Effectiveness Of Off-label Use Research Articles

An Issue about Off-Label-Use of Controlled Medicines: The Popularity and the Worry of Propofol— On the Legal Effects of Off-Label Use of Controlled Substance by Physicians

An Issue about Off-Label-Use of Controlled Medicines: The Popularity and the Worry of Propofol— On the Legal Effects of Off-Label Use of Controlled Substance by Physicians

The effect of off-label use of reduced-dose direct oral anticoagulants therapy in the treatment of pulmonary embolism comparable to standard-dose therapy

Direct oral anticoagulants (DOACs) have been shown to be effective and safe in preventing pulmonary embolism recurrence. In this single-center retrospective observational study, we aimed to evaluate the efficacy and safety of reduced-dose DOACs in 86 consecutive patients with acute pulmonary embolism. Patients were divided into standard-dose and reduced-dose DOACs groups. Initial clot volume did not significantly differ between the two groups (standard-dose DOACs vs. reduced-dose DOACs, 18.8 [Q1–Q3 7.3–30.8] mL vs. 10.0 [Q1–Q3 3.2–27.9] mL, p = 0.1). Follow-up computed tomography (CT) within 30 days showed a higher rate of clot volume reduction or disappearance in the standard-dose group compared to the reduced-dose group (standard-dose DOACs vs. reduced-dose DOACs, 81.6% vs. 53.9%, p = 0.02). However, at the final follow-up CT, there was no significant difference in clot volume change between the two groups (standard-dose DOACs vs. reduced-dose DOACs, 91.5% vs. 82.0%, p = 0.19). Major bleeding occurred in two patients in the standard-dose group (4.3%) and three patients in the reduced-dose DOACs group (7.7%) (p = 0.5). In conclusion, while standard-dose DOACs demonstrated superior efficacy in early clot reduction, reduced doses of apixaban and edoxaban showed comparable efficacy and safety profiles in long-term treatment of acute pulmonary embolism in certain patients.

Metabolic adverse effects of off-label use of second-generation antipsychotics in the adult population: a systematic review and meta-analysis.

Prescription rates of second-generation antipsychotics (SGAs) are rapidly increasing for non-indicated (i.e., off-label) usage. SGAs used for approved indications are associated with significant metabolic adverse effects, including weight gain. The objective of this systematic review and meta-analysis is to evaluate the metabolic adverse effects of SGA use for off-label management of psychiatric illnesses in the adult population. We performed a systematic database search to identify randomized controlled trials (RCTs) that reported on weight and other metabolic outcomes with off-label use of SGAs among adults. Thirty-eight RCTs met inclusion criteria for this review; 35 of these studies, with a total of 4930 patients, were included in the quantitative meta-analysis. Patients treated with olanzapine, risperidone, and quetiapine were more likely to report weight gain as a side effect and experience clinically significant (≥7%) weight gain compared to those treated with a placebo. Among studies that reported weight as a continuous outcome, olanzapine was associated with significantly greater weight gain across all disorders (mean difference (MD) = 3.24 kg, 95% CI: 2.57-3.90 p = 0.001, N = 12 studies). Similar trends were noted with quetiapine and risperidone. A meta-regression analysis revealed a positive dose-response association between olanzapine dose and weight gain (regression coefficient: 0.36, p = 0.001). This review demonstrates that off-label use of SGAs, and particularly olanzapine, is associated with significant weight gain among adult patients. Our findings are concerning given the widespread off-label use of SGAs. Further studies are required to better understand the effects of off-label SGA use on other metabolic parameters. The study was registered with the PROSPERO international database of prospectively registered systematic reviews (PROSPERO #143186).

A Stalled Revolution? Misoprostol and the Pharmaceuticalization of Reproductive Health in Francophone Africa.

