On- and off-label utilisation of antipsychotics in Australia (2000-2021): Retrospective analysis of two medication datasets.

OBJECTIVE: To determine antipsychotic utilisation patterns in Australian adults from 2005 to 2021, with a focus on on-label and off-label prescriptions. METHODS: We examined antipsychotic dispensing trends in adults from 2005 to 2021 using a 10% sample of the Pharmaceutical Benefits Scheme (PBS) dataset, which contains patient-level information on medicines dispensed throughout Australia. The lack of diagnostic information in PBS was substituted by analysing BEACH (Bettering the Evaluation And Care of Health) dataset, a cross-sectional national survey from 2000 to 2016, consisting of data from general practitioner-patient encounters. RESULTS: There were 5.6 million dispensings for 164,993 patients in PBS throughout this period; 69% patients had >1 dispensing, with a median of 6 per patient. Calculating the estimated period of exposure gave a total of 693,562 treatment episodes, with a median duration of 80 days. There were steady increases in both the incidence and prevalence of antipsychotic dispensings, mainly due to oral second-generation antipsychotics. The most commonly prescribed antipsychotics were quetiapine, olanzapine and risperidone, with a significant portion of patients receiving low-dose quetiapine without dose titration. Analysis of diagnostic indications from BEACH indicated that 27% of antipsychotic prescriptions were off-label for indications such as depression, dementia, anxiety and insomnia, at much lower prescribed daily dosages. CONCLUSION: The increasing prescribing and off-label use highlights concerns about chronic adverse effects caused by antipsychotics. The combined analysis of medication dispensings and the diagnostic indications for which they are prescribed is a novel approach and throws a spotlight on the need for additional monitoring of antipsychotics.

Risankizumab as a Therapeutic Approach for Recalcitrant Pyoderma Gangrenosum.

ABSTRACT: Pyoderma gangrenosum (PG) is a neutrophilic dermatosis that is challenging to diagnose and treat. Clinicians frequently use fast-acting corticosteroids, which are subsequently combined with slower-acting immunosuppressants to progressively taper the corticosteroid dosage. Current research is focused on the use of monoclonal antibodies (mAbs) directed against target molecules involved in the pathogenesis of PG. However, available data on their efficacy are based on sporadic case reports and clinical experiences, so the authors aimed to evaluate the efficacy of risankizumab, an anti-interleukin-23 mAb, in the management of two complex PG cases. The authors enrolled two patients with PG who were already treated with immunosuppressive therapies. Their management was based on the off-label use of an mAb directed against the p19 subunit of interleukin-23: risankizumab. Patients received subcutaneous injections of 150 mg at the start of treatment, at week 4, and then every 10 weeks thereafter. Systemic therapy was combined with local management of ulcers, based on the principles of TIME (tissue, infection, moisture balance, and epithelialization) applied to the inflammatory and noninflammatory phases of PG. Clinical resolution was obtained at week 24 for patient 1 and week 16 for patient 2 and was maintained until week 40, without adverse effects or disease recurrence. These clinical cases demonstrate that risankizumab is a valid tool in terms of efficacy and safety for complicated cases of multirefractory PG when provided in parallel with local personalized wound management.

[Chinese expert consensus on off-label use of Tocilizumab in rheumatic diseases].

The interleukin-6 (IL-6) pathway plays a crucial role in various rheumatic diseases. Tocilizumab, a biologic targeting IL-6 receptor, has been widely used in clinical practice, though it's officially approved in China for only three indications. To address clinical challenges associated with the off-label use of tocilizumab in treating rheumatic diseases, the Committee of Chinese Primary Health Care Foundation for Rheumatologists and Immunologists engaged multidisciplinary experts and highlight 12 related clinical issues. We aggregated the drug specifications, the guidelines for clinical management of rheumatic diseases and the evidence from clinical research. Recommendations were formed through voting with the consensus conference method incorporating the Oxford evidence-based medicine criteria to evaluate the strength of evidence and recommendations. We have formulated 10 recommendations for off-label use of tocilizumab related to giant cell arteritis, polymyalgia rheumatica, Takayasu arteritis, systemic sclerosis, adult-onset Still's disease, rheumatoid arthritis, and juvenile idiopathic arthritis. This consensus aims to provide references for the rational use of tocilizumab in clinical practice and enhance pharmacovigilance monitoring.

