Generic Tacrolimus Research Articles

SUN-343 EVALUATION OF CLINICAL AND SAFETY OUTCOMES AFTER CONVERSION FROM BRAND NAME TACROLIMUS TO A GENERIC FORMULATION IN RENAL TRANSPLANTATION: A RETROSPECTIVE STUDY

Tacrolimus is the primary immunosuppressive drug used in kidney transplant patients. Replacing brand name products with generic is a controversial issue. The comparison of clinical and safety outcomes of the generic tacrolimus versus the reference drug ( Prograf) is essential. De Novo transplanted recipients who received the princeps (23patients) were compared with de Novo transplant recipient who received the generic (13patients). We studied the episodes of graft rejection, the drug toxicity, the incidence of infectious complications, glucose abnormalities and number of hospitalizations. There is no significant difference between the two groups in the acute rejection rate, respectively 21.7%, 38.5% (p=0.289) the 1st year, 4.5%, 12.5 %( p=0.46) the 2ndyear, 9.1%, 16.7% (p=0.53) the 3rd year post transplant. The Creatinine rate at month 1, 3, and 1 year were not significantly different between the 2 groups. Infectious complications and NODAT were not significantly different between the 2 groups. The mean number of hospitalizations at 1 year was significantly higher in the generic group (p=0.013). Substitution to a generic formulation of tacrolimus from the innovator product in the kidney transplant recipients was safely implemented.

Immunosuppression with generic tacrolimus in liver and kidney transplantation-systematic review and meta-analysis on biopsy-proven acute rejection and bioequivalence.

SummaryWhile rejection prevention with innovator tacrolimus (Tac) is one of the key factors for long‐lasting graft function, the use of generic Tac is still under debate. Thus, we performed a systematic review and meta‐analysis to provide an overview on the current body of evidence for the effect of generic Tac in adult liver (LT) and kidney transplantation (KT) with focus on both biopsy‐proven acute rejection (BPAR) and bioequivalence. A systematic literature search for trials comparing generic versus innovator Tac was conducted accordingly. Seventeen studies (5 LT, 11 KT, 1 LT/KT) including 1412 patients were identified. About 92.9% (13/14; 5/5 LT, 8/9 KT) of studies reported the same or lower BPAR with generics (pooled RR: 0.84, 95% CI: 0.65–1.09); however, de novo studies showed a significantly lower risk with generic Tac (RR: 0.75, 95% CI: 0.63–0.90), whereas conversion studies showed increased risk (RR: 1.93, 95% CI: 1.00–3.70). Bioequivalence was demonstrated primarily in studies on conversion. The current evidence is mostly based on observational data and studies showing some risk of bias. In conclusion, whereas overall there was no significant difference in terms of BPAR, there is some evidence suggesting lower BPAR risk with generic Tac for de novo use.

Evaluation of Bioequivalence of Generic Imatinib Products and Generic Tacrolimus Products Based on Indirect Comparison of the Results of Their Bioequivalence Studies

Generic drugs are widely discussed in the scientific literature. Their key advantage is high availability in the medical practice due to the possibility of a significant reduction in developer costs. In most cases the efficacy and safety of generic oral drugs are confirmed based on the acceptable results of pharmacokinetic evaluation of their bioequivalence with the reference drug. However, generic drugs are not directly compared with one another, and this calls into question the validity of the conclusion about the interchangeability of the generic drugs.The aim of this study was to evaluate the results of indirect comparison of generic drugs by the ratios of their AUC0-t and Сmax based on the information obtained in bioequivalence studies involving the reference drug.Materials and methods: the authors performed an indirect comparison of the results of bioequivalence studies of generic drugs containing one active pharmaceutical ingredient. The analysis was based on bioequivalence study reports over the last 7 years dealing with risk/benefit assessment of imatinib and tacrolimus products.Results: the results of indirect assessment of 90 % confidence intervals of the ratios of imatinib products’ geometric means show that in 46.7 % of cases the intervals fall outside the generally accepted limits (80–125 %) for at least one of the estimated parameters. As for tacrolimus products, the intervals did not go beyond the generally accepted limits (80–125 %) for the AUC0-t ratio, but a discrepancy was found in 10 % of cases for the Cmax ratio. However, when narrower limits of 90–111 % were used to assess the AUC0-t ratio, 90 % of the compared pairs did not meet the recommended standards. Conclusions: thus, conclusions on the acceptable degree of bioequivalence of two generic drugs to the reference product cannot constitute a scientifically sufficient reason for regarding these generic drugs as clinically equivalent.

