Generic Immunosuppressive Drugs Research Articles

Current status of generic immunosuppressive drugs for organ transplantation in Japan

Current status of generic immunosuppressive drugs for organ transplantation in Japan

Important considerations for drugs, nutritional, and herbal supplements in pediatric solid organ transplant recipients.

Pediatric transplant recipients are on multiple prescription and non-prescription drugs. Many patients also use dietary, nutritional, and herbal supplements. This manuscript researched formulations of immunosuppressive drugs currently available and presents information on generic immunosuppressive drugs, commonly used non-prescription medications, dietary supplements, and herbal supplements. Immunosuppressive drugs are available in various formulations. Not all formulations are interchangeable. A number of FDA-approved generic formulations are available commercially in the United States. Generally generic formulations produce similar blood concentration vs time profiles compared to brand name products in adults and are considered to be bioequivalent. NSAID should be avoided in transplant patients due to potential drug interactions and increased risk associated with NSAID use; and appropriate doses of acetaminophen should be used for treatment of pain. Over-the-counter medications, such as guaifenesin and dextromethorphan, antihistamine medications, including diphenhydramine, loratadine, cetirizine, and fexofenadine, can be safely used in pediatric solid organ transplant population. Many safe and effective over-the-counter options exist for stool softening and as laxative. Diarrhea can lead to an increase in calcineurin inhibitor levels. Food can alter the absorption of immunosuppressive drugs. Several herbal products can alter immune status of the patients or alter the blood concentration of immunosuppressive drugs or may produce renal or hepatic toxicities and should be avoided in pediatric transplant recipients. It is important to educate pediatric transplant recipients and their families about not only immunosuppressive drug therapy but also about non-prescription drugs, dietary, and herbal supplement use.

L’utilisation de génériques en transplantation : vers des solutions rationnelles et sures !

Generic immunosuppressive drugs are available in Europe Canada and the United States. Between countries, there are large differences in penetration of generic drugs in general, and for immunosuppressive drugs in particular. The registration for generic immunosuppressive drugs are slightly different, but the criteria for registration of narrow therapeutic index drugs and bioequivalence studies, performed only in healthy volunteers, will remain in the medical landscape. About 50 studies compare the clinical efficacy and bioequivalence of the generic immunosuppressive drugs in patients with solid organ transplants. To allow for safe substitution, a number of criteria need to be fulfilled. Consensus statements were made by most transplant organizations. Authorities and payers should refrain from forcing pharmacists to dispense generic drugs in patients on maintenance immunosuppressive treatment. Generic substitution could be safe if realized by the treating physician, for a well-informed patient. Substitution must be followed by control visits to check if the patient is taking the medication correctly and if the drug exposure, through a close monitoring, remains stable. Substitution from one generic to another generic should be avoided, in all cases.

Bioavailability, Efficacy and Safety of Generic Immunosuppressive Drugs for Kidney Transplantation: A Systematic Review and Meta-Analysis

Background: Concerns exist over the extrapolation of bioavailability studies of generic immunosuppressive drugs in healthy volunteers, regarding their efficacy and safety in kidney transplant recipients. We conducted a meta-analysis of trials examining the bioavailability of generic (test) immunosuppressive drugs relative to their brand (reference) counterparts in healthy volunteers, based on the US Food and Drug Administration requirements for approval of generics, and their efficacy and safety in kidney transplant recipients. Methods: Eligible studies were identified in PubMed, Cochrane Central Register of Controlled Trials, Scopus, ClinicalTrials.gov, and conference abstracts. Results: Twenty crossover trials of healthy volunteers (n = 641) and 6 parallel-arm randomized controlled trials of kidney transplant recipients (n = 594) were identified. The 90% CI of the pooled test-to-reference drug ratio for maximum or peak plasma concentration (C_max) and area under the plasma concentration time-curve from time 0 to time of last determinable concentration (AUC_(0-t)) fell within the required range (0.80-1.25) for cyclosporine (C_max 0.91; 90% CI 0.86-0.95; and AUC_(0-t) 0.97; 90% CI 0.94-1.00), tacrolimus (C_max 1.17; 90% CI 1.09-1.24; and AUC_(0-t) 1.00; 90% CI 0.97-1.03) and mycophenolate mofetil (C_max 0.98; 90% CI 0.96-1.01; and AUC_(0-t) 1.00; 90% CI 0.99-1.01). In subgroup analyses, some generic cyclosporine formulations did not meet criteria for bioequivalence. No significant differences were observed in the time to maximum plasma concentration and terminal plasma half-life between generic and brand drugs. In parallel-arm trials, generic cyclosporine was non-inferior to brand counterpart in terms of acute allograft rejection, infections, and death. Conclusions: Not all generic immunosuppressive drugs have similar relative bioavailability to their brand name counterparts. Evidence on their efficacy and safety is inconclusive. Tighter regulatory requirement for approval of generic drugs with narrow therapeutic index is needed.