Off-Label Use of the 8-F Angio-Seal for Closure of Greater than 8-F Common Femoral Arterial Access: A Systematic Review and Meta-Analysis.

PURPOSE: To evaluate the safety of >8-F access closures using 8-F Angio-Seal. MATERIALS AND METHODS: An electronic search was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines using Web of Science, Embase, Scopus, and PubMed databases from inception until January 17, 2022. Actionable and nonactionable bleeding events were defined in conjugation with the Bleeding Academic Research Consortium definition. Prevalence rates with corresponding 95% CIs were calculated using R software version 4.2.2. Eight articles, with 422 patients, were included in the analysis. RESULTS: The overall groin adverse event rate was 5.92% (95% CI, 3.01-11.34). The most commonly reported adverse events were any bleeding (5.74%; 95% CI, 3.23-10.00) (nonactionable bleeding, 0.96% [95% CI, 0.10-8.30]; actionable bleeding, 2.30% [95% CI, 0.89-5.84]), pseudoaneurysm (1.18%; 95% CI, 0.49-2.81), and groin hematoma (1.28%; 95% CI, 0.23-6.79). The least commonly reported adverse events were device failure and vessel occlusion/stenosis, with rates 0.29% (95% CI, 0.01-7.41) and 0.45% (95% CI, 0.02-7.74), respectively. No studies recorded events regarding the following adverse events: mortality, infection, deep venous thrombosis, and retroperitoneal hematoma. Moreover, the results showed significant differences, based on the sheath size used, in actionable bleeding (P = .04) and the rate of need for surgical repair (P < .01). CONCLUSIONS: Common femoral artery access of >8-F can be effectively closed with the Angio-Seal with comparable outcomes to those of <8 F; however, larger access approaching 14 F is associated with a significant increase in morbidity. Further safety is needed, especially for the larger access sizes.

[Clinical practice guidelines for the treatment of primary Sjögren's syndrome by off-label drug use in China(2023 edition)].

Sjögren's syndrome (SjS) is one of the most prevalent rheumatic diseases. Off-label drug use is very common in the clinical practice of the treatment of SjS. In order to establish evidence-based justifications and systematically evaluate the off-label drug use in SjS treatment, the Committee of Chinese Primary Health Care Foundation for Rheumatologists and Immunologists referred to published guidelines, consensus statements, and case series, and reevaluated the outcomes of the randomized controlled trials about the marketed immunosuppressive drugs treating SjS. The single-item breakdown of the Sjögren's tool for assessing response (STAR) which was proposed in 2022 was employed as the outcome. The committee established the corresponding clinical questions based on the population, intervention, comparison, and outcome (PICO) principle, and then carried out evidence retrieval, and synthesized meta-analysis using the grading of recommendations, assessment, development, and evaluation (GRADE) methodology. Finally, 21 recommendations addressing twelve clinical questions were formed which included two strong recommendations, fourteen weak recommendations, and five consensus-based recommendations. The overarching objective of the guideline is to provide clinicians with a rational basis for medication selection and to offer guidance to pharmacy departments for management purposes.

[Multidisciplinary expert consensus on the rational use of tetracyclines commonly used in clinical practice].