Assessing the Impact of Endogenously Derived Crystalline Drug on the in Vivo Performance of Amorphous Formulations.

Crystallization of drug from an amorphous formulation is expected to negatively impact its bioperformance following oral delivery. In evaluating this in vivo, neat crystalline drug is typically mixed with the amorphous formulation. However, this approach may not adequately mimic the effect of drug crystals that form within the amorphous matrix, because crystal properties are highly dependent on the crystallization environment. The aim of this study was to evaluate the in vivo impact of crystals formed in a generic tacrolimus amorphous formulation, relative to noncrystallized formulations and a reference suspension containing neat crystalline drug. Crystallization of tacrolimus was induced in the generic product by exposing it to moderate temperatures and high relative humidity. Controlled levels of crystallinity in the formulations were achieved by mixing maximally crystallized and fresh formulations at the desired ratios. These formulations were then characterized in vitro and used for oral dosing to beagle dogs. Analysis of blood concentrations versus time revealed that formulations containing 50 and 100% crystalline tacrolimus resulted in lower area under the curve (AUC) and maximum concentration (Cmax) values as compared to the fresh amorphous formulation. However, the AUC and the Cmax values for these formulations were significantly higher than those observed after dosing the pure crystalline tacrolimus suspension. The innovator formulation, Prograf, showed comparable pharmacokinetics before and after exposure to accelerated stability conditions, confirming the robustness of the innovator product to drug crystallization. This study provides insight into the impact of endogenously crystallized material on the oral absorption of a poorly water-soluble compound and highlights the importance of using representative crystalline material when undertaking risk assessment of amorphous formulations.

P4.24: EVALUATION OF CLINICAL AND SAFETY OUTCOMES AFTER CONVERSION FROM BRAND-NAME TO GENERIC TACROLIMUS IN ADULT INTESTINAL TRANSPLANT RECIPIENTS

Introduction: The introduction of generic immunosuppressants may offer an opportunity for cost savings in intestinal and other solid organ transplantation if equivalent clinical outcomes to the branded counterparts can be achieved. Methods: At our center 14 clinically stable adult intestinal/multivisceral transplant recipients were switched from Prograf (®) to Adoport (®) starting from 1st January 2018: 8 male and 6 female; 11 of them underwent isolated intestinal transplant, 3 of them multivisceral transplant (1 associated with abdominal wall transplant). After the immunosuppression switch we conducted an acute monitoring with regard to safety and efficacy: acute cellular rejection on intestinal biopses and tacrolimus C0 levels were checked every 3 months. Pre conversion tacrolimus level was compared to those revealed at 3, 6, 9 and 12 months after conversion; at the same timepoint an intestinal endoscopy and biopsy was performed. Results: After 1 year of follow up from the conversion, tacrolimus C0 levels did not canged (pre conversion mean level 5.1 ng/mL ± 1.8 vs 4.8 ng/mL ± 1.7, 5 ng/mL ± 1.7, 5.1 ng/mL ± 1.9, 5.2 ng/mL ± 1.9 respectively at 3, 6, 9 and 12 months after tacrolimus conversion). Survival was 100% of the patients. No episodes of ACR or enteritis or other complication were collected. No patient reverted back to gtand name tacrolimus. Conclusion: Our clinical experience as well as research data showed that the use of generic tacrolimus results in comparable trough concentration. Given the lack of adverse events reported and the cost savings recognized, conversion from brand name tacrolimus to generic one should be encouraged also in intestinal transplant recipients

Evaluation of Clinical and Safety Outcomes Following Uncontrolled Tacrolimus Conversion in Adult Transplant Recipients.

