established the management practices of drug supply and pharmaceutical care from four aspects: personnel, drugs supply management, off-label drug use management and pharmaceutical care. During the outbreak, the pharmaceutical department of THJU completed its assigned workload to ensure drug supply. So far, no nosocomial infections and medication errors have occurred, which has stabilized the mood of the staff and boosted the pharmacists' confidence in fighting the epidemic. For the treatment of COVID-19, pharmacists conducted adverse reaction monitoring and participated in the multidisciplinary consultation of COVID-19. Up to now, the COVID-19 patients admitted to THJU have not shown any new serious adverse reactions and been cured finally. The hospital pharmacy department timely adjusted the work mode, and the formed management practices is a powerful guarantee for the prevention and control of the COVID-19 epidemic. This paper summarized the details and practices of drug supply and pharmaceutical services management to provide experience for the people who involving in COVID-19 prevention and contain in other abroad epidemic areas.

Off-label and unlicensed drug use in Ayder comprehensive specialized hospital neonatal intensive care unit

BackgroundOff- label drug use refers to the use of medicines outside of their marketing authorization with respect to dose, dosage form, route of administration, indication or age. Off-label/unlicensed drug use significantly associated with adverse drug reactions and medication errors in neonates and critically ill neonates are more vulnerable to these problems.ObjectiveTo assess the prevalence and associated factors with off-label and unlicensed drug use in neonatal intensive care unit of Ayder Comprehensive Specialized Hospital.MethodsA cross-sectional study was conducted from March 01,2019 to April 30, 2019 in neonatal intensive care unit of Ayder Comprehensive Specialized Hospital. Neonates admitted for 24 h and took at least one medicine were included in the study. Data was collected from prescription and medical charts. The off-label and license status of the medicine was verified based on European medicine Agency electronic medicine compendium. Data was analyzed by SPSS version 21.0. Binary and multivariate logistic regression was done to assess the predictors of off-label/unlicensed medicine use at p-value ≤0.05 significance level.ResultA total of 364 medicines prescribed for 122 neonates were analyzed. The prevalence of off-label and unlicensed drug use was 246 (67.58%), and 86 (23.63%) respectively. Of the total 122 neonates, 114(93.44%), and 57(46.72%) of them were exposed to at least one off-label and unlicensed drug respectively. Antibiotics were the most commonly prescribed off-label and unlicensed drugs. No statistically significant association was found between demographic as well as health related variables with off-label/unlicensed medicine use at p-value of ≤0.05 significance level.ConclusionOff-label and unlicensed medicine use was high among neonates admitted to intensive care unit of the hospital. Selecting the safest medicines for such vulnerable patients is crucial to promote rational prescribing and better therapeutic benefit.

Medicines for pediatric use: problems and research

The prescription of drugs in pediatrics is currently associated with problems. Therapists are often faced with "off-label drug use", the lack of drugs in appropriate doses for children and, the need to develop appropriate dosage forms.

The CJEU’s ruling in the Novartis Farma case: Money, health and medicines

In the Novartis Farma SpA case (Case C-29/17), the Court of Justice of the European Union (CJEU) held that the decision of a Member State (Italy) to reimburse a drug used off-label (Avastin), and for that purpose submitted to repacking procedures, is not in violation of European law, even if there is a duly approved therapeutic alternative (Lucentis) on the market and the procedure is solely to reduce health care expenditures. This was not the CJEU’s first ruling on off-label drug use. The novelty of the Novartis Farma SpA case is the economic element attached to the assessment of off-label prescriptions, even though the Court failed to consider this essential feature of the case. This paper analyses the Court’s ruling in light of two main principles of European pharmaceutical law: the imposition of marketing authorization for drugs used in the European market; and the predominance of public health concerns over economic considerations. The paper concludes that the Court failed to identify a major issue in the Italian policy – the reimbursement of off-label drug used when there is a properly approved therapeutic alternative on the market – at the risk of undermining the entire European pharmaceutical framework and endangering public health.

Use of apixaban and rivaroxaban in young adults with acute venous thromboembolism: a multi-center retrospective case series.