What Is the Future of Generics in Transplantation?

Generic immunosuppressive drugs are available in Europe, Canada, and the United States. Between countries, there are large differences in the market penetration of generic drugs in general, and for immunosuppressive drugs in particular. The registration criteria for generic immunosuppressive drugs are often criticized. However, it is unlikely that the criteria for registration of narrow therapeutic index drugs are going to change, and bioequivalence studies, performed in healthy volunteers, will remain the backbone of the registration process. It would be good if the registration authorities would demand that all generic variants of an innovator drug have the same pill appearance to reduce errors and promote drug adherence.To allow for safe substitution, a number of criteria need to be fulfilled. Generic substitution should not be taken out of the hands of the treating physicians. Generic substitution can only be done safely if initiated by the prescriber, and in well-informed and prepared patients. Payers should refrain from forcing pharmacists to dispense generic drugs in patients on maintenance treatment with innovator drug. Instead, together with transplant societies, they should design guidelines on how to implement generic immunosuppressive drugs into clinical practice. Substitutions must be followed by control visits to check if the patient is taking the medication correctly and if drug exposure remains stable. Inadvertent, uncontrolled substitutions from 1 generic to another, initiated outside the scope of the prescriber, must be avoided as they are unsafe. Repetitive subsequent generic substitutions result in minimal additional cost savings and have an inherent risk of medication errors.

Generic immunosuppression in solid organ transplantation: systematic review and meta-analysis

Objective To compare the clinical efficacy and bioequivalence of generic immunosuppressive drugs in patients with solid organ transplants.Design Systematic review and meta-analysis of all studies comparing generic with innovator immunosuppressive...

Chronic kidney disease in disadvantaged populations.

The increased burden of chronic kidney disease (CKD) in disadvantaged populations is due to both global factors and population-specific issues. Low socioeconomic status and poor access to care contribute to health care disparities and exacerbate the negative effects of genetic or biological predisposition. Provision of appropriate renal care to these populations requires a two-pronged approach: expanding the reach of dialysis through development of low-cost alternatives that can be practiced in remote locations, and implementation and evaluation of cost-effective prevention strategies. Kidney transplantation should be promoted by expansion of deceased donor transplant programs and use of inexpensive, generic immunosuppressive drugs. The message of World Kidney Day 2015 is that a concerted attack against the diseases that lead to end-stage renal disease, by increasing community outreach, better education, improved economic opportunity, and access to preventive medicine for those at highest risk, could end the unacceptable relationship between CKD and disadvantage in these communities.

Chronic kidney disease in disadvantaged populations.

The increased burden of chronic kidney disease (CKD) in disadvantaged populations is due to both global factors and population-specific issues. Low socioeconomic status and poor access to care contribute to health care disparities and exacerbate the negative effects of genetic or biological predisposition. Provision of appropriate renal care to these populations requires a two-pronged approach: expanding the reach of dialysis through development of low-cost alternatives that can be practiced in remote locations, and implementation and evaluation of cost-effective prevention strategies. Kidney transplantation should be promoted by expansion of deceased donor transplant programs and use of inexpensive, generic immunosuppressive drugs. The message of World Kidney Day 2015 is that a concerted attack against the diseases that lead to end-stage renal disease, by increasing community outreach, better education, improved economic opportunity, and access to preventive medicine for those at highest risk, could end the unacceptable relationship between CKD and disadvantage in these communities.

Przewlekła choroba nerek w populacjach nieuprzywilejowanych

The increased burden of CKD in disadavantaged populations is due to both global factors and population-specific issues. Low socioeconomic status and poor access to care contribute to health care disparities, and exacerbate the negative effects of genetic or biologic predisposition. Provision of appropriate renal care to these populations requires a two-pronged approach: expanding the reach of dialysis through development of low-cost alternatives that can be practiced in remote locations, and implementation and evaluation of cost-effective prevention strategies. Kidney transplantation should be promoted by expanding deceased donor transplant programs and use of inexpensive, generic immunosuppressive drugs. The message of WKD 2015 is that a concerted attack against the diseases that lead to ESRD, by increasing community outreach, better education, improved economic opportunity, and access to preventive medicine for those at highest risk, could end the unacceptable relationship between CKD and disadvantage in these communities.