To compare clinical and safety outcomes of transplant recipients converted between different tacrolimus formulations to those patients who remained on a single formulation in an outpatient environment. This was a single-center, retrospective cohort study at a large tertiary care medical center with an associated institutional outpatient pharmacy system. Adult transplant recipients with institutional pharmacy refill from August 1, 2009, to May 31, 2016, were assessed. Patients were allocated into four separate groups: Group (A) innovator tacrolimus (no conversion), Group (B) generic tacrolimus (no conversion), Group (C) single conversion (from innovator to single generic or from generic to innovator tacrolimus), and Group (D) multiple conversions. Index date was either the date of first tacrolimus product conversion (Groups C and D) or a pre-specified post-transplant time (Groups A and B). Overall, 100 patients were included in the analysis, 63% were male, 62% were Caucasian, and 59% were renal transplant recipients. When compared between groups, linear trends in dose-normalized tacrolimus levels were similar in the pre-index date period (p=0.52) and in the post-index date period (p=0.08). When groups were compared individually, linear trends in dose-normalized tacrolimus levels were significantly different pre- versus post-index date for Group B (p=0.008). There were no differences in the linear trends of dose-normalized tacrolimus levels across the other groups (p>0.05 for all). After the index date, 43% of patients across all groups required tacrolimus dose modification with no differences by group (p=0.32). Allograft function and hospitalizations were similar across all groups. Conversion between tacrolimus generic formulations has been suggested to be unsafe. This study demonstrates that switching tacrolimus products in post-transplant recipients does not alter dose-normalized tacrolimus trough concentrations, renal or hepatic function, pathology, or hospitalizations.

Secular Trends in the Cost of Immunosuppressants after Solid Organ Transplantation in the United States.

Immunosuppressive medications are critical for maintenance of graft function in transplant recipients but can represent a substantial financial burden to patients and their insurance carriers. To determine whether availability of generic immunosuppressive medications starting in 2009 may have alleviated some of that burden, we used Medicare Part D prescription drug events between 2008 and 2013 to estimate the average annualized per-patient payments made by patients and Medicare in a large national sample of kidney, liver, and heart transplant recipients. Repeated measures linear regression was used to determine changes in payments over the study period. Medicare Part D payments for two commonly used immunosuppressive medications, tacrolimus and mycophenolic acid (including mycophenolate mofetil and mycophenolate sodium), decreased overall by 48%-67% across organs and drugs from 2008 to 2013, reflecting decreasing payments for brand and generic tacrolimus (21%-54%), and generic mycophenolate (72%-74%). Low-income subsidy payments, which are additional payments made under Medicare Part D, also decreased during the study period. Out-of-pocket payments by patients who did not receive the low-income subsidy decreased by more than those who did receive the low-income subsidy (63%-79% versus 24%-44%). The decline in payments by Medicare Part D and by transplant recipients for tacrolimus and mycophenolate between 2008 and 2013 suggests that the introduction of generic immunosuppressants during this period has resulted in substantial cost savings to Medicare and to patients, largely reflecting the transition from brand to generic products.

The adoption of generic immunosuppressant medications in kidney, liver, and heart transplantation among recipients in Colorado or nationally with Medicare part D.

The transplant community is divided regarding whether substitution with generic immunosuppressants is appropriate for organ transplant recipients. We estimated the rate of uptake over time of generic immunosuppressants using US Medicare Part D Prescription Drug Event (PDE) and Colorado pharmacy claims (including both Part D and non-Part D) data from 2008 to 2013. Data from 26070 kidney, 15548 liver, and 6685 heart recipients from Part D, and 1138 kidney and 389 liver recipients from Colorado were analyzed. The proportions of patients with PDEs or claims for generic and brand-name tacrolimus or mycophenolate mofetil were calculated over time by transplanted organ and drug. Among Part D kidney, liver, and heart beneficiaries, the proportion dispensed generic tacrolimus reached 50%-56% at 1year after first generic approval and 78%-81% by December 2013. The proportion dispensed generic mycophenolate mofetil reached 70%-73% at 1year after generic market entry and 88%-90% by December 2013. There was wide interstate variability in generic uptake, with faster uptake in Colorado compared with most other states. Overall, generic substitution for tacrolimus and mycophenolate mofetil for organ transplant recipients increased rapidly following first availability, and utilization of generic immunosuppressants exceeded that of brand-name products within a year of market entry.