Since 2012 four direct oral anticoagulants (DOAC) have been approved by the US Food and Drug Administration (FDA) for treatment of acute venous thromboembolism (VTE). Clinical trials comparing DOACs to warfarin included more than 13,500 patients. However, included patients were all age 39years or older. We sought to describe real-world use of DOACs among young adults with acute VTE. Multi-center retrospective case series of young adult patients (age 18-40years) at two large academic medical centers who initiated any DOAC for VTE therapy in 2015 or 2016. Thrombotic and bleeding events as well as off-label drug use were described using summary statistics. Fifty-seven patients were identified (63.2% female). One of the 57 patients (1.8%) had a thromboembolic event. Seven of the 57 patients (12.3%) experienced a bleeding event, one categorized as a major bleed and six being categorized as clinically relevant non-major bleeding. One of the ten (10%) patients receiving apixaban was not initiated on the FDA-recommended 10mg twice daily for the first 7days. Seven of the 47 (14.9%) patients receiving rivaroxaban were not initiated on the FDA-recommended 15mg twice daily dosing for the first 21days. Bleeding occurred in approximately 14% of young adult patients treated with DOAC therapy. However, only one patient had their DOAC discontinued due to a major bleeding event. Recurrence of DVT while on DOAC therapy was rare.

Treating COVID-19—Off-Label Drug Use, Compassionate Use, and Randomized Clinical Trials During Pandemics

Chenguang Shen, PhD; Zhaoqin Wang, PhD; Fang Zhao, PhD; Yang Yang, MD; Jinxiu Li, MD; Jing Yuan, MD; Fuxiang Wang, MD; Delin Li, PhD; Minghui Yang, PhD; Li Xing, MM; Jinli Wei, MM; Haixia Xiao, PhD; Yan Yang, MM; Jiuxin Qu, MD; Ling Qing, MM; Li Chen, MD; Zhixiang Xu, MM; Ling Peng, MM; Yanjie Li, MM; Haixia Zheng, MM; Feng Chen, MM; Kun Huang, MM; Yujing Jiang, MM; Dongjing Liu, MD; Zheng Zhang, MD; Yingxia Liu, MD; Lei Liu, MD

Análisis del uso de fármacos fuera de indicación autorizada en hematología y oncología

Antecedentes y objetivo: El uso de medicamentos en condiciones diferentes a las autorizadas es el uso de medicamentos en condiciones distintas a las incluidas en su ficha técnica. El objetivo del presente trabajo es analizar las solicitudes de medicamentos fuera de ficha técnica y sus resultados, realizadas por el Servicio de Oncología y Hematología en un hospital de segundo nivel.
 Materiales y métodos: Se realizó un estudio observacional retrospectivo de todas las peticiones de fármacos “off label” recibidas por el Servicio de Farmacia. Los medicamentos se clasificaron según impacto económico, una clasificación propia según el tipo de fármaco y motivo de petición y según su grado de evidencia. Se analizó para cada solicitud los datos demográficos, de diagnóstico y de tratamiento de los pacientes. Se presenta un seguimiento de los efectos adversos, mediana de supervivencia libre de progresión y mediana de supervivencia global.
 Resultados: Se aprobaron 85 solicitudes de tratamiento. La mayoría de tratamientos fueron de alto impacto dirigidos principalmente a patologías raras y últimas opciones de tratamiento. Un 22% de las solicitudes tenían alto grado de evidencia. La media de supervivencia libre de progresión (SLP) y la supervivencia global (SG) fueron de 6,6 (IC 95% 5,2-8) y 9,7 meses (IC95% 8,2-11,2). Un 18,7% pacientes presentaron toxicidad de grado 3-4 al recibir el tratamiento.
 Conclusiones: A pesar de la heterogeneidad de las patologías, y la baja evidencia, los resultados obtenidos en SLP y SG, junto a la escasa toxicidad, nos obliga a seguir avanzando en la evaluación de este tipo de tratamientos.

Pharmacological Human Enhancement: An Overview of the Looming Bioethical and Regulatory Challenges.

Cognitive enhancement, a rather broad-ranging principle, can be achieved in various ways: healthy eating and consistent physical exercise can lead to long-term improvements in many cognitive domains; commonplace stimulants such as caffeine, on the other hand, temporarily raise levels of alertness, attentiveness, and concentration; sedative substances are also used as an indirect form of enhancement to relax before an exam or an important meeting. Such approaches raise no ethical issue. Nonetheless, clinical research has led to the off-label use of drugs called nootropics or “smart drugs”, which can, under certain conditions, elicit some degree of cognition-improving effects: methylphenidate and modafinil can enhance working memory and concentration in healthy individuals, although the significance and effectiveness of such applications are dubious. Such “cognitive enhancement” methods, however, do raise multiple ethical issues, and their contentious nature has caused bioethical authorities to lay out opinions and recommendations meant to regulate their use. Most notably, the Italian Committee on Bioethics has extensively dealt with the spread of nootropics, which resulted in the Italian Code of Medical Ethics including “cognitive enhancement” drugs and their prescription by doctors as critical points, along with cosmetic surgery (the latest version of the Code, updated in December 2017, deals with the two separately, in Article 76 and 76 BIS). The United States Presidential Commission for the Study of Bioethical Issues broadened the scope of cognitive enhancement techniques so as to include neural modifiers, i.e. mechanisms of brain and nervous system change: a much wider array of interventions, technologies, behaviors, and environmental conditions that may potentially affect several aspects of the human brain and nervous system. The potential of neuroscience to profoundly reshape society is nothing short of mind-blowing.