In recent years, the emergence of newly detected pathogens and the increase of drug resistant bacterial bring serious challenges for the diagnosis and treatment of infectious diseases. Tetracycline drugs are widely used in clinical practice, and the varieties of these drugs are constantly being updated. However, there is still a lack of guidance documents for the rational clinical application of tetracycline drugs in China. Meanwhile, some healthcare workers have doubts about their pharmaceutical characteristics, timing and methods of clinical application. In order to further standardize the clinical application of tetracycline drugs and provide professional evidence-based medicine suggestions for medical personnel in medical institutions, under the leadership of Hospital Infection Control Branch of Chinese Preventive Medicine Association and Clinical Pharmacology Branch of Chinese Pharmacological Society, experts from areas of infection, respiratory medicine, critical care medicine, emergency, infection control, pharmacy and other disciplines organized a consensus meeting and formulated multidisciplinary expert consensus on the rational use of tetracyclines commonly used in clinical practice. This expert consensus is based on the pharmaceutical characteristics of tetracyclines commonly used in China, the mechanism of action and drug resistance status of tetracyclines, combined with the infection site, pathogen characteristics and bacterial drug resistance. This expert consensus also pays attention to special populations and off-label drug use, and integrates domestic and foreign recommendations and the latest evidence-based medicine evidence, and 17 expert consensus opinions for clinical physicians, pharmacists, and other professionals in medical institutions to refer to were formed. In view of the particularity and complexity of infectious diseases and the individual differences of patients, in order to benefit patients, individualized anti-infection strategies should be implemented.

Off-label underdosing of four individual NOACs in patients with nonvalvular atrial fibrillation: A systematic review and meta-analysis of observational studies.

BACKGROUND: Although several meta-analyses have examined the effects of off-label underdosing of nonvitamin K antagonist oral anticoagulants (NOACs) compared with their recommended doses in patients with atrial fibrillation (AF), they combined different kinds of NOACs in their primary analyses. Herein, we first conducted a meta-analysis to separately assess the effects of off-label underdosing versus on-label dosing of four individual NOACs on adverse outcomes in the AF population. METHODS: The PubMed and Embase database were systemically searched until November 2021 to identify the relevant studies. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were pooled by utilizing a random-effects model. RESULTS: A total of nine studies with 144,797 patients taking NOACs were included in the meta-analysis. In the pooled analysis, off-label underdosing of rivaroxaban was related to an increased risk of stroke or systemic embolism (HR = 1.31, 95% CI 1.05-1.63; p = .02), whereas off-label underdosing of apixaban was associated with a higher risk of all-cause death (HR = 1.21, 95% CI 1.05-1.40; p = .01). When comparing off-label underdosing versus on-label dosing of dabigatran or edoxaban, no differences were found in the primary and secondary clinical outcomes. CONCLUSION: Off-label underdosing of rivaroxaban may increase the risk of stroke or systematic embolism, whereas off-label underdosing of apixaban may heighten the incidence of all-cause death.

Off-label use of mycophenolate mofetil in the treatment of rare and complex rheumatic connective tissue diseases.

OBJECTIVES: We aimed to investigate the clinical off-label use of mycophenolate mofetil (MMF), including its safety and efficacy in patients with rare and complex rheumatic connective tissue diseases (rCTDs). METHODS: A survey was distributed across experts from ERN-ReCONNET reference centres in order to assess the experience with MMF off-label use. Patient-level data of patients with rCTDs under treatment with MMF was also collected for analysis of safety and efficacy. RESULTS: Twelve experts from eleven centres distributed throughout Europe (7 countries) answered the survey. The experience was concordant in that, despite of its off-label use, experts reported opting frequently for this therapeutic alternative with robust confidence on its efficacy and safety. The analysis of 108 patients with rCTDs under MMF revealed a good safety profile, as well as good clinical outcomes, especially for systemic lupus erythematosus and idiopathic inflammatory myopathies. The presence of interstitial lung disease was, as expected, associated with a worse clinical outcome despite use of MMF. CONCLUSIONS: MMF is widely used in reference centres for rCTDs. Its safety profile and efficacy seem to be recognised by experts and demonstrated with patient-level analysis. While selected rCTDs will likely remain an off-label indication for MMF, robust data seem to support this therapy as an appropriate alternative for safely and effectively treating many manifestations of rCTDs.

Treatment indications and potential off-label use of antidepressants among older adults: A population-based descriptive study in Denmark.

