Off-label Indications Research Articles

Off-label Antidepressant Use for Treatment and Management of Chronic Pain: Evolving Understanding and Comprehensive Review.

While clinicians have been using antidepressants for off-label indications in the treatment of chronic pain in recent years, newer studies have proven effectiveness and provided additional mechanistic understanding and defined potential adverse effects. As depression and chronic pain are frequently comorbid conditions, the use of antidepressants has allowed for treatment of both conditions concomitantly in the same patient population. The most commonly used antidepressants for chronic pain are tricyclic antidepressants (TCAs), though selective serotonin or noradrenaline reuptake inhibitors and other atypical antidepressants have been shown to be effective at treating chronic pain. In addition to neuropathic pain, bupropion has also demonstrated effectiveness in treating chronic pain caused by inflammatory bowel disease. Selective norepinephrine receptor inhibitors (SNRIs), including duloxetine, serve to suppress neuropathic pain by altering recovery of the noradrenergic descending inhibitory system in the spinal cord. While the direct mechanism of action is largely unknown, TCAs may suppress the noradrenergic descending inhibitory system to produce an antihyperalgesic effect. The use of antidepressants offers alternative and adjunctive therapy options for patients suffering from chronic pain from various modalities. TCAs, mono-amine oxidase inhibitors, selective serotonin receptor inhibitors, SNRIs, and atypical antidepressants have been shown to have analgesic and sometimes antiinflammatory capabilities that are independent of their mood-stabilizing effects. Further studies are warranted to establish better safety profiles and efficacy of antidepressant use in chronic pain.

Real-Life Experience of Using Hydroxycarbamide to Treat Children Affected with Sickle Cell Disease: The ESCORT-HU Cohort Study

Background: Several controlled studies had established hydroxycarbamide as a gold standard for treatment of children affected with sickle cell disease. The European Sickle Cell Disease Cohort - Hydroxyurea (ESCORT-HU) is a cohort study designed to monitor in a large number of patients over a long period of time the use of hydroxycarbamide in current practice. Here we present the results on the paediatric cohort. Methods: Children were enrolled between January 2009 and June 2017. Patients were followed-up according to usual clinical monitoring. Efficacy was studied in a subpopulation naive for the treatment at enrolment, by comparing changes in Hb and HbF% levels, and in clinical outcomes after 12 months of treatment. Safety was assessed from the occurrence of adverse events in the total cohort. Findings: Eight hundred and twelve children (10.1 ± 2.3 years) have been enrolled; of these 141 were naive to the treatment. Median duration of follow-up for the whole cohort was 29 months (0-108). Seventy-four % of the patients were treated within the licensed indication (painful crisis and acute chest syndrome); 26% of children were treated for off-label indications, mostly severe anaemia and brain protection. Mean dosages ranged from 16.6 ± 3.1 mg/kg/d at initiation to 22.0 ± 4.4 mg/kg/d after 4 years. No attempt was made in most cases to reach the maximal tolerated dose. Mean increases of Hb at 6 and 12 months (g/dl), and HbF at 6 months (%) were + 0.68, +1.0, and + 6.1% respectively. Hydroxycarbamide also reduced the number of painful crises (p<0.001), number of episodes of ACS (p<0.001), number (p<0.001) and duration of hospitalisations related to SCD (p<0.001).The most common hydroxycarbamide-related adverse events were neutropenia and thrombocytopenia. No unexpected side-effect was observed. Interpretation: These real-life data confirm the effectiveness and safety of hydroxycarbamide in children with SCD. Trial Registration: This study is registered at ClinicalTrials.gov, reference NCT02516579 and in the the EU registries site under the reference ENCEPP/SDPP/10565. Funding Statement: The ESCORT-HU study was funded by Addmedica. The sponsor participated with investigators in the study design, the collection, analysis and interpretation of data, and the review of the manuscript. Declaration of Interests: Mariane de Montalembert: Grants and personal fees from Novartis and Addmedica, during the conduct of the study. Lena Oevermann: No conflict of interest outside the submitted work Malika Benkerrou: No conflict of interest outside the submitted work Valentine Brousse: Grants and personal fees from Addmedica, during the conduct of the study Corinne Pondarre: Grants and personal fees from Addmedica during the conduct of the study; personal fees from Blue Bird bio, Lydia Diavalle-Doumdo: No conflict of interest outside the submitted work Marie Bello: No conflict of interest outside the submitted work Narcisse Elenga: No conflict of interest outside the submitted work Stephan Lobitz: Nordic Pharma, personal fees from Addmedica, during the conduct of the study; grants and personal fees from Novartis, personal fees from Bluebird, personal fees from Celgene, personal fees from Jazz pharma , personal fees from Emmaus/myTomorrows, outside the submitted work. Ethics Approval Statement: An independent Ethics committee approved the study in each country. Patients (or persons having parental authority) gave consent to participate.