High prevalence of off-label and unlicensed paediatric prescribing in a hospital in Indonesia during the period Aug.-Oct. 2014.

Data on off-label and unlicensed prescribing in children in Indonesia is limited. The aims of this study were to determine the prevalence of off-label and unlicensed prescribing for paediatric patients in a public hospital, Indonesia. A retrospective cross-sectional study of 200 randomly selected paediatric patients admitted to hospital between August and October 2014, collected patient details and all drugs prescribed. Licensed drugs were classified as off-label if there was a non-compliance with the Product Information for age, weight, indication, dose, frequency and route of administration, if there was a contraindication, special precautions or not recommended for children. Unlicensed drugs were those not approved for use in Indonesia. The main outcome was the prevalence of off-label or unlicensed prescribing to infants, children and adolescents and the impact of age group on off-label prescribing. A total of 200 patients received 1961 medicines of which 1807/1961 (92.1%) were licensed and 154/1961 (7.9%) were unlicensed. There were 1403/1961 (71.5%) drugs prescribed off-label. More than half of the total drugs (n = 1066; 54.4%) were administered parenterally. Every patient was prescribed at least one off-label drug. Indication (n = 810; 34.6%) was the most common reason for off-label prescribing. Ranitidine was the most frequent drug prescribed off label. Darplex® (dihydroartemisinin and piperaquine), although manufactured in Indonesia, was unlicensed. There was a significant difference between age group and off-label prescribing in that children were prescribed significantly less off-label drugs (p<0.0003). This study revealed a high prevalence of off-label and unlicensed drug use in paediatric patients in this hospital, exposing them to drug treatments or regimens that had not been approved by regulatory authorities. The high incidence of invasive parenteral prescribing is of concern for paediatric patients. Incentives are needed to encourage specific drug evaluation in paediatric populations.

Off-label drug use in pediatric patients: a comparative analysis with nationwide routine prescription data.

Children constitute a special population for off-label drug use (OLDU), yet limited drug-focused data exist regarding pediatric OLDU in clinical practice. This study aimed to investigate pediatric OLDU practice and compare it with pediatric drug utilization patterns of routine prescribing data. This cross-sectional study examined all approved pediatric OLDU applications, compared with electronic prescription data on national Prescription Information System of Turkish Medicines and Medical Devices Agency in 2015. OLDU applications and prescriptions were analyzed for demographic characteristics, healthcare/socioeconomic indices as well as details of drugs and diagnoses. We found 7,896 OLDU applications and 7,029,512 prescriptions for the pediatric population in 2015. OLDU applications and prescriptions were mostly practiced for `2-11-year-old` children (52.7% vs. 63.4%, respectively; p < 0.01). OLDU applications and prescriptions were detected to have a positive correlation with socio-economic development index (r = 0.45, p < 0.0001 and r: 0.40, p = 0.0002; respectively) and the physician density (r = 0.66, p < 0.0001 and r: 0.43, p < 0.0001; respectively). In addition, OLDU was also positively correlated with the number of hospital beds per province (r = 0.39, p = 0.0003). Antineoplastic/immunomodulating agents were the most commonly applied drug category in OLDU (47.0%), compared with respiratory system drugs (36.6%) in routine prescribing. Eculizumab (6.5%), mycophenolate (5.6%), and canakinumab (4.4%) were the top drugs used as off-label. OLDU applications and routine prescription data revealed the most frequent diagnosis as `I27-other pulmonary heart diseases` (7.4%) and `J06-acute upper respiratory infections` (12.6%), respectively. This is the first nationwide study to show indication- and drug-centered aspects of pediatric OLDU and prescribing practice. Though OLDU applications is overall consistent with routine clinical practice in terms of demographics and institutional capacity, substantial variations exist regarding main drug classes and diseases. Our findings are expected to shed light on interventions focused on improving `indicated` pediatric use of drugs currently applied as off-label.