OBJECTIVES: Off-label prescriptions of antidepressants may be of special concern in older-adults. We aimed to study the potential off-label use of antidepressants among adults ≥65 years by describing the patterns, trends, and factors associated with missing and unspecified treatment indications. METHODS: We used registry data to describe indications of all antidepressant prescriptions (N = 13.8 million) redeemed by older-adults in 2006-2019. We investigated factors associated with off-label use by considering prescriptions with missing and unspecified indications of the first antidepressant prescription using a multinomial logistic regression with the 'depression' indication as a reference category and reported odds ratios (ORs) with 95% confidence intervals (CI). RESULTS: Overall, 18.1% of all antidepressant prescriptions had missing indications, and 9.9% had unspecified indications. The proportion of potential off-label use based on missing and unspecified prescriptions remained mostly consistent during 2006-2019. We identified similar associations in user characteristics whether considering missing or unspecified first prescription. ORs with 95% CI were raised in non-western ethnicity (vs. Danish, 1.12 (0.99-1.26) for missing indication and 1.28 (1.11-1.48) for unspecified indication) and female sex (vs. male, 1.05 (1.02-1.07) and 1.05 (1.02-1.07) respectively). ORs were reduced for shorter educational attainment (vs. long, 0.90 (0.87-0.94) and 0.92 (0.88-0.96)), older age (≥81 vs. 67-70 years, 0.66 (0.65-0.71) and 0.73 (0.70-0.76)) and hospital psychiatric diagnosis (per diagnosis 0.76 (0.73-0.78) and 0.88 (0.86-0.91)). CONCLUSIONS: Nearly one-third of all antidepressant prescriptions redeemed by older-adults in Denmark had either missing or unspecified treatment indications. Whether these prescriptions were actual off-label use needs to be validated. Clinicians should pay special attention to patients' characteristics linking missing and unspecified indications and maintain adequate documentation while prescribing medication.

Off-label drug use in neonates and infants in Spain: A five-year observational study.

OBJECTIVES: To provide information about the off-label rate of all drug prescriptions in neonates and infants up to 1 year in Spain. Also, to analyse the off-label prescription of medicines under current practice in this age group according to different evidence sources. STUDY DESIGN: A five-year (2015-2019) exploratory observational study about off-label prescription in neonates and infants (0 to 1 year) at primary health care in Spain. All drug prescriptions in this age group were analysed and classified according to their labelling in off-label or on-label. The drugs prescribed off-label were subsequently reviewed in national formularies and other databases to assess its evidence of use beyond what is recommended in the Summary of Product Characteristics (SmPC). RESULTS: On average 34.50% of total prescriptions were prescribed off-label according to the SmPC. 17.93% of total prescriptions in neonates and infants up to 1 year old were not based on clinical evidence from SmPC, Pediamécum, BNF or DailyMed. In more than 88% of cases, off-label use was related to the posology section of the SmPC, followed by the therapeutic indications and contraindications sections, in 35.20% and 24.10% of cases, respectively. Almost 13% of off-label drugs were over-the-counter. Salbutamol followed by topical tobramycin and colecalciferol were the drugs most prescribed off-label. CONCLUSIONS: Off-label use of drugs remains as an important public health concern, especially for neonates and infants up to 1 year, who receive the greatest proportion of off-label prescriptions. The evidence-based off-label prescription is a widespread practice that has shown a stable trend during the 5-year study period providing also a certain extent of flexibility to paediatricians in some therapeutic decisions.

Off-label use limitation of the Super Arrow-Flex® sheath introducer in congenital heart disease interventions.

Many interventionists are infatuated by the recent resurgence of the coilwire design with the Super Arrow-Flex® sheath (Teleflex, Inc., NC, United States of America). This exclusive sheath is a highly flexible, durable, conduit intended for use in diagnostic and interventional procedures with several advantages and maximum effectiveness in challenging cases. We report failure to easily advance memory shape occluders through Super Arrow-Flex® sheaths larger than the recommended implant French size. We detail the technical reasons behind this non-previously reported drawback and describe benchside tests as possible solutions.

Use of Rituximab as an Off-Label Medication in Glomerular Diseases: Clinical Perspective.