The BC Glomerulonephritis Network: Improving Access and Reducing the Cost of Immunosuppressive Treatments for Glomerular Diseases

Glomerulonephritis (GN) is a common cause of end-stage renal disease in Canada and worldwide, and results in significant health care resource utilization and patient morbidity. However, GN has not been a traditional priority of provincial renal health care organizations, despite the known benefits to health services delivery and patient outcomes from integrated provincial care in other types of chronic kidney disease. To address this deficiency, the British Columbia (BC) Provincial Renal Agency created the BC GN Network in 2013 to coordinate provincial GN health services delivery informed by robust population-level data capture on all GN patients in the province via the BC GN Registry. This report describes the use of the BC GN Network infrastructure to systematically develop and evaluate a provincial GN drug formulary to improve patient and physician access to evidence-based immunosuppressive treatments for GN in a cost-efficient manner that successfully halted historical trends of increasing medication costs. An example is provided of using the provincial infrastructure to implement and subsequently evaluate an evidence-informed health policy of converting brand to generic tacrolimus for the treatment of GN. The BC GN Network, including the provincial drug formulary and data infrastructure, is an example of the benefits of expanding the mandate of provincial renal health administrative organizations to include the care of patients with GN, and constitutes a viable health delivery model that can be implemented in other Canadian provinces to achieve similar goals.

Investigating the Impact of Drug Crystallinity in Amorphous Tacrolimus Capsules on Pharmacokinetics and Bioequivalence Using Discriminatory In Vitro Dissolution Testing and Physiologically Based Pharmacokinetic Modeling and Simulation

Delivering a drug in amorphous form in a formulated product is a strategy used to enhance the apparent solubility of a drug substance and its oral bioavailability. Drug crystallization in such products may occur during the manufacturing process or on storage, reducing the solubility advantage of the amorphous drug. However, the impact of partial drug crystallization in the drug product on the resulting bioavailability and pharmacokinetics is unknown. In this study, dissolution testing of commercial tacrolimus capsules (which are formulated to contain amorphous drug), both fresh and those containing different amounts of crystalline drug, was conducted using both United States Pharmacopeia and noncompendial dissolution tests with different dissolution media and volumes. A physiologically based pharmacokinetic (PBPK) absorption model was developed to predict the impact of crystallinity extent on the oral absorption of the products and to evaluate the discriminatory ability of the different dissolution methods. Virtual bioequivalence simulations between partially crystallized tacrolimus capsules versus fresh Prograf or generic tacrolimus capsules were performed using the PBPK model and in vitro dissolution data of the various fresh and partially crystallized capsules under United States Pharmacopeia and noncompendial dissolution conditions. The results suggest that compendial dissolution tests may not be sufficiently discriminatory with respect to the presence of crystallinity in an amorphous formulation. Nonsink dissolution tests using lower dissolution volumes generate more discriminatory profiles that predict different pharmacokinetics of tacrolimus capsules containing different extents of drug crystallinity. In conclusion, the PBPK modeling approach can be used to assess the impact of partial drug crystallinity in the formulated product and to guide the development of appropriate dissolution methods.

Outcome following switch between brand name and generic tacrolimus in paediatric population

Introduction For many medicines, a switch between formulations can be done with little monitoring. Tacrolimus provides an interesting challenge due to its narrow therapeutic window requiring careful medical supervision and therapeutic monitoring. Currently, there is limited evidence to show the effects of a switch between tacrolimus formulations in paediatric patients. We present the effects of our study switching our patients from brand to generic formulation. Method Patients were given written and verbal advice to switch from Prograf® to the same dose of Adoport® two weeks before their next clinical review and bloods were tested. Then, we reviewed the data for tacrolimus and creatinine levels before and after the switch and assessed for any clinical variation. Results Forty-one stable patients were switched from Prograf® to Adoport®. Four patients were lost to tertiary follow-up. Six patients had a rise in creatinine more than 15%: in 2 patients, the rise was associated with UTI, 2 patients were treated empirically with high dose steroids for concerns of rejection, 1 patient developed swelling of legs (cause unidentified, DVT ruled out with scan) managed with increase in maintenance dose steroids and the cause was unclear in the last patient. In remaining 31 patients, there was no significant change noted in the creatinine levels [t-test −2.38, P-value 0.01]. One patient developed hair loss and requested to go back onto Prograf®, but all others continued on Adoport® and patients with initial rise in creatinine stabilized to baseline. Conclusion This study assessed the clinical outcomes for paediatric renal transplant/nephrotic patients switching from Prograf® to Adoport®. The majority of patients tolerated the switch well. There was significant cost saving associated for NHS England of approximately £36,000 (2015–2016). Our outcome data therefore support the switch from Prograf® to Adoport® and its continued use as a potentially safe and cost-saving measure.