Predictors of Clinical Outcome After Treatment of Intracranial Aneurysms with the Pipeline Embolization Device

Flow-diverting stents have revolutionized the endovascular treatment of intracranial aneurysms. The purpose of this study is to identify predictors of adverse outcomes associated with the pipeline embolization device (PED). A retrospective analysis of all patients treated with PED at a single high-volume center from January 2014 to September 2018. Patient outcomes, neurologic morbidity/mortality, and other clinical variables were analyzed. We treated 204 aneurysms in 170 patients with PED. Mean length of follow-up was 11 months. Most (181) aneurysms (89%) were located in the anterior circulation, and 23 (11%) were found in the posterior circulation. Most aneurysms were saccular (82%), followed by fusiform (11%), blister (4%), and dissecting pseudoaneurysms (3%). Mean aneurysm size was 8.2+ 5.7 mm with 145 (71%) small aneurysms (≤10 mm), 53 (26%) large aneurysms(between 10 and 25 mm), and 6 (3%) giant aneurysms (≥25 mm). Ninety-two percent of aneurysms were unruptured, and 8% were ruptured. The overall major neurologic morbidity/mortality was 4.7% and 1.8%,respectively. The all-cause mortality was 2.9%. Predictors of neurologic morbidity/mortality included the baseline modified Rankin Scale (P= 0.001), aneurysm neck size (P= 0.003), aneurysm size (P= 0.006), anterior versus posterior location (P= 0.02), and rupture at presentation (0.006). The P2Y12 Reactivity Unit, parent vessel diameter, and patient age did not correlate with adverse events. The PED has a satisfactory safety profile in both on- and off-label indications. A poor clinical patient baseline, wider aneurysm neck or larger size, and rupture predict an increased risk of an unfavorable outcome.

Off-Label Use of Second-generation Antipsychotics in Bipolar Disorder: A Survey of Italian Psychiatrists.

Bipolar disorder (BD) is characterized by recurrent depressive and manic episodes. Lithium, valproate, lamotrigine, and some second-generation antipsychotics (SGAs) are the most typical pharmacological treatments for BD, the main goal being mood stabilization. However, despite these treatments, most patients continue to experience recurrent mood episodes and residual symptoms. Findings from several studies suggest that some SGAs may be beneficial beyond approved indications. The goal of the survey presented in this article was to examine Italian psychiatrists' attitudes concerning the off-label use of SGAs in depressive and maintenance phases of BD. A questionnaire about the off-label prescription of SGAs was e-mailed to 300 psychiatrists from Northern, Central, and Southern Italy affiliated with the Italian Society of Psychopharmacology (SINPF) to investigate the frequency of and motivation for off-label use of SGAs and evaluate the psychiatrists' attitude toward use of specific SGAs in BD; 202 questionnaires were completed. The respondents were equally distributed in terms of sex, and the mean age of respondents was 44.1 years. The majority of the sample reported use of SGAs for off-label indications either very often (16.7%), often (33.7%), or occasionally (34.7%). The main motivation for off-label use of the SGAs was the presence of published evidence (51.5%), followed by patients' nonresponse to previous treatment (37.1%). With regard to the use of specific SGAs in BD, off-label aripiprazole was considered appropriate for depressive episodes by 46% of the psychiatrists, followed by olanzapine which was considered appropriate by 33.7%. For maintenance treatment of BD, off-label asenapine was considered appropriate by 45% of the psychiatrists, followed by long-acting aripiprazole and olanzapine pamoate, which were considered appropriate by 37.1% and 23.8%, respectively. In summary, ~50% of Italian psychiatrists frequently (very often or often) prescribe SGAs for off-label indications. Given the relatively limited number of indicated effective treatments for BD, the use of some SGAs off-label may be considered appropriate when dealing with patients whose BD is resistant to medications with labeled indications for BD.