Misoprostol entered the global market under the name Cytotec in the mid-1980s for the treatment of gastric ulcers. Decades of research have since demonstrated the safety and effectiveness of off-label use of misoprostol as a uterotonic in pregnant women to prevent and treat post-partum hemorrhage, treat incomplete abortion, or terminate first-trimester pregnancy. Global health experts emphasize misoprostol’s potential to revolutionize access to reproductive health care in developing countries. Misoprostol does not require refrigeration, can be self-administered or with the aid of a non-physician, and is relatively inexpensive. It holds particular promise for improving reproductive health in sub-Saharan Africa, where most global maternal mortality related to post-partum hemorrhage and unsafe abortion occurs. Although misoprostol has been widely recognized as an essential obstetric medication, its application remains highly contested precisely because it disrupts medical and legal authority over pregnancy, delivery, and abortion. I draw on fieldwork in Francophone Africa to explore how global health organizations have negotiated misoprostol’s abortifacient qualities in their reproductive health work. I focus on this region not only because it has some of the world’s highest rates of maternal mortality, but also fertility, thereby situating misoprostol in a longer history of family planning programs in a region designated as a zone of overpopulation since the 1980s. Findings suggest that stakeholders adopt strategies that directly address safe abortion on the one hand, and integrate misoprostol into existing clinical protocols and pharmaceutical supply systems for legal obstetric indications on the other. Although misoprostol has generated important partnerships among regional stakeholders invested in reducing fertility and maternal mortality, the stigma of abortion stalls its integration into routine obstetric care and availability to the public. I demonstrate the promises and pitfalls of pharmaceuticalizing reproductive health: despite the availability of misoprostol in some health facilities and pharmacies, low-income and rural women continue to lack access not only to the drug, but to quality reproductive health care more generally.

Metabolic Adverse Effects of Off-Label Use of Second-Generation Antipsychotics in the Adult Population: A Systematic Review and Meta-Analysis

Second generation antipsychotics (SGAs) are approved by the US Food and Drug Administration for treatment of schizophrenia, bipolar disorder, and refractory depression. Since the 1990’s, antipsychotic prescription has more than doubled, with off-label use disproportionately contributing. SGAs used “on-label’ have significant metabolic adverse effects (MAEs). Currently, there is no literature systematically investigating the MAEs of ‘off-label’ use to guide clinical decision-making practices.

Real-Life Study of Mepolizumab in Idiopathic Chronic Eosinophilic Pneumonia.

Idiopathic chronic eosinophilic pneumonia (ICEP) is an orphan lung disease characterized by concomitant systemic and local eosinophilia, along with bilateral lung infiltrates. Symptoms include dyspnea of subacute/chronic onset, cough, and general systemic signs. Although all patients do respond to oral corticosteroids, relapse rate is very high, which highlights the need for alternative therapies in case of relapsing ICEP. Mepolizumab is a fully humanized antibody directed against interleukin 5, a key growth factor of eosinophils. In the present study, we retrospectively studied the effect of off-label use of mepolizumab for relapsing ICEP. All data from patients treated with mepolizumab for relapsing ICEP were included in our database and diagnoses were reviewed. We analyzed the effect of treatment on relapse rate, oral corticosteroids (OCS) use, and lung lesions on high-resolution computed tomography (HRCT). We included ten patients in the final analysis, with a median follow-up of 9months after initiation of mepolizumab. Beside its expected effect on circulating eosinophils, treatment with mepolizumab was associated with a significant reduction of annual rate of exacerbations and a reduced consumption of corticosteroids. We also observed a remission of lung lesions on follow-up HRCT. In this open-label retrospective study, treatment of ICEP with mepolizumab was associated with a reduction of relapses, OCS use, and the disappearance of lung infiltrates.

Reconsideration of 2008 decision: Food and Drug Administration approval of etanercept for systemic treatment of moderate to severe pediatric psoriasis.

Although systemic etanercept was approved in 2004 for adults, the Food and Drug Administration (FDA) denied approval for use in children with psoriasis in 2008. Revision of the FDA's risk-benefit assessment in response to understanding of disease burden, unmet medical need, and the effect of off-label use in children with psoriasis led to the 2016 approval as the first systemic biologic product for the treatment of children aged 4-17 with moderate to severe psoriasis. This article delineates the thinking that led to this reconsideration. The underlying thinking paved the way to inform current pediatric drug development as the FDA continues to bring needed medical products to children.

Off Label Use of Drugs with Special Focus On CNS: Views From the Industry

Introduction The common off label use of drugs will be reviewed from the perspective of drug development and the support of marketed products. Objectives, Aims and Methods A review of the current effects of off label use, using publically available information with conclusions based on the experience of an active drug development scientist. Results Off label drug prescription (OLP) is common, it has been estimated that 20% of prescriptions are for a not approved use. While legal and sometimes useful, OLP presents serious challenges. Doctors often prescribe a drug off label without realizing it is not approved and do not know if commonly used drug treatments are approved. This makes it difficult for pharmaceutical representatives. Manufacturers are prohibited and most have been fined for promoting OLP. OLP is common when a drug is newly approved. Doctors want to prescribe without waiting for formal proof. This can make recruitment for clinical trials difficult. Also populations at special risk are usually not fully studied at the time a new drug is approved. It is often felt to be not ethical to withhold treatment from these groups while waiting for drug approvals. However, this practice can harm patients, as has been seen with the use of antipsychotics in the elderly. Conclusions Guidelines are needed to help the use and development of drugs understanding that approval is a needed and worthwhile goal for all medications; the practice of medicine should not be harmed by the drug approval process.