OBJECTIVES: The aim of this study was to review the use rituximab (RTX) and outcomes in immune-mediated glomerular diseases (glomerulonephritis [GN]) and to compare it to the established literature. METHODS: Adult GN patients who received RTX between January 2014 and January 2018 in three public hospitals were reviewed. Membranous nephropathy (MN) and minimal change disease (MCD) were considered diseases with the literature supporting RTX use. Lupus nephritis (LN), primary focal segmental glomerulosclerosis (1o FSGS), IgA nephropathy, IgG4-related disease (IgG4-RD), and C3GN had insufficient literature support for RTX use. Clinical remission was assessed 6 months after receiving RTX. RESULTS: A total of 61 cases were analyzed. RTX was an add-on therapy in 87%. The remission rate was 95% in the MCD and MN versus 56% in the off-label group (p = 0.002). LN patients had a mean initial estimated glomerular filtration rate (eGFR) of 69 mL/min. All class III LN achieved remission, and 11 of 21 class IV achieved remission. The mean initial eGFR for 1o FSGS was 33 mL/min, and it did not improve, and only 2 of 5 had partial resolution of proteinuria. Proteinuria improved in 3 of 5 IgG4-RD cases with eGFR stabilization but failed to improve in C3GN cases with eGFR deterioration. Vasculitis cases (6 ANCA-associated vasculitis and 2 IgA vasculitis) were analyzed separately. Remission was achieved in only 2 ANCA-associated vasculitis cases, and none in IgA vasculitis cases. CONCLUSIONS: Our data support the use of RTX in resistant MCD and MN. RTX showed success in LN and IgG4-RD but not FSGS or C3GN. The small number of cases of vasculitis does not allow drawing a conclusion on RTX effectiveness.

Practical approaches for diagnosis and management of prurigo nodularis: United States expert panel consensus.

BACKGROUND: Prurigo nodularis (PN) is a chronic disease characterized by intensely pruritic, raised, nodular lesions. Because there are currently no United States Food and Drug Administration-approved therapies specifically for PN, management is highly variable, and no consensus exists on treatment regimens. OBJECTIVE: To provide practical guidance to help United States dermatologists diagnose and effectively treat patients with PN. METHODS: We participated in a roundtable discussion to develop consensus recommendations on diagnosis and treatment of PN from a United States perspective. RESULTS: The core findings in PN are the presence of firm, nodular lesions; pruritus lasting at least 6 weeks; and a history or signs, or both, of repeated scratching, picking, or rubbing. The diagnostic workup involves a complete review of systems, considering potential systemic diseases, and assessment of disease severity, including disease burden and pruritus intensity. Treatment should be selected based on a patient's clinical presentation, comorbidities, and response to prior treatments and should address both neural and immunologic components of pruritus. LIMITATIONS: Data on PN are from anecdotal or small clinical trials, and all treatments are currently used off-label. CONCLUSION: An effective treatment approach for patients with PN should be based on clinical judgment and tailored to the individual needs of the patient.

The Use of Tranexamic Acid to Prevent and Treat Post-Inflammatory Hyperpigmentation.

The risk of post-inflammatory hyperpigmentation (PIH) in patients undergoing dermatologic procedures is well known. It is especially common after laser procedures and chemical peels but can be seen with any procedure. PIH is also a sequela of acne, burns, and other trauma. High-risk patients are thought to have excessive production and abnormal distribution of melanin within the skin that triggers PIH, but the exact pathophysiology is unknown.1 We define high-risk patients as Fitzpatrick skin types 3–5, those with existing PIH, or a history of PIH.1,2 Tranexamic acid (TXA) is an antifibrinolytic medication prescribed to treat bleeding and is also used off-label to treat melasma. TXA is contraindicated in patients with hypercoagulable conditions, renal impairment, vision impairment disorders, pregnancy, breast-feeding, or on hormone therapies.3,4,5 From 2015–2020, we have used TXA off-label to successfully treat and/or prevent PIH in approximately 82 high-risk patients after injuries or prior to procedures that disrupt the epidermis. We also have used TXA to prevent PIH after acute injuries such as irritant dermatitis, thermal burns, and abrasions. We now consider TXA treatment for all at risk patients prophylactically before undergoing microneedling, cryotherapy, cryolipolysis, chemical peels, and laser treatments. J Drugs Dermatol. 2021;20(3) doi:344-345. 10.36849/JDD.5622.

Prospects for Enforcing Prohibitions on Off-Label Drug Promotion after United States v. Caronia: An Analysis of Litigated Cases.