Off-Label Use of Antipsychotic Agents in Dementia: Evidence for the Revision of the Reimbursement Policy.

Harmonized requirements apply for the marketing authorization of medicinal products in the EU Member States. On the contrary, the national legislations on the drug reimbursement are not harmonized. The aim of this study was to find out if they are robust enough to ensure high standards of public health protection with focus on the symptomatic treatment of dementia in the elderly. A computerized search of authorized therapeutic indications of haloperidol and trihexyphenidyl in the national databases of 8 EU member states and an analysis of the national legislation on reimbursement policies in Lithuania and Latvia was performed. There is a discrepancy in the decisions on the marketing authorization vs the reimbursement in Lithuania and Latvia (reimbursement of haloperidol and trihexyphenidyl for the off-label treatment of dementia). National legislation on the drug reimbursement in Lithuania and Latvia does not provide safeguards for public health at the same level as the marketing authorization does. Absence of a revision of former decisions in the light of new evidence is a critical weakness of the drug reimbursement in Lithuania and Latvia. Reimbursement for the off-label indications may pose a risk to public health.

Emerging Trends in Metformin Prescribing in the United States from 2000 to 2015.

Metformin (MET) is used as first-line treatment for type 2 diabetes mellitus but has been shown to have pleiotropic effects that have expanded its use to various conditions. Limited current data exist regarding unconventional use within various patient populations. The aim of this study was to evaluate US FDA-approved and off-label MET utilization in the US from 2000 to 2015. We performed a retrospective analysis of outpatient MET prescribing in the US from 2000 to 2015. Data from the Medical Expenditure Panel Survey (MEPS) administered by the Agency of Healthcare Research and Quality were analyzed. Demographic characteristics, including age, sex, socioeconomic status, comorbidities, and region, were analyzed using the MEPS Household Component (HC). Prescription rates were defined as the annual number of MET prescriptions divided by the corresponding population estimate. Population denominators were derived using the MEPS HC. The MEPS estimates US populations based on sampled persons in the target population (civilian, non-institutionalized) for an entire year. MET prescribing is represented by population per 1000 persons. We determined if changes of MET prescribing were uniform across five age groups: < 18years, 18-29years, 30-49years, 50-64years, and 64 years and older. An estimated 553,291,094 MET prescriptions were dispensed in the US from 2000 to 2015. Prescribing rates steadily increased from 2000 to 2015. FDA-approved MET prescription rates increased from 2.27 per 1000 persons in 2000 to 235 per 1000 persons in 2015, while off-label MET prescription rates increased from 0.74 per 1000 persons in 2000 to 20.3 per 1000 persons in 2015. The top indications for off-label MET use were endocrine disorders (45.8%), cardiovascular disorders (18.2%), female reproductive disorders (12.9%), and metabolic disorders (10.9%). MET prescribing rates for FDA-approved indications increased across all age groups in 2000 and 2015, with the most substantial increase seen in adults aged 50-64years and > 65years (1.7 per 1000 persons to 20.6 per 1000 persons, and 2.3 per 1000 persons to 18.7 per 1000 persons, respectively). While off-label MET increased across all age groups from 2000 to 2015, a tenfold increase (< 1.0 to 10.6) was seen in adults aged 30-49years of age. Overall, MET use has substantially increased within the past 15years, which was mainly driven by older adults. Our study highlights the emerging prevalence of MET use in both FDA-approved and off-label indications.