Off-label use of memantine as adjunctive treatment in schizophrenia: a retrospective case series study.

Memantine, an uncompetitive N-methyl D-aspartate receptor (NMDAR) open-channel blocker holds great promise for its potential clinical effectiveness as add-on therapy to on-going treatment with antipsychotics. We report here the results of a chart review-based retrospective case series study that examined the effectiveness of off-label use of memantine in patients with schizophrenia when used as adjunctive therapy to standard neuroleptic therapy. 17 of the 26 patients, whose case files were reviewed using a study-specific proforma showed clinical improvement in positive and/or negative psychopathology as well as in cognitive and/or functional domains. The doses of on-going antipsychotic medications could be reduced in a sizeable number of responders. None of the subjects reported serious adverse events. Memantine holds great promise as adjunctive therapy for treatment of schizophrenia. Randomized controlled trials, wherein memantine is administered at adequate doses for an adequate period of time to ongoing antipsychotic treatment are required to confirm its efficacy in alleviating symptoms of schizophrenia.

Activity and safety of sunitinib in patients with advanced radioactive iodine-refractory differentiated thyroid carcinoma in clinical practice

Our aim was to evaluate the effectiveness of off-label use of sunitinib in patients with advanced differentiated thyroid carcinoma (DTC) refractory to radioactive iodine (RAI) therapy. We performed a retrospective analysis of patients treated in the setting of clinical practice in a University General Hospital. Eleven consecutive patients (5 women, 6 men, mean age 63.0±12.9year) with advanced papillary (n=7) or follicular (n=4) thyroid carcinoma not suitable for curative surgery or RAI therapy were studied. Two patients were treated with one line of tyrosine kinase inhibitors before sunitinib therapy. All patients had evidence of objective progressive disease (PD). We analysed the objective response rate (ORR) and changes in thyroglobulin levels during therapy. Complete response was achieved in 1 patient (9%) and partial response (PR) in 2 patients (18%). Five patients (45%) had stable disease (SD). Therefore, ORR was 27% and disease control rate was 72%. We found that the decrement in thyroglobulin concentrations was significantly higher in patients with radiological disease control than in patients with PD. Most frequent grade 1 and 2 adverse events were fatigue, mucositis, hand-and-foot syndrome, hyporexia, rash, hypertension, and edema. In routine clinical practice, sunitinib appears to be effective and feasible in patients with advanced RAI-refractory DTC. Most patients achieved SD or PR, despite having PD at the start of treatment, and safety profile was consistent with that reported in previous clinical trials.

Abstract P3-07-09: Prevalence and effects of off-label use of chemotherapeutic agents in elderly breast cancer patients: estimates from Surveillance, Epidemiology and End Results-Medicare data

Abstract Purpose: To gain FDA approval, drug companies submit evidence from clinical trials demonstrating that a drug is safe and efficacious in a certain setting. Current regulations allow oncologists to prescribe approved drugs for uses other than those for which the drug was approved (off-label use). While there seems to be a consensus that off-label use is common in oncology, there is a lack of published data on recent trends and on utilization in different populations. The strength of evidence demonstrating safety and efficacy varies for drugs used in the off-label setting, and patients may be at risk for unacceptable toxicity. The risk of toxicity may be higher among older patients, whose ability to tolerate chemotherapy is compromised by age-related organ decline and comorbidities. Our objective was to describe the prevalence of off-label use of chemotherapeutic agents in elderly breast cancer patients with Medicare coverage and to compare toxicity between patients using off-label drugs and patients using only approved drugs. Materials and Methods: We identified women 65 and older with a first primary breast cancer diagnosed in 2000–2007 from Surveillance, Epidemiology and End Results (SEER) cancer registry data linked with Medicare claims. Specific chemotherapeutic agents used following diagnosis were identified in Medicare claims and classified as on- or off-label use based on whether the drug was approved for breast cancer as of May 2012. Thirty-day toxicity (ER visit, hospitalization or death) was compared between patients whose first line regimen contained only approved drugs and patients whose first line regimen contained at least one off-label drug using the Cochran-Mantel-Haenszel test. Results: The most commonly-used approved drugs were cyclophosphamide (used in 14% of patients), doxorubicin (10%), docetaxel (5%), fluorouracil (5%), and paclitaxel (5%). In total, forty-five off-label agents were used. Vinorelbine and carboplatin were each used in 1% of patients. No other off-label drug was used in more than 109 (0.11%) of patients. Toxicity was significantly higher for patients treated with off-label agents compared to patients treated with only approved drugs, after adjusting for stage at diagnosis (p = 0.01). Conclusions: In this population-based cohort, rates of chemotherapy use were generally low, and rates of off-label use were even lower, with only 3% of patients treated off-label. Off-label use became more common as stage at diagnosis increased, with use increasing from 1% in stage 0/1 patients to 12% in stage 4 patients. The higher toxicity rates observed in patients treated with off-label drugs may indicate that these drugs are less safe than approved agents. This result will be confirmed in a matched analysis accounting for age, stage and comorbidities. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-07-09.