Use of generic tacrolimus in elderly renal transplant recipients: precaution is needed.

Proper bioequivalence studies comparing original with generic immunosuppressive drugs in patients are limited, especially in the increasing population of elderly renal transplant recipients. We performed an open-label, single-center, prospective, randomized, cross-over study and compared steady-state pharmacokinetics (PK) of a generic tacrolimus (Tacni) formulation with the original (Prograf) in renal transplant recipients older than 60 years. Twenty-eight patients, with a median age of 69 years (range, 60 to 78), were randomized at time of transplantation to receive original or generic tacrolimus, and 25 (21 men, 4 women) provided two evaluable 12-hr PK profiles. The PK investigations were performed in a stable phase approximately 6 and 8 weeks postengraftment. After the first PK investigation, tacrolimus formulations were switched (1:1 dose ratio). Generic tacrolimus did not meet the bioequivalence criteria; the area under the curve(0-12) ratio of generic-original tacrolimus formulation was 1.17 (90% confidence interval, 1.10-1.23) and the Cmax ratio was 1.49 (90% confidence interval, 1.35-1.65). The generic formulation also showed a shorter time to C(max) (T(max)) (P=0.04). Importantly, the lack of bioequivalence was not reflected in the standard monitoring parameter, trough concentrations (P=0.80). Generic tacrolimus (Tacni) was not found to be bioequivalent to the original formulation in elderly renal transplant recipients. The significantly higher systemic exposure of tacrolimus, despite similar trough concentrations, may in the long run increase the risk of adverse effects.

Chronic kidney disease in disadvantaged populations.

The increased burden of CKD in disadavantaged populations is due to both global factors and population-specific issues. Low socioeconomic status and poor access to care contribute to health care disparities, and exacerbate the negative effects of genetic or biologic predisposition. Provision of appropriate renal care to these populations requires a two-pronged approach: expanding the reach of dialysis through development of low-cost alternatives that can be practiced in remote locations, and implementation and evaluation of cost-effective prevention strategies. Kidney transplantation should be promoted by expanding deceased donor transplant programs and use of inexpensive, generic immunosuppressive drugs. The message of WKD 2015 is that a concerted attack against the diseases that lead to ESRD, by increasing community outreach, better education, improved economic opportunity, and access to preventive medicine for those at highest risk, could end the unacceptable relationship between CKD and disadvantage in these communities.

Chronic kidney disease in disadvantaged populations.

The increased burden of chronic kidney disease (CKD) in disadvantaged populations is due to both global factors and population-specific issues. Low socioeconomic status and poor access to care contribute to health care disparities and exacerbate the negative effects of genetic or biological predisposition. Provision of appropriate renal care to these populations requires a two-pronged approach: expanding the reach of dialysis through development of low-cost alternatives that can be practiced in remote locations, and implementation and evaluation of cost-effective prevention strategies. Kidney transplantation should be promoted by expansion of deceased donor transplant programs and use of inexpensive, generic immunosuppressive drugs. The message of World Kidney Day 2015 is that a concerted attack against the diseases that lead to end-stage renal disease, by increasing community outreach, better education, improved economic opportunity, and access to preventive medicine for those at highest risk, could end the unacceptable relationship between CKD and disadvantage in these communities.

Is It Ethical to Prescribe Generic Immunosuppressive Drugs to Our Transplanted Patients?