CONTEXT: Food and Drug Administration (FDA) rules restrict pharmaceutical manufacturers from promoting drugs for non-FDA-approved (off-label) indications. When manufacturers violate this rule, it has in many cases led to unsafe prescribing. However, in 2012, a federal circuit court ruled in United States v. Caronia that truthful off-label promotion was protected under the First Amendment, threatening government enforcement in this area. METHODS: The authors extracted cases from the WestLawNext database that mentioned Caronia from 2012 to 2019. They collected information about plaintiff, procedural history, product and manufacturer involved, and case outcome. Cases were categorized as either "follows," "does not follow," or "distinguishes" from Caronia. The authors qualitatively reviewed the full text of each case to verify whether Caronia was given substantive discussion for perceptions of off-label promotion, application of commercial speech rights, and how courts interpreted Caronia. FINDINGS: Among 42 cases in the study cohort, 22 (52%) followed Caronia's core holding that truthful, non-misleading off-label promotion was not actionable under FDA rules. By contrast, 20 cases (48%) treated Caronia negatively, either declining to follow (9 cases) or distinguishing it (11 cases). CONCLUSIONS: Enforcement of restrictions on off-label marketing became more challenging after Caronia. This gives manufacturers greater flexibility to promote drugs for unapproved uses despite the substantial public health risks.

[Off label uses of tigecycline]. / Les utilisations hors-autorisation de mise sur le marché de la tigécycline.

INTRODUCTION: Tigecycline is a relatively new antibiotic that have very limited valid indications. When no other alternative is available, this drug is widely used off label with promising results. The objective of this study is to summarize the different off label uses of tigecycline so that we can decide when and how to prescribe it in the absence of guidelines. MATERIAL AND METHODS: This study a revue of the literature collecting all the articles concerning the off label uses of tigecycline. RESULTS: Tigecycline was widely prescribed, off label, to treat infections with controversial results. Randomised clinical trials were conducted to evaluate its use to treat pneumonia. The results for this indication have a respectable level of evidence. For the other indications, the data collected was insufficient to support tigecycline prescription. In fact, different protocols were used which makes it hard to evaluate the efficacy and to conclude to the best treatment regimen. A tendency to prescribe high doses of the molecule was noted in different studies. When prescribed off label, tigecycline prescriptions were associated with a higher mortality and incidence of side effects. CONCLUSION: The tigecycline remains a valid option for the treatment of infections dues to multi-resistant bacteria especially when other alternatives are scarce or in cases of renal failure.

Review-Insights into Off-Label therapeutic strategies against mild and severe COVID-19 infection.

Currently, prevention and control of the coronavirus disease pneumonia epidemic situation are grim globally. To cope with total sheer carriers and patients of COVID-19 requires intensive medical support and adjunctive therapies to overcome the disease. The epidemic can be controlled with the help of both, disease suppression via community health measures and adjunctive therapies for patients suffering from infection. Till date, we do not have any proper anti-COVID-19 therapy. In order to achieve the overall realization of this pandemic, there is a need to identify treatments depending upon their direct or indirect targets; like inhibition of polyprotein synthesis, transmembrane serine protease, inhibition of viral entry and endocytosis. This could be possible by turning the focus in the direction towards the development of numerous tentative drugs, particularly in the severe to badly ill. Though, majority of these off-label adjunctive medicines are being inspected in a lot of clinical trials at different stages, scientific organizations have endeavored to elucidate the situation where these adjunctive drugs might be practiced as off-label, open- label or compassionate. Our review compiles the adjunctive therapies adopted in COVID-19 infected patients according to clinical severity in conjugation with practicing recommendations from existing guidance rules issued by global professional bodies in healthcare.

Impact of direct oral anticoagulant off-label doses on clinical outcomes of atrial fibrillation patients: A systematic review.

