BACKGROUND:

Although generic ciclosporin-A (CsA) and tacrolimus (TAC) have been used for the prophylaxis of organ rejection in transplant patients for decades, evidence in their safety profile compared to reference listed drugs (RLDs) in real-world transplant patients remains limited.

OBJECTIVES:

To compare safety outcomes of generic CsA and TAC with the reference-listed drugs in solid organ transplant patients.

METHODS:

We systematically searched MEDLINE, International Pharmaceutical Abstracts, PsycINFO, and Cumulative Index of Nursing and Allied Health Literature from inception until March 15, 2022, to select randomized and observational studies comparing safety profiles of generic versus brand CsA and TAC in de novo and/or stable solid organ transplant patients. Primary safety outcomes were changes in serum creatinine (Scr) and glomerular filtration rate (GFR). Secondary outcomes included incidences of infection, hypertension, diabetes, other serious adverse events (AEs), hospitalization, and death. Mean difference (MD) and relative risk (RR) with 95% confidence intervals (CIs) were calculated using random-effects meta-analyses.

RESULTS:

Of 2612 publications identified, 32 studies met inclusion criteria. Seventeen studies had a moderate risk of bias. Scr was statistically significantly lower in patients using generic CsA compared to brand at 1 month (MD = -0.07; 95% CI: -0.11, -0.04), while there were no statistically significant differences at 4 months, 6 months, and 12 months. No differences were detected in Scr (MD = -0.04; 95% CI: -0.13, 0.04) and estimated GFR (MD = -2.06; 95% CI: -8.89, 4.77) between patients using generic and brand TAC at 6 months. No statistically significant differences between generic CsA and TAC with their RLDs were observed for secondary outcomes.

CONCLUSION:

Findings support similarity in safety outcomes between generic and brand CsA and TAC in real-world solid organ transplant patients.

OBJECTIVES:

To determine whether spontaneous reporting rates of myocarditis and pericarditis differed in immunocompromised patients compared with the whole population overall, and in terms of demographics, vaccine dose and time-to-onset.

DESIGN:

Systematic review of spontaneously reported data from the European Union/European Economic Area (EU/EEA), the USA and the UK.

DATA SOURCES:

EudraVigilance (EU/EEA), Vaccine Adverse Event Reporting System (VAERS; USA) and the Medicines and Healthcare products Regulatory Agency (UK) spontaneous reporting databases were searched from date of vaccine launch to 1 December 2021.

ELIGIBILITY CRITERIA:

Publicly available spontaneous reporting data for 'myocarditis' and 'pericarditis' from EU/EEA and USA following COVID-19 messenger RNA vaccines. Reports with comorbidities or concurrent medication indicative of transplantation, HIV infection or cancer ('immunocompromised' population) were compared with each overall database population.

DATA EXTRACTION AND SYNTHESIS:

Two researchers extracted data. Spontaneously reported events of myocarditis and pericarditis were presented for immunocompromised populations for each data source, stratified by age, sex, dose and time-to-onset (where available). Seriousness of each event was determined according to the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Guideline E2A definition. Proportional reporting ratio (PRR) was calculated.

RESULTS:

There were 178 reports of myocarditis and pericarditis among immunocompromised individuals overall. Seriousness was comparable between the immunocompromised and overall populations in both databases. No trends in age or sex were observed among immunocompromised individuals. Most reports followed a second vaccine dose and occurred within 14 days. The frequency of reporting was similar to the wider population (PRR=1.36 (95% CI=0.89 to 1.82) for VAERS population).

CONCLUSIONS:

Myocarditis and pericarditis following COVID-19 vaccination are very rare, and benefits of COVID-19 vaccination continue to outweigh any perceived risks. Reporting rates of myocarditis and pericarditis were similar in immunocompromised individuals, however defining characteristics differed compared with the whole population; therefore, continued monitoring of adverse events following vaccination remains vital to understand differences between population subgroups.

INTRODUCTION:

Great advancements in solid organ transplantation (SOT) have allowed patients to have better chances to survive longer and enjoy a quality life after surgery. This increasing number of SOTs and improved long-term survival rates lead to an increasing demand for plastic, esthetic and reconstructive breast procedures.

MATERIAL AND METHODS:

A literature search following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and using searching terms related to esthetic and reconstructive breast surgery was conducted across three databases: PubMed, Scopus and Google Scholar. Included articles were analyzed to extract data points of interest including patient age, type of surgery, organ transplanted, underlying conditions associated with organ transplantation, follow-up, immunosuppressive drugs and their side effects, perioperative management and complications related to the breast plastic procedures in SOT recipients.

RESULTS:

A total of 1,298 articles were retrieved from the mentioned electronic databases. Eight full articles were finally included in this systematic review. In these articles, a total of 41 cases of breast plastic surgery after solid organ transplantation were reported. Procedures were esthetic in nature in 26.83% of cases (11 of 41 cases) and reconstructive in 73.17% of them (30 of 41 cases). No deaths were reported.

CONCLUSIONS:

Although esthetic and reconstructive breast surgery could be performed safely in SOT recipients, the dosage of immunosuppression and patient's overall health status with regard to the length and extent of the planned procedure should always be taken into account. From the literature data analysis, it is not possible to draw a statistical conclusion that the complication rate of surgery in immunosuppressed post-transplant patients is the same as in normal, not immunosuppressed population. Further and more valid clinical studies are warranted.