In various countries, drug patents for immunosuppressive drugs have recently expired or are about to expire. As a result, generic versions of these immunosuppressive drugs have emerged on the market. The use of generic drugs is widely accepted for chronic diseases such as hypertension and dyslipidemia. In organ transplantation, the use of generic drugs is debated. Some transplant societies discourage their use while others recommend extreme caution. This reluctance to use generic drugs in organ transplantation is partly related to the fact that most of these drugs are “critical dose drugs” and either low dosing of the drug or overdosing could have serious adverse consequences for the patient. This situation led us to question whether it was ethical to prescribe generic immunosuppressive drugs to transplanted patients. How much evidence and how many bioequivalence studies are needed to ensure the safety of generic drugs? Do the beneficence and nonmaleficence principles require the use of brand name immunosuppressive drugs? Given that transplant physicians are stewards of a precious resource (organs), should they prescribe brand name immunosuppressants in order to minimize the risk of rejection? Should patients be involved in the debate and how should physicians help them make informed decisions? Are there any conflicts of interest that might influence the debate? From a societal point of view, is the use of brand name immunosuppressive drugs a fair allocation of resources? Our review of the literature and ethical analysis led us to conclude that it would be ethical, under certain circumstances, to prescribe generic immunosuppressive drugs. That said, further health economics studies are needed to look at all of the costs related to the substitution (e.g., frequent and closer monitoring of patients).

Is it ethical to prescribe generic immunosuppressive drugs to renal transplant patients?

Purpose of the reviewThis review was conducted to determine the ethical acceptability of prescribing generic immunosuppressive drugs to renal transplant patients.Sources of informationThe literature search was conducted using Pubmed and Google Scholar.FindingsThe use of generic immunosuppressive drugs (ISDs) in transplantation is a controversial topic. There is a consensus among transplant societies that clinical data is lacking and that caution should be exercised. The reluctance to use generic ISDs in organ transplantation is partly related to the fact that most are “critical dose drugs”, and that either low dosing or overdosing could have serious adverse consequences for both patients and society (i.e., the loss of scarce organs). In this paper, we examine the various ethical issues involved such as distributive justice, physician duties, risks versus benefits, conflict of interest, informed consent, and logistical and economic issues.LimitationsOur analysis was limited by the paucity of clinical data on generic ISDs and the absence of health economics studies to quantify the benefits of prescribing generic ISDs.ImplicationsOur study led us to conclude that it would be ethical to prescribe generic ISDs provided certain conditions were met. These include regulatory safeguards to minimize the risks of substitution; education of patients; and further clinical and health economics studies to better inform clinicians, patients and society of the risks and costs related to drug substitution.

CKD in Disadvantaged Populations

The increased burden of CKD in disadvantaged populations is due to both global factors and population-specific issues. Low socioeconomic status and poor access to care contribute to health-care disparities and exacerbate the negative effects of genetic or biologic predisposition. Provision of appropriate renal care to these populations requires a two-pronged approach: expansion of the reach of dialysis through development of low-cost alternatives that can be practiced in remote locations, and implementation and evaluation of cost-effective prevention strategies. Kidney transplantation should be promoted by expansion of deceased-donor transplant programs and use of inexpensive, generic immunosuppressive drugs. The message of WKD 2015 is that a concerted attack against the diseases that lead to ESRD, by increased community outreach, better education, improved economic opportunity, and access to preventive medicine for those at highest risk, could end the unacceptable relationship between CKD and disadvantage in these communities.

Prograf Five Milligrams Versus Tacrolimus Medis in Healthy Volunteers: A Bioequivalence Study

For FDA approval, bioequivalence of a generic version of Tacrolimus must be demonstrated in a randomized, two-treatments, two-periods, two-sequences, single-dose crossover study in healthy adult volunteers. Currently there are at least 3 differents generic equivalent for Tacrolimus, that are approved by the EMA and the FDA, with a USA market share of nearly 50%. However, the market share of generic immunosuppressive drugs in the Middle East region is still very low due to the reluctance of the physician to accept Tacrolimus generics, considered to be a narrow therapeutic window drug, that are approved using the standard bioequivalence criteria of 80% to 125%. Herein we present a bioequivalence study of a new Tacrolimus generic, Tacrolimus Medis 5 mg developed by Medis Tunisia batch number 12G3003 compared with Prograf® 5 mg batch number 7202 manufactured by Astellas Toyama Co., Ltd. Japan and HIKMA Pharmaceuticals, Amman-Jordan in healthy adult volunteers using the 90%–111% criteria recommended for drugs with narrow therapeutic window. The study was, balanced, randomized, two-treatments, two-periods, two-sequences, single dose, crossover, comparative oral bioavailability study in healthy adult human volunteers. The study was carried out in accordance with the Basic Principles defined in the U.S. 21 CFR Part 312.20, the principles enunciated in the Declaration of Helsinki (World Medical Association Declaration of Helsinki). Thirty six non-smoking healthy, as determined by medical history, volunteers, 18 years and older, were included. Following randomization using a computer software (pharma solution) the volunteers were given a single oral dose of 5 milligrams following a 12 hour fast with a wash out period of 7 days. Pharmacokinetics profile with blood levels at: 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours were performed following each dose. Tacrolimus plasma level was determined using an HPLC validated method (Transmedical For Life S.A.R.L. Beirut Lebanon), for accuracy, suitability, reproducibility, precision , long-term stability and robustness. Physical examinations, hematology, urine analysis and serum chemistry tests were performed at screening and before dosing in each period and at end of the study. Volunteers were monitored for safety and adverse events throughout the study. Both products were bioequivalent at the entire pharmacokinetic parameters tested. The LSM were 95.31%–101.21% for AUC, 94.65%–101.11% for AUC0-inf, 97.15%–100.02% for Cmax and 91.54%–103.75% for Half-life. Respectively all of which are within the EU and FDA approval limits (90–111%) indicating that the 2 products are equivalent and switchable.