AIMS: Worldwide observational studies are evidencing discordance between guidelines and real-world practice regarding direct oral anticoagulant drug (DOAC) doses. This systematic review summarizes and evaluate DOACs use in real-world practice. METHODS: This review was performed following the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines searching PubMed (MEDLINE) and Medscape databases. RESULTS: Data from 75 studies showed that most of the patients treated with DOACs for stroke prevention in atrial fibrillation received doses in accordance to the guidelines. However, a significant number of patients received off-label doses (25-50% in most of the studies evaluated). DOAC overdosing was associated with increased all-cause mortality and worse bleeding events while underdosing was associated with increased cardiovascular hospitalization and, particularly for apixaban, with a nearly 5-fold increased risk of stroke. CONCLUSION: Patients prescribed with off-label DOAC doses did not receive the full benefit of anticoagulation and presented an increased risk of stroke, bleeding and/or adverse effects.

Pharmacoepidemiology of testosterone: Impact of reimbursement policy on curbing off-label prescribing.

OBJECTIVES: To estimate the impact on testosterone prescribing over 3 years following the 2015 tightening of Pharmaceutical Benefits Scheme (PBS) criteria. DESIGN: Analysis of testosterone prescribing data from PBS and private (non-PBS) sources between 2012 and 2018 covering 2015 change in PBS prescribing criteria. MAIN OUTCOME MEASURES: New and total PBS testosterone prescriptions estimating usage by quarter analyzed by product type, patient age-group, indication and prescriber type. Total national testosterone prescriptions (private plus PBS) was verified from an independent data supplier (IQVIA). RESULTS: PBS usage peaked in 2014 declining by 30% in 2017-8 with PBS prescribing covering a fall from 97.6% by usage in 2014 to 74% in 2017-18 of all testosterone prescribing. The tighter 2015 PBS restrictions sustained the selective reduction in GP initiation of prescriptions for middle-aged men without pathological hypogonadism whereas specialist initiations and prescription for adult hypogonadism or pediatric/prepubertal indications were largely unaffected. CONCLUSIONS: The tightening of PBS criteria from 1 April 2015 to curb off-label prescribing remained effective and selective over 3 years yet total national testosterone prescribing continued with little change, reflecting a shift to private prescriptions. The continuation of off-label testosterone prescribing for unproven indications suggests that long-term androgen dependence is created in men without pathological hypogonadism who commence testosterone. This highlights the need to avoid prescribing testosterone to men without pathological hypogonadism in the absence of sound evidence of efficacy and safety, the latter including the little unrecognized risks of long-term androgen dependency when trying to quit.

Efficacy and safety of low dose ticagrelor in patients with acute coronary syndrome: a systematic review and meta-analysis.

Our aim was to examine clinical trials, provide guidance to practitioners and estimate the efficacy and safety of two agents by comparing low dose ticagrelor with standard dose clopidogrel in patients with acute coronary syndrome. We systematically looked through Pubmed, Embase, the Cochrane Library, Wanfang data and CNKI for trials comparing low dose ticagrelor with standard dose clopidogrel for the treatment of patients with ACS since the database was created. The primary endpoint for efficacy was the rate of major adverse cardiac events (MACEs). The primary endpoint for safety was the rate of major bleeding events. We also evaluated platelet function between low dose ticagrelor and standard dose clopidogrel in ACS patients. From 6744 articles, 16 studies including 1629 patients met the inclusion criteria. In contrast with standard dose clopidogrel, low dose ticagrelor significantly reduced MACEs (OR 0.39, 95% CI 0.26, 0.58) and the difference was statistically significant (p<0.01). No difference was noted for major bleeding events (OR 1.16, 95% CI 0.43, 3.08) between the two agents (p=0.77). In addition, low dose ticagrelor showed lower platelet aggregation rate than clopidogrel (standardised mean difference (SMD) -0.68, 95% CI -0.83 to 0.53) (p<0.01). Platelet reaction units for low dose ticagrelor were much lower than those for standard dose clopidogrel (SMD -2.46, 95% CI -2.85 to -2.07) (p<0.01). In comparison with standard dose clopidogrel, low dose ticagrelor significantly lowered the incidence of MACEs, improved left ventricular ejection fraction, decreased left ventricular end diastolic dimension and did not expand the risk of major bleeding events or minor or minimal bleeding events in ACS patients with a considerable safety and efficacy profile. In addition, low dose ticagrelor was associated with dramatically lower platelet aggregation compared with standard dose clopidogrel.