Off-label use of drugs by age in Brazilian children: a population study.

To estimate the prevalence of off-label drug use by age in children 12 years old and younger in Brazil. Population-based cross-sectional study (National Survey on Access, Use and Promotion of Rational Use of Medicines - PNAUM), including 7,528 children aged 12 years or younger. Face-to-face interviews were used to collect the data in the domiciles. The age-related off-label classification was carried out using the electronic medication compendium of National Agency of Sanitary Surveillance (ANVISA). Sociodemographic characteristics, presence of chronic disease, use of health services and characteristics of the informant were collected. Data were expressed by relative frequencies and 95% confidence intervals. Pearson's chi-square test was used to evaluate the statistical significance of the differences between the groups, with a significance level of 5%. Main outcome measure was the prevalence of off-label use. The prevalence of off-label use by age was 18.7% (95%CI 16.4 - 21.3). Children younger than 2 years old presented the highest prevalence of off-label use. The most frequently used off-label drugs by age were amoxicillin, nimesulide and the combination of phenylephrine and brompheniramine. The off-label use of drugs by age is common in the Brazilian pediatric population, especially among children under two years old.

Çocuklarda Endikasyon Dışı İlaç Kullanımı

Çocuklarda Endikasyon Dışı İlaç Kullanımı

Pozarejestracyjne sposoby podawania leków w opiece paliatywnej – przegląd narracyjny

Pozarejestracyjne sposoby podawania leków w opiece paliatywnej – przegląd narracyjny

Pozarejestracyjne zastosowanie leków w opiece paliatywnej w Polsce

Pozarejestracyjne zastosowanie leków w opiece paliatywnej w Polsce

Multi-Center Phase 2 Study of Pembroluzimab (Pembro) and Azacitidine (AZA) in Patients with Relapsed/Refractory Acute Myeloid Leukemia (AML) and in Newly Diagnosed (≥65 Years) AML Patients

Multi-Center Phase 2 Study of Pembroluzimab (Pembro) and Azacitidine (AZA) in Patients with Relapsed/Refractory Acute Myeloid Leukemia (AML) and in Newly Diagnosed (≥65 Years) AML Patients

Prednisone, Vinblastine, Doxorubicin and Bendamustine (PVAB) Regimen in First Line Therapy for Older Patients with Advanced-Stage Classical Hodgkin Lymphoma: Results of a Prospective Multicenter Phase II Trial of the Lymphoma Study Association (LYSA)

Prednisone, Vinblastine, Doxorubicin and Bendamustine (PVAB) Regimen in First Line Therapy for Older Patients with Advanced-Stage Classical Hodgkin Lymphoma: Results of a Prospective Multicenter Phase II Trial of the Lymphoma Study Association (LYSA)

Trends in Off-Label Drug Use in Ambulatory Settings: 2006-2015.

Off-label drug use in children is common and potentially harmful. In most previous off-label use research, authors studied hospitalized children, specific drug classes, or non-US settings. We characterized frequencies, trends, and reasons for off-label systemic drug orders for children in ambulatory US settings. Using nationally representative surveys of office-based physicians (National Ambulatory Medical Care Surveys, 2006-2015), we studied off-label orders of systemic drugs for children age <18 based on US Food and Drug Administration-approved labeling for age, weight, and indication. We characterized the top classes and diagnoses with off-label orders and analyzed factors and trends of off-label orders using logistic regression. Physicians ordered ≥1 off-label systemic drug at 18.5% (95% confidence interval: 17.7%-19.3%) of visits, usually (74.6%) because of unapproved conditions. Off-label ordering was most common proportionally in neonates (83%) and in absolute terms among adolescents (322 orders out of 1000 visits). Off-label ordering was associated with female sex, subspecialists, polypharmacy, and chronic conditions. Rates and reasons for off-label orders varied considerably by age. Relative and absolute rates of off-label orders rose over time. Among common classes, off-label orders for antihistamines and several psychotropics increased over time, whereas off-label orders for several classes of antibiotics were stable or declined. US office-based physicians have ordered systemic drugs off label for children at increasing rates, most often for unapproved conditions, despite recent efforts to increase evidence and drug approvals for children. These findings can help inform education, research, and policies around effective, safe use of medications in children.