The journey of canakinumab; on- and off-label indications

The role of interleukin-1 (IL-1) has been studied in many diseases, ranging from auto-inflammatory diseases to malignancies, and much has been discovered. There are currently four IL-1 inhibitors available, but only two have been approved in Europe: the receptor antagonist anakinra, and the IL-1b selective inhibitor canakinumab. The aim of this paper is to summarise the on- and off-label use of canakinumab (ILARIS®).

Classification and characteristics of on-label and off-label apixaban use in Denmark and Sweden.

To estimate the proportion of apixaban users who received the drug for on-label indications and characterise the patients using apixaban for on-label and off-label indications. We report results from two independently conducted studies in Denmark and Sweden, with 19,709 Danish and 17,592 Swedish patients, who received at least one outpatient dispensing of apixaban as identified through nationwide prescription registries. Indications, inferred from inpatient and hospital diagnoses recorded at the initial apixaban dispensing, were classified as on-label, off-label, or unclassified according to the Summary of Product Characteristics. All diagnoses were retrieved using inpatient or outpatient hospital diagnoses at the first outpatient dispensing during the study period. Men comprised 52% of the users in both Denmark and Sweden. The median age was 76 years (interquartile range [IQR]: 68-83 years) among Danish patients and 74 years (IQR: 67-82 years) among Swedish patients. An on-label indication could be assigned to 82.6% (95% confidence interval [CI]: 82.1%-83.1%) of the Danish patients and 86.4% (95% CI: 85.9%-86.9%) of the Swedish patients. The main on-label indication for apixaban was non-valvular atrial fibrillation (NVAF), which accounted for 76.1% of the indications in Denmark and 69.1% of the indications in Sweden. Off-label indications were assigned to 10.8% (95% CI: 10.3-11.2) of the Danish patients (main indication possible mechanical heart valve) and 7.7% (95% CI: 7.3-8.1) of the Swedish patients (main indication off-label atrial fibrillation). The majority of apixaban initiators in Denmark and Sweden received apixaban for an on-label indication, primarily for NVAF.

The Extended Use of Eculizumab in Pregnancy and Complement Activation⁻Associated Diseases Affecting Maternal, Fetal and Neonatal Kidneys-The Future Is Now?

Excessive complement activation is involved in the pathogenesis of many diseases and the kidney is an organ with particular susceptibility to complement-mediated injury. Apart from paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS), there are several other diseases with clear evidence of complement activation affecting both maternal and fetal kidneys during pregnancy and causing long-term adverse outcomes. Several novel drugs have been recently developed for blocking the complement cascade, including purified plasma proteins, new monoclonal antibodies, recombinant proteins, small molecules, and small interfering RNA agents. Eculizumab, the humanized monoclonal IgG2/4-antibody targeting C5 was approved by the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for treatment of two rare diseases: PNH in 2007 and aHUS in 2011. There is an increasing number of publications of successful use of eculizumab for off-label indications, e.g., in pregnant women with antiphospholipid syndrome, sickle-cell anemia, and HELLP syndrome. These severe diseases are associated with both high maternal and fetal morbidity and mortality rate and substantial prematurity. Eculizumab has considerably improved overall outcome of patients with PNH and aHUS, enabling safe pregnancy for many women. Prolongation of pregnancy and the use of eculizumab, even for only a few weeks, may protect not only maternal renal function, but also alleviate acute and long-term renal consequences of prematurity in offspring.

Misoprostol – Drug That Changed the Practice of Gynecology and Obstetrics with Its Off-Label Indications

Misoprostol is a synthetic analogue of prostaglandin E 1 . The drug was developed by G. D. Searle & Company in 1973 for prevention of stomach ulcers. Since 1986, it is being used for its ‘off label’ indications in obstetrics and gynecology. [1] The common indications are medical termination of pregnancy (MTP), medical management of incomplete abortion, induction of labor, cervical ripening before surgical procedures and prevention and treatment of postpartum hemorrhage [2]. Since it is inexpensive, heat stable, no drug interactions and wide range of applications in reproductive health, ‘WHO’ in 2011 has added it in the model list of essential medicines. In this article we have reviewed misoprostol its uses and recommendations in modern obstetrics and gynecology.