Bioequivalence between innovator and generic tacrolimus in liver and kidney transplant recipients: A randomized, crossover clinical trial.

BackgroundAlthough the generic drug approval process has a long-term successful track record, concerns remain for approval of narrow therapeutic index generic immunosuppressants, such as tacrolimus, in transplant recipients. Several professional transplant societies and publications have generated skepticism of the generic approval process. Three major areas of concern are that the pharmacokinetic properties of generic products and the innovator (that is, “brand”) product in healthy volunteers may not reflect those in transplant recipients, bioequivalence between generic and innovator may not ensure bioequivalence between generics, and high-risk patients may have specific bioequivalence concerns. Such concerns have been fueled by anecdotal observations and retrospective and uncontrolled published studies, while well-designed, controlled prospective studies testing the validity of the regulatory bioequivalence testing approach for narrow therapeutic index immunosuppressants in transplant recipients have been lacking. Thus, the present study prospectively assesses bioequivalence between innovator tacrolimus and 2 generics in individuals with a kidney or liver transplant.Methods and findingsFrom December 2013 through October 2014, a prospective, replicate dosing, partially blinded, randomized, 3-treatment, 6-period crossover bioequivalence study was conducted at the University of Cincinnati in individuals with a kidney (n = 35) or liver transplant (n = 36). Abbreviated New Drug Applications (ANDA) data that included manufacturing and healthy individual pharmacokinetic data for all generics were evaluated to select the 2 most disparate generics from innovator, and these were named Generic Hi and Generic Lo. During the 8-week study period, pharmacokinetic studies assessed the bioequivalence of Generic Hi and Generic Lo with the Innovator tacrolimus and with each other. Bioequivalence of the major tacrolimus metabolite was also assessed. All products fell within the US Food and Drug Administration (FDA) average bioequivalence (ABE) acceptance criteria of a 90% confidence interval contained within the confidence limits of 80.00% and 125.00%. Within-subject variability was similar for the area under the curve (AUC) (range 12.11–15.81) and the concentration maximum (Cmax) (range 17.96–24.72) for all products. The within-subject variability was utilized to calculate the scaled average bioequivalence (SCABE) 90% confidence interval. The calculated SCABE 90% confidence interval was 84.65%–118.13% and 80.00%–125.00% for AUC and Cmax, respectively. The more stringent SCABE acceptance criteria were met for all product comparisons for AUC and Cmax in both individuals with a kidney transplant and those with a liver transplant. European Medicines Agency (EMA) acceptance criteria for narrow therapeutic index drugs were also met, with the only exception being in the case of Brand versus Generic Lo, in which the upper limits of the 90% confidence intervals were 111.30% (kidney) and 112.12% (liver). These were only slightly above the upper EMA acceptance criteria limit for an AUC of 111.11%. SCABE criteria were also met for the major tacrolimus metabolite 13-O-desmethyl tacrolimus for AUC, but it failed the EMA criterion. No acute rejections, no differences in renal function in all individuals, and no differences in liver function were observed in individuals with a liver transplant using the Tukey honest significant difference (HSD) test for multiple comparisons. Fifty-two percent and 65% of all individuals with a kidney or liver transplant, respectively, reported an adverse event. The Exact McNemar test for paired categorical data with adjustments for multiple comparisons was used to compare adverse event rates among the products. No statistically significant differences among any pairs of products were found for any adverse event code or for adverse events overall. Limitations of this study include that the observations were made under strictly controlled conditions that did not allow for the impact of nonadherence or feeding on the possible pharmacokinetic differences. Generic Hi and Lo were selected based upon bioequivalence data in healthy volunteers because no pharmacokinetic data in recipients were available for all products. The safety data should be interpreted in light of the small number of participants and the short observation periods. Lastly, only the 1 mg tacrolimus strength was utilized in this study.ConclusionsUsing an innovative, controlled bioequivalence study design, we observed equivalence between tacrolimus innovator and 2 generic products as well as between 2 generic products in individuals after kidney or liver transplantation following current FDA bioequivalence metrics. These results support the position that bioequivalence for the narrow therapeutic index drug tacrolimus translates from healthy volunteers to individuals receiving a kidney or liver transplant and provides evidence that generic products that are bioequivalent with the innovator product are also bioequivalent to each other.Trial registrationClinicalTrials.gov NCT01889758.