Pregnancy rates to fixed-time AI in Bos indicus-influenced beef cows using PGF2α with (Bee Synch I) or without (Bee Synch II) GnRH at the onset of the 5-day CO-Synch + CIDR protocol

Objectives were to 1) characterize fixed-time AI (FTAI) pregnancy rates using the 5-Day CO-Synch + CIDR protocol in mature, suckled Bos indicus-influenced beef cows, 2) compare FTAI pregnancy rates in the latter to a modified version (5-Day Bee Synch + CIDR; Bee Synch I) that included treatment with prostaglandin F2α (PGF2α) at CIDR insertion on Day 0, and 3) test the hypothesis that elimination of both GnRH-1 at the onset of synchronization and the double dose of PGF on Day 5 (Bee Synch II) would not reduce FTAI pregnancy rates compared to Bee Synch I. For Experiment 1-trial 1, Brahman x Hereford (F-1) cows (n = 168) at least 40 d postpartum (PP; r = 40–92 d) at the time of CIDR insertion were administered the 5-Day CO-Synch + CIDR protocol with FTAI at 72 h after CIDR removal. Pregnancy rates to FTAI averaged 34.9 ± 1.9%. In Experiment 1-trial 2, fall- and spring-breeding Brahman x Hereford (F-1) beef cows (n = 269) were stratified by days PP and assigned randomly to receive either the 5-Day CO-Synch + CIDR (n = 136) or Bee Synch I (n = 133) protocol, with FTAI at 66 h after CIDR removal. Pregnancy rate to FTAI was greater (P < 0.05) in Bee Synch I (52.6 ± 0.9%) than in the 5-Day CO-Synch + CIDR procedure (40.4 ± 5.7%). For Experiment 2, 422 mature Braford, Brangus, Nelore x Brahman, and Brahman crossbred cows (Bos indicus proportion unknown) at 4 locations were treated with Bee Synch I, with FTAI at 66 h. Overall FTAI pregnancy rate averaged 51.7 ± 2.1%. Finally, from 2013 through spring 2018, we used a switchback design using fall- and spring-breeding herds to compare Bee Synch I (402 observations) to Bee Synch II (393 observations). Overall frequency of detected estrus at 66 h using ESTROTECT™ breeding indicator patches was 57.2 ± 2.4%, conception rates of those detected in estrus was 64.4 ± 3.5%, and FTAI pregnancy rates averaged 52.3 ± 2.4%, none of which differed between treatments. Moreover, pregnancy rates to FTAI in both treatments did not differ in cows synchronized between 40 and 80 d PP but increased after 80 d PP (P < 0.05). Bee Synch II, which eliminates GnRH-1 and the double dose of PGF2α on Day 5, results in FTAI pregnancy rates essentially identical to Bee Synch I but reduces synchronization costs and avoids the need for off-label (double dose PGF2α) drug use.

Identification of Actionable Genomic Alterations Using Circulating Cell-Free DNA.

Cell-free DNA (cfDNA) next-generation sequencing is a noninvasive approach for genomic testing. We report the frequency of identifying alterations and their clinical actionability in patients with advanced/metastatic cancer. Prospectively consented patients had cfDNA testing performed. Alterations were assessed for therapeutic implications. We enrolled 575 patients with 37 tumor types. Of these patients, 438 (76.2%) had at least one alteration detected, and 205 (35.7%) had one or more alterations of high potential for clinical action. In diseases with 10 or more patients enrolled, 50% or more had at least one alteration deemed of high potential for clinical action. Trials were identified in 80% of patients (286 of 357) with any alteration and in 92% of patients (188 of 205) with one or more alterations of high potential for clinical action of whom 57.6% (118 of 205) had 6 or more months of follow-up available. Of these patients, 10% (12 of 118) had received genomically matched therapy through enrollment in clinical trials (n = 8), off-label drug use (n = 3), or standard of care (n = 1). Although 88.6% of all patients had a performance status of 0 or 1 upon enrollment, the primary reason for not acting on alterations was poor performance status at next treatment change (28.1%; 27 of 96). cfDNA testing represents a readily accessible method for genomic testing and allows for detection of genomic alterations in most patients with advanced disease. Utility may be higher in patients interested in investigational therapeutics with adequate performance status. Additional study is needed to determine whether utility is enhanced by testing earlier in the treatment course.

Investigation and category management of off-label drug use in the outpatient department prescriptions of Maternity and Child Health Care Center of Putuo District of Shanghai

Investigation and category management of off-label drug use in the outpatient department prescriptions of Maternity and Child Health Care Center of Putuo District of Shanghai