Multicenter clinical experience of real life Dalbavancin use in gram-positive infections

Dalbavancin, a lipoglycopeptide with prolonged half-life approved for the treatment of acute bacterial skin and soft tissue infections, can be used for the treatment of infections caused by gram-positive bacteria requiring long term treatment such as endocarditis, prosthetic joint infections (PJI) or osteomyelitis. Clinical data are limited in these settings. ObjectivesTo evaluate indications, safety, tolerability and long-term outcomes of dalbavancin-treated patients.Patients and methods Our multicenter, retrospective study includes patients who received dalbavancin in Austria from September 2016 to March 2018. 90-day outcomes and tolerability were determined. ResultsA total of 101 patients were included in 3 centers (57% male, median age 65 years). The treated infections were PJI (31%), osteomyelitis (29%), endocarditis (25%) and acute bacterial skin and soft tissue infections (12%). Concomitant use of other antimicrobial substances was common (63%). The mean total cumulative dose of dalbavancin was 3,357mg (±2,283mg). Clinical success rate was 89%. Side effects occurred in 3/101 patients. ConclusionIn this real-life study dalbavancin was primarily used in off-label indications for treatment of PJI, osteomyelitis and endocarditis. Success rate was high (89%), tolerability and safety were excellent in this setting. Dalbavancin may therefore be used in these off-label indications as alternative treatment approach.

Pharmacology, Pharmacokinetics and Pharmacodynamics of Eculizumab, and Possibilities for an Individualized Approach to Eculizumab.

Eculizumab is the first drug approved for the treatment of complement-mediated diseases, and current dosage schedules result in large interindividual drug concentrations. This review provides insight into the pharmacokinetic and pharmacodynamic properties of eculizumab, both for reported on-label (paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, generalized myasthenia gravis) and off-label (hematopoietic stem cell transplantation-associated thrombotic microangiopathy) indications. Furthermore, we discuss the potential of therapeutic drug monitoring to individualize treatment and reduce costs.

Off-label use of tamoxifen in a Chinese tertiary care hospital.

Background Tamoxifen is an estrogen receptor modulator used for the treatment of breast cancer; however, currently, it is used in many off-label indications. Objective To investigate the prevalence of tamoxifen off-label prescribing and explore available scientific evidence that supports those uses in outpatients. Setting Xiamen maternity and child health care hospital in Xiamen city of China. Method All the prescriptions of outpatients receiving tamoxifen were exported from an electronic prescribing system during a 1-year period. Tamoxifen use was then classified as either on- or off-label according to the criteria we established previously, and the details of the off-label prescriptions were collected. Logistic regression was applied to explore predictive variables. Evidence search was limited to Up-To-Date, the Micromedex database and PubMed. Main outcome measure The rate of off-label use, risk factors identified by logistic regression and evidence exhibition. Results A total of 75% of all the prescriptions available were classified as off-label use. Hyperplasia of the breast was the most frequently prescribed off-label indication. According to the analysis of logistic regression, male patients, patients less than 34years old, and physicians with a higher professional title were more likely associated with off-label prescribing. After a search in Up-To-Date, the Micromedex database and PubMed, only male infertility, atypical hyperplasia, mastodynia, peripheral precocious puberty and gynecomastia were found to have strong evidence supporting the use of tamoxifen off-label (22.75%). Conclusion Although the off-label use of tamoxifen was common in our hospital, there was a relative shortage of evidence available supporting those uses.