PUK6 - A Cost-Effectiveness Analysis of Tacrolimus XL in Comparison to Generic Tacrolimus from the Public Healthcare Sector in Mexico

PUK6 - A Cost-Effectiveness Analysis of Tacrolimus XL in Comparison to Generic Tacrolimus from the Public Healthcare Sector in Mexico

Impact of Conversion From Advagraf to Twice-Daily Generic Tacrolimus in Kidney Transplant Recipients: A Single-Center Study-A 3-Year Follow-Up.

Impact of Conversion From Advagraf to Twice-Daily Generic Tacrolimus in Kidney Transplant Recipients: A Single-Center Study-A 3-Year Follow-Up.

Nationwide conversion to generic tacrolimus in pediatric kidney transplant recipients.

Bioequivalence between Tacrolimus Prograf® and generic tacrolimus formulations has been demonstrated in adult populations, however clinical experience and safety data regarding generic tacrolimus in pediatric transplant recipients is limited. This study aimed to evaluate conversion from Tacrolimus Prograf® to Sandoz® in pediatric renal transplant recipients nationwide. The primary outcome was a change in mean trough tacrolimus concentration. Additionally, changes in tacrolimus intra-patient coefficient of variation (CoV), allograft function, requirement for dose adjustments, and episodes of biopsy-proven rejection were evaluated. Retrospective cohort study in 37 pediatric renal transplant recipients who switched to Tacrolimus Sandoz®. Each patient had three pre-conversion tacrolimus trough and creatinine concentrations within the 4months prior and three post-conversion concentrations on day 3, 10, and the next subsequent level. Mean pre- and post-conversion tacrolimus trough concentrations and glomerular filtration rate (eGFR) were calculated. Tacrolimus concentration, CoV, and creatinine differences were compared by paired ttest. Thirty-seven patients (41% females, age 3-18 years) were included. Average intra-patient difference in trough tacrolimus concentration was 0.05μg/l (95% CI -0.37 to 0.47). Average intra-patient difference in eGFR was -1.20ml/min/1.732 (95%CI -3.53 to 1.13). Three patients had acute rejection during 12 months post-conversion compared to none during 12 months pre-conversion. Pediatric renal transplant recipients can be converted from Tacrolimus Prograf® to Sandoz® with negligible change in trough concentration, dose adjustments, or immediate allograft function. Of concern was the number of acute rejection episodes, however non-adherence contributed to at least one episode and this difference was determined clinically and statistically not significant.

The Impact of Conversion from Prograf to Generic Tacrolimus in Liver Transplant Recipients With Stable Graft Function

The Impact of Conversion from Prograf to Generic Tacrolimus in Liver Transplant Recipients With Stable Graft Function

Differences in Peripheral Blood Lymphocytes between Brand-Name and Generic Tacrolimus Used in Stable Liver Transplant Recipients

Objectives: In this study, peripheral blood lymphocytes were compared between a brand-name and a generic tacrolimus group in stable liver transplant recipients. Subjects and Methods: Sixteen patients who underwent ABO-compatible living donor liver transplants between 2012 and 2013 and had stable graft function were included in this study. Ten patients received brand-name tacrolimus and 6 patients received generic tacrolimus. CD3, CD4, CD8, γδ, CD4+FoxP3+, and CD3-CD56+ T cells were analyzed in peripheral blood obtained preoperatively and 4, 8, 12, and 24 weeks after liver transplantation. Categorical variables were compared using a χ² test or Fisher exact test, and continuous variables were compared using the Mann-Whitney U test. Results: Regarding the baseline and perioperative characteristics, there were no statistically significant differences between the 2 groups. Immunosuppression also was not different. Subtype analysis of T-cell populations carried out in parallel showed similar levels of CD3, CD4, CD8, and γδT cells with brand-name tacrolimus and generic tacrolimus in stable liver transplant recipients. However, the levels of CD4+Foxp3+ and CD3-CD56+ T cells were higher in the brand-name tacrolimus group than in the generic tacrolimus group 8 weeks after transplantation (p < 0.05). Conclusions: The level of CD4+Foxp3+ T cells was higher in the brand-name tacrolimus group than in the generic tacrolimus group after transplantation. This finding showed that brand-name tacrolimus could have more potential immunosuppressive activity than generic tacrolimus regarding the contribution of CD4+Foxp3+ T cells to graft tolerance in liver transplant recipients.