Treatment of recurrent respiratory papillomatosis and adverse reactions following off-label use of cidofovir (Vistide®)

Recurrent respiratory papillomatosis (RRP) is caused by a human papilloma virus (HPV). It is a rare, sometimes debilitating disease compromising voice and airway. RRP is characterized by a variable course of disease, potentially leading to frequent annual surgical procedures, the number of which may exceed a hundred during the life time. The therapy focuses on surgical removal of the mucosal lesions in order to keep the airway open and the voice satisfactory. Till now, there is no curative therapy for the virus infection in itself. As recurrent surgery alone has proven to be insufficient in many cases, adjuvant therapy is increasingly being used. One of the mainstays of adjuvant therapy is the administration of intralesional cidofovir (Vistide®). Cidofovir is an antiviral agent, registered for the treatment of cytomegalovirus (CMV) retinitis in patients with AIDS. Since 1998 the drug has been used to treat patients with RRP [1]. Cidofovir can be regarded as a prodrug. It exerts the antiviral effect by decreasing the efficiency of DNA transcription following incorporation into the growing DNA chain [2]. Its use has been advocated in cases of papilloma refractive to repeated surgery, either due to its spread, or to its recurrence rate. Some case reports and series showed the effect of cidofovir treatment with few or no side effects [3–8]. The only prospective double-blind randomized controlled trail showed a significant improvement in the Derkay severity score between the cidofovir and placebo group but failed to show significant benefit in number of procedures performed [9]. On January 31 2011, an alarming news was communicated by Gilead (the producer of cidofovir) concerning very serious side effects of its off-label use [10]. The warning included reports on nephrotoxicity, neutropenia, oncogenicity and even some fatalities. The manufacturer emphasized that cidofovir is formulated for intravenous infusion only and the indication is CMV infection of AIDS patients. The manufacturer did not specify the severity of the reported complications, neither the off-label indication of the drug nor its way of administration. Unfortunately, up to the end of May 2011 the above mentioned communication was not received by the laryngologists in most countries. The warning caused a lot of discussion within the European Laryngological Society (ELS). The ELS (having >350 active members) is the main laryngological organization in Europe, representing laryngologists from more than 55 countries on all continents (http://www.elsoc.org). The ELS has taken its responsibility and initiated a research project on the side effects of off-label use of cidofovir in RRP patients. The purpose of such a study is to determine whether there are known nephrotoxic, neutropenic, or oncogenic side effects after having used intralesional cidofovir in patients with RRP. Facts are needed to decide whether or not intralesional use of cidofovir in the larynx is safe or not. Side effects might be dose dependent, and occur as a consequence of the number of administrations, the interval between applications or the cumulative dose. To determine the aforementioned, a multicenter retrospective analysis has been initiated among members of the ELS for which, among others, all members of its Scientific Council have been approached. Parallel to the retrospective study we are conducting an update on reported side effects in the literature. Reports of the studies will be submitted for publication in the official journal of the ELS, the European Archives of Otorhinolaryngology, Head and Neck Surgery.

Ethnic Disparities in Antipsychotic Drug Use in British Columbia: A Cross-Sectional Retrospective Study

Ethnic Disparities in Antipsychotic Drug Use in British Columbia: A Cross-Sectional Retrospective Study

Successful treatment of choroidal neovascularization complicating a choroidal osteoma with intravitreal bevacizumab.