Essential Pharmacotherapies for Bipolar Disorder

The evidence basis for treatment of bipolar disorder, both for adults and children, is fairly varied and while Federal Drug Administration (FDA) approval provides one marker of evidence, many psychotropic medications are used for off-label indications. Primary care providers are increasingly at the forefront of initiating treatment for patients with mental health disorders. The purpose of this review is to discuss the current state of evidence for medications treating bipolar disorder, highlighting the evidence, exploring contraindications, side effects, and monitoring requirements for each of the major agents available. Currently, there are three major classes of medication to treat bipolar disorder: lithium, anti-seizure drugs, and a growing range of second-generation antipsychotics. The guiding principle in initiation of treatment is to target treatment to the primary phase of illness while balancing side effect profiles with patient characteristics and comorbidities. While FDA approval of medications for the treatment of bipolar disorder is somewhat limited for both children and adults, in practice, a wider range of medications have shown to be useful. Increasing second-generation antipsychotic medications can be used as first-line agents for both bipolar mania and bipolar depression.

Lamotrigine Uses in Psychiatric Practice.

Lamotrigine (LAM), an antiepileptic, with panoply of indications and uses in neurology, is FDA approved, in psychiatry, for bipolar prophylaxis. Apart from this indication, trend of its use in psychiatry is on the rise addressing a multitude of disorders. LAM remains one of only few psychotropic drugs with antiglutamate activity. This might render LAM a potential therapeutic option in treatment-resistant major psychiatric disorders. We reviewed LAM pharmacology and its diverse indications while examining the extant evidence. EMBASE, Ovid MEDLINE, PubMed, Scopus, Web of Science, and Cochrane Database of Systemic Reviews were searched for all relevant studies up to date of June 2016. Sound evidence supports use of LAM for acute bipolar depression and prophylaxis, treatment-resistant schizophrenia, treatment-resistant obsessive-compulsive disorder, posttraumatic stress disorder, depersonalization disorder, and affective dysregulation and behavioral dyscontrol domains of borderline personality disorder. Less compelling evidence is present for use in behavioral and psychological symptoms of dementia and neuropsychiatric sequelae of traumatic brain injury. No evidence supports use in autism spectrum disorder or acute unipolar depression. LAM is an important addition to the psychopharmacological armamentarium. Level of evidence supporting the use of LAM in off-label indications is highly variable, and hence, sound clinical judgment is necessary for its proper use and placement in real-life psychiatric practice and psychopharmacotherapy algorithms.

Oral Tofacitinib: Contemporary Appraisal of Its Role in Dermatology.

Tofacitinib, an oral Janus kinase inhibitor (Jakinib), is an emerging treatment modality whose well-established efficacy in systemic inflammatory diseases is now being actively explored for cutaneous disorders (arising due to the patient's dysimmune responses) that are not responding to and/or sustaining intolerable adverse effects with the classical immunosuppressives and other targeted therapies such as the biologics. The most common dermatoses for which oral as well as topical Jakinibs such as tofacitinib have been evaluated and are being used albeit as an off-label indication include psoriasis, psoriatic arthritis, alopecia areata, vitiligo, and atopic dermatitis. This article provides a succinct review on the current status of oral tofacitinib in dermatology through literature search of PubMed database and stresses on the need for further evidence generation to define the drug's place in the therapeutic arsenal of dysimmune cutaneous disorders.

Analysis of sialic acid levels in Chinese intravenous immunoglobulins by high-performance liquid chromatography with fluorescence detection.

Intravenous immunoglobulin (IVIg) is increasingly used for the treatment of autoimmune and systemic inflammatory diseases with both licensed and off-label indications. Recent studies indicated that IVIg-mediated immunomodulation and anti-inflammation are closely associated with the IgG sialylation, especially with IgG crystallizable fragment (Fc) sialylation. The sialic acid levels of the IgG molecules and Fc fragments in 12 IVIg preparations from six Chinese manufacturers were evaluated. The Fc fragments were derived from the papain digestion of IVIg, followed by affinity and size exclusion chromatography. The sialic acid levels in Fc fragments and IVIg preparations were determined by high-performance liquid chromatography with fluorescence detection, after the sialic acid residues were released from the proteins. The results showed that the sialic acid levels in Chinese IVIg preparations ranged from 0.875 (mol/mol IgG) to 1.085 (mol/mol IgG), and the sialic acid levels in Fc fragments were from 0.321 (mol/mol Fc) to 0.361 (mol/mol Fc). Furthermore, the sialic acid levels of IVIg preparations and Fc fragments from different Chinese manufactures were significantly different. These findings will contribute to an increased understanding of Chinese IVIg preparations and the relationship between the sialic acid levels in IVIg preparations and their clinical efficacy in future clinical studies.