Why bioequivalence and unconditional interchangeability of generic drugs are not the same

The patents for a number of cornerstone immunosuppressive drugs used in the field of solid organ transplantation have expired. Generic formulations are now available and several professional societies and individual physicians have given their opinions on the issue of generics substitution. In this issue of GaBI Journal, several hot topics related to implementation of generic immunosuppressive drugs in clinical practice were discussed in different perspectives.

Evolution of deceased-donor transplantation in India with decline of commercial transplantation: a lesson for developing countries

The positive impact of a structured deceased-donor program has resulted in a reduction in the number of commercial transplantation operations taking place in India. The engagement of private and government stakeholders has revealed the positive impact of deceased organ donation in India. The best example is the Tamil Nadu state model, where deceased donations have increased to 1.2 per million population compared to the national average of 0.08 per million population. In the last 30 months 994 organs were transplanted. The donation and transplantation in the Government-run hospitals have provided organs to the poor sections of the society free of cost. Immunological surveillance of the prospective recipients remains a challenge, as there is a paucity of immunological laboratories in transplant centers. Generic immunosuppressive drugs manufactured by the local pharmaceutical industry have been shown to be noninferior, and have greatly reduced the cost of achieving immunosuppression.

Generic Immunosuppression in Solid Organ Transplantation

The introduction of generic immunosuppressant medications may present an opportunity for cost savings in solid organ transplantation if equivalent clinical outcomes to the branded counterparts can be achieved. An interprofessional working group of the Canadian Society of Transplantation was established to develop recommendations on the use of generic immunosuppression in solid organ transplant recipients (SOTR) based on a review of the available data. Under current Health Canada licensing requirements, a demonstration of bioequivalence with the branded formulation in healthy volunteers allows for bridging of clinical data. Cyclosporine, tacrolimus, and sirolimus are designated as "critical dose drugs" and are held to stricter criteria. However, whether this provides sufficient guarantee of therapeutic equivalence in SOTR remains controversial, and failure to maintain an appropriate balance of immunosuppression may have serious consequences, including rejection, graft loss, and death. Published evidence supporting therapeutic equivalence of generic formulations in SOTR is lacking. Moreover, in the setting of multiple generic formulations the potential for uncontrolled product switching is a major concern, since generic preparations are not required to demonstrate bioequivalence with each other. Although close monitoring is recommended with any change in formulation, drug product switches are likely to occur without prescriber knowledge and may pose a significant patient safety risk. The advent of generic immunosuppression will require new practices including more frequent therapeutic drug and clinical monitoring, and increased patient education. The additional workload placed on transplant centers without additional funding will create challenges and could ultimately jeopardize patient outcomes. Until more robust clinical data are available and adequate regulatory safeguards are instituted, caution in the use of generic immunosuppressive drugs in solid organ transplantation is warranted.

The Once-Daily Formulation of Tacrolimus

Nonadherence is a critical issue in transplantation. Recently, Astellas designed a once-daily-extended release formulation of tacrolimus (Tac). Despite initial reports showing bioequivalence of Tac once-daily (Advagraf) with the original formulation requiring twice-daily intake (Tac twice-daily, Prograf), several groups have now shown a sustained decrease in Tac exposure upon conversion from Prograf to Advagraf. Here, we discuss the possible reasons for this observation and how it could affect the expected benefits of Advagraf, and we comment on the fact that a similar lack of bioequivalence might prevail with generic immunosuppressive drugs.