AIMS:

Tacrolimus is the cornerstone of immunosuppression management in heart and lung transplant recipients, improving overall survival. However, tacrolimus-associated toxicities, including nephrotoxicity, neurotoxicity, new-onset diabetes mellitus after transplant (NODAT), and gastrointestinal toxicity, are known contributors to increased post-transplant morbidity outcomes and reduced graft and recipient survival rates. The aim of this systematic review was to identify correlations between pharmacokinetic measures of tacrolimus exposure in heart and lung recipients and tacrolimus toxicities.

METHODS:

MEDLINE, Embase, the Cochrane Library, CENTRAL and WHO Clinical Trial Registries were searched for published studies evaluating tacrolimus toxicities and their correlation to pharmacokinetic monitoring parameters in thoracic transplant recipients. Studies were reviewed by two authors, with data extracted for evaluation. Risk of bias was assessed using the PEDro scale for randomised control trials and the Newcastle Ottawa Scale for non-randomised cohort studies.

RESULTS:

Eighteen studies were eligible; a randomised control trial, 11 observational cohort studies, and 6 case series or studies. Of these, 9 studies were in heart transplant recipients alone and 5 in lung transplant recipients alone, 2 studies were in heart and lung transplant recipients and 2 were heart, lung, liver or renal transplant recipients. Studies used variable criteria to define toxicities. Tacrolimus trough concentration (C0) was the marker of tacrolimus exposure most commonly used. Ten studies reported on nephrotoxicity. Elevated tacrolimus C0 was associated with acute kidney injury occurrence and severity in three observational studies. Increasing C0 was a predictor of renal impairment in 6 studies. One study found that for each 5 ng/mL per year of tacrolimus exposure, defined by consecutive AUC, eGFR declined by 1.3 mL/min/1.73m2 (p < 0.001). Comparatively, 2 studies failed to find a significant association between nephrotoxicity and tacrolimus exposure. Seven studies reported on neurotoxicity, including neuro-encephalopathies, polyneuropathies and symptomatic change in neurological status. Neurotoxicity occurred both with tacrolimus C0 within therapeutic range and with supratherapeutic C0. No significant association was found between NODAT and tacrolimus C0 in two studies. One study reported on gastrointestinal toxicity, with supratherapeutic C0 and elevated peak concentration in one lung transplant recipient three days prior to symptom development.

CONCLUSION:

No clearly defined relationship between tacrolimus exposure and toxicities is described in the literature. Studies with clear toxicity criteria and pharmacokinetic markers of tacrolimus exposure are required to provide valuable information that may optimise tacrolimus therapy, helping to reduce toxicities in heart and lung transplant recipients.

BACKGROUND AND OBJECTIVES:

Numerous population pharmacokinetic (PK) models of tacrolimus in adult transplant recipients have been published to characterize tacrolimus PK and facilitate dose individualization. This study aimed to (1) investigate clinical determinants influencing tacrolimus PK, and (2) identify areas requiring additional research to facilitate the use of population PK models to guide tacrolimus dosing decisions.

METHODS:

The MEDLINE and EMBASE databases, as well as the reference lists of all articles, were searched to identify population PK models of tacrolimus developed from adult transplant recipients published from the inception of the databases to 29 February 2020.

RESULTS:

Of the 69 studies identified, 55% were developed from kidney transplant recipients and 30% from liver transplant recipients. Most studies (91%) investigated the oral immediate-release formulation of tacrolimus. Few studies (17%) explained the effect of drug-drug interactions on tacrolimus PK. Only 35% of the studies performed an external evaluation to assess the generalizability of the models. Studies related variability in tacrolimus whole blood clearance among transplant recipients to either cytochrome P450 (CYP) 3A5 genotype (41%), days post-transplant (30%), or hematocrit (29%). Variability in the central volume of distribution was mainly explained by body weight (20% of studies).

CONCLUSION:

The effect of clinically significant drug-drug interactions and different formulations and brands of tacrolimus should be considered for any future tacrolimus population PK model development. Further work is required to assess the generalizability of existing models and identify key factors that influence both initial and maintenance doses of tacrolimus, particularly in heart and lung transplant recipients.

OBJECTIVES:

Solid organ transplant recipients are at increased risk of skin cancer, affecting more than 50% of recipients. We aimed to determine the effectiveness of interventions for behavioural change for sun protection or skin cancer prevention in solid organ transplant recipients.

DESIGN:

Systematic review.

DATA SOURCES:

We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL) and CINAHL from inception to November 2019.

ELIGIBILITY CRITERIA:

We included randomised controlled trials that evaluated the effect of behavioural or pharmaceutical interventions on behavioural change or skin cancer prevention in solid organ transplant recipients.

DATA EXTRACTION AND SYNTHESIS:

Risks of bias and evidence certainty were assessed using Cochrane and the Grading of Recommendations Assessment Development and Evaluation framework.

RESULTS:

Twenty trials (n=2295 participants) were included. It is uncertain whether behavioural interventions improve sun protection behaviour (n=3, n=414, standardised mean difference (SMD) 0.89, 95% CI -0.84 to 2.62, I2=98%) and knowledge (n=4, n=489, SMD 0.50, 95% CI 0.12 to 0.87, I2= 76%) as the quality of evidence is very low. We are uncertain of the effects of mammalian target of rapamaycin inhibitors on the incidence of non-melanocytic skin cancer (n=5, n=1080, relative risk 0.46, 95% CI 0.28 to 0.75, I2 =72%) as the quality of evidence is very low.

CONCLUSIONS:

Behavioural and pharmaceutical preventive interventions may improve sun protective behaviour and knowledge, and reduce the incidence of non-melanocytic skin cancer, but the overall quality of the evidence is very low and insufficient to guide decision-making and clinical practice.

PROSPERO REGISTRATION NUMBER:

CRD42017063962.