Thesaurus for off-label indications for systemic antifungal agents

ObjectivesFollowing the removal of temporary treatment protocol procedures, we developed a thesaurus for off-label indications for systemic antifungals at our facility to update clinical practices and to control off-label prescriptions. Materials and methodsClinical practice guidelines and literature data were analyzed. This work was part of an antifungal stewardship program. ResultsOff-label wording (prophylaxis, preemptive, empirical, curative) and corresponding antifungals and references were validated by the multidisciplinary group for antifungal agents under the aegis of the Commission for the use of drugs and sterile medical devices and of the anti-infective committee. ConclusionConsidering the complexity of invasive fungal infection management, this thesaurus needs to be shared and used as a helping tool to review off-label situations.

Evaluation of Recombinant Factor VIIa Utilization and Development of a Cost-Effective Dose Minimization Protocol in Adult Cardiac Surgery Patients at an Academic Medical Center

Background: Although recombinant factor VIIa is often utilized to mitigate critical bleeding following cardiac surgery, the optimal dosing strategy in this population is not well-established. At our institution, hospital guidelines recommend administration of recombinant factor VIIa 60 mcg/kg for all off-label indications. However, available data suggest doses as low as 17 mcg/kg have been efficacious in cardiac surgery patients with critical bleeding. Additionally, although low-dose recombinant factor VIIa (< 40 mcg/kg) and high-dose (50-109 mcg/kg) dosing strategies have been reported equally efficacious according to retrospective, observational studies, higher doses may be associated with increased incidence of adverse events. Therefore, we aimed to evaluate the safety of recombinant factor VIIa in cardiac surgery patients with critical bleeding, and estimate potential cost-savings associated with implementation of a low-dose recombinant factor VIIa protocol in this population.Methods: All adult cardiac surgery patients who received one or more doses of recombinant factor VIIa during a 1-year period (July 1, 2016 to June 30, 2017) were included. Thromboembolic event rates documented within 14 days following recombinant factor VIIa administration were evaluated in patients alive at discharge. An average wholesale price of 2.59 USD per mcg was utilized for recombinant factor VIIa cost calculations.Results: A total of 16 patients received 24 doses of recombinant factor VIIa during the study period. The median weight-based dose administered was 55 mcg/kg (utilizing actual body weight), and the median dose was 5 mg. The median cost per recombinant factor VIIa dose was 12,950 USD, resulting in a total expenditure of 277,174 USD. Nine of sixteen patients (56%) survived to hospital discharge. Five of nine (56%) patients alive at discharge experienced thromboembolic complications following recombinant factor VIIa administration, three (60%) of which were central nervous system (CNS) thromboembolic events. Based on data supporting low-dose strategies, a proposed weight-based recombinant factor VIIa dose-minimization protocol was developed by leadership in the departments of pharmacy, hematology, cardiac surgery, and cardiac anesthesia (Table 1). Implementation of this protocol would result in an estimated annual cost-avoidance of 168,376 USD.Conclusions: Recombinant factor VIIa administration at a dose of 55 mcg/kg in adult cardiac surgery patients with critical bleeding is associated with a high rate of thromboembolic events, including CNS thromboembolism. Additionally, this recombinant factor VIIa dosing strategy is associated with significant cost, which can be substantially reduced with implementation of a low-dose recombinant factor VIIa protocol in the cardiac surgery population. DisclosuresNo relevant conflicts of interest to declare.

Trends in First Gabapentin and Pregabalin Prescriptions in Primary Care in the United Kingdom, 1993-2017

This study examined the rates of patients in the United Kingdom treated with gabapentin and pregabalin for the first time, and the rates of these patients with an off-label indication or a coprescription of opioids or benzodiazepines.