To report the effect of off-label use of bevacizumab (Avastin) in the treatment of choroidal neovascularization associated with a choroidal osteoma. Interventional case report examining antivascular endothelial growth factor therapy used for choroidal neovascularization complicating a choroidal osteoma. A 24-year-old man with a choroidal osteoma presented with metamorphopsia and decreased vision in his left eye of 20/60. Clinical examination, fluorescein angiography, B-scan ultrasonography, and optical coherence tomography revealed a well-circumscribed macular choroidal osteoma with overlying subretinal hemorrhage and a choroidal neovascular membrane. The patient was treated with a series of 3 intravitreal bevacizumab (Avastin) injections (1.25 mg/0.05 mL) performed at baseline, 1 month, and 2 months. Treatment resulted in resolution of subretinal hemorrhage and fluid with improvement in visual acuity to 20/30 at the 5-month follow-up. Intravitreal bevacizumab seems to be a promising treatment for choroidal neovascularization (CNV) associated with choroidal osteomas.

16. Serum biomarkers and clinical effect of off-label use of miglustat in GM1 gangliosidosis

16. Serum biomarkers and clinical effect of off-label use of miglustat in GM1gangliosidosisLawrence Charnas, University of Minnesota, Minneapolis, MN, USABackground: GM1 gangliosidosis, a deficiency in beta-galactosidasewith storage of gangliosides causes skeletal, neurologic and other organdysfunction. Glucocerebroside synthesis inhibition by miglustat mightdecrease GM1 accumulation and offer clinical benefit. Study Design:Observational clinical experience Patient Descriptions: Three patients (1infatntile, 2 juvenile onset) with GM1 gangliosidosis were treated withmiglustat. Patient 2, Outcomes: Dosage ranged from 5 to 15 mg/kg/dayin divided doses titrated to tolerability. Side effects included weight lossin the two juvenile onset patients without diarrhea. Chitotriosidase(CHITO) levels, angiotensin converting enzyme (ACE) and tartrateresistant acid phosphatase (TRAP) measures were markedly elevated inthe infant. No follow up studies were available. The infantile patientwas treated from 7 to 19 months, and died at 23 months of age. ACE levelswere consistently normal in both juvenile patients. TRAP levels wereconsistently in the 11-year-old patient during treatment. After 12 monthsof therapy, she showed marked progression of neurologic disease andelevation of CHITO with normalization of CHITO but not TRAP afterstopping miglustat. Patient 3 showed consistently elevated CHITO levelswithout response to miglustat and no clinical change.Conclusions: Miglustat at the prescribed doses produced no demon-strable clinical benefit in 3 patients. Serum biomarkers of macrophageactivation are variable across disease forms, but do not appear to respondin juvenile patients.doi:10.1016/j.ymgme.2007.10.02817. Immunosuppression as a novel therapeutic target in Batten disease?Jonathan Cooper

Off-Label Use of Antidepressant, Anticonvulsant, and Antipsychotic Medications Among Georgia Medicaid Enrollees in 2001

To determine the prevalence of and factors associated with the off-label use of antidepressant, anticonvulsant, and antipsychotic medications. A retrospective analysis of Georgia Medicaid recipients was conducted. Recipients prescribed antidepressant, anticonvulsant, or antipsychotic medications were identified. Logistic regression analysis was used to identify factors associated with off-label use. A total of 46,976 (75.42%) antidepressant recipients, 38,497 (80.12%) anticonvulsant recipients, and 21,252 (63.62%) antipsychotic recipients received at least 1 of these medications off-label in 2001. The likelihood of receiving off-label medications increased remarkably with advancing age (>or= 65 vs. < 65 years: antidepressant: OR = 5.15, 95% CI = 4.76 to 5.56; anticonvulsant: OR = 4.54, 95% CI = 4.16 to 4.96; antipsychotic: OR = 5.21, 95% CI = 4.82 to 5.63). Although receiving new anticonvulsants launched after 1993 was the strongest predictor (OR = 7.63, 95% CI = 7.07 to 8.23) of receiving off-label anticonvulsant medications, exposure to newer antidepressants and antipsychotics did not confer a higher chance of receiving off-label medications (selective serotonin reuptake inhibitors vs. tricyclic antidepressants: OR = 0.43, 95% CI = 0.40 to 0.45; atypical vs. conventional antipsychotics: OR = 0.76, 95% CI = 0.72 to 0.80). The off-label use of antidepressant, anticonvulsant, and antipsychotic medications is highly prevalent. Further research to study the effects of off-label use among this high risk subpopulation may be an important step toward defining the scope of and potential for such use.