A 1-year Comparison of Generic Tacrolimus (Tacni®) and Prograf® in Renal Transplant Patients: A Retrospective Matched Group Analysis

Introduction: The 1-year-outcome of adult patients treated with Tacni® or Prograf® following de novo renal transplantation, including patient survival, graft loss, Biopsy Proven Acute Rejection (BPAR) and serious adverse events were compared. 186 patients who underwent their first renal transplantation between 2011 and 2014 were included in a retrospective matched group analysis (91 patients treated with Tacni® which were compared with a matched control group (n=95).Material and Methods: This was a retrospective study of two different time cohorts of patients who underwent kidney transplantation at Sahlgrenska University Hospital. Data was obtained from patient charts and from the local quality registry. Patients from the two groups were matched in a group matching fashion. The matching was based upon the patient’s age and gender, age of the donor, living/deceased donor and Cold Ischemia Time (CIT).Results: The two groups were well matched for living donor transplants; gender; donor and recipient age. The combined endpoint of freedom from BPAR, graft loss and death 12 months post-transplantation was 85% in the P-group and 86% in the T-group (p=0.90). There was one death in the T-group, which was not related to the drug (p=1.00). Graft survival at 12 months was similar, 99% in both groups (p=0.97). The BPAR at 12 months was 12% (T) and 14% (P), respectively (p=0.72). The measured GFR at 12 months was also similar, 54.5 and 56.0 ml/min/1.73 m2 (p=0.59). There were no significant differences in Tacrolimus levels.Conclusion: One year after transplantation, generic Tacrolimus is no different to the original version. Both drugs show good efficacy, the safety is comparable and the drug concentrations do not differ.

Switching Stable Kidney Transplant Recipients to a Generic Tacrolimus Is Feasible and Safe, but It Must Be Monitored.

Background. Tacrolimus is the primary immunosuppressive drug used in kidney transplant patients. Replacing brand name products with generics is a controversial issue that we studied after a Chilean Ministry of Health mandate to implement such a switch. Methods. Forty-one stable Prograf (Astellas) receiving kidney transplant patients were switched to a generic tacrolimus (Sandoz) in a 1 : 1 dose ratio and were followed up for up to 8 months. All other drugs were maintained as per normal practice. Results. Neither tacrolimus doses nor their trough blood levels changed significantly after the switch, but serum creatinine did: 1.62 ± 0.90 versus 1.75 ± 0.92 mg/dL (p < 0.001). At the same time, five graft biopsies were performed, and two of them showed cellular acute rejection. There were nine infectious episodes treated satisfactorily with proper therapies. No patient or graft was lost during the follow-up time period. Conclusion. Switching from brand name tacrolimus to a generic tacrolimus (Sandoz) is feasible and appears to be safe, but it must be monitored carefully by treating physicians.

Transition from brand to generic tacrolimus is associated with a decrease in trough blood concentration in pediatric heart transplant recipients.

There are limited data available on the bioequivalence of generic and brand-name tacrolimus in pediatric and heart transplant patients. We characterized changes in 12-hour trough concentrations and clinical outcomes after transition from brand to generic tacrolimus in pediatric thoracic organ transplant recipients. Patients with a pharmacy-confirmed date of switch between generic and brand tacrolimus were identified, as well as a matched control group that did not switch for comparison. We identified 18 patients with a confirmed date of switch, and in 12 patients that remained on the same dose, trough concentrations were 14% less than when they were on brand (p = 0.037). The average change was -1.15 ± 1.76 ng/mL (p = 0.045). The control group did not experience a change in trough concentration and was different than the switched group (p = 0.005). There were no differences in dosage changes or kidney or liver function. In the year after switch, 24% of patients who were switched to generic experienced a rejection event vs. 18% in the patients on brand. We suggest a strategy of monitoring around the time of transition, and education of the patient/family to notify the care team when changes from brand to generic or between generics occur.