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Clinical and Translational Research

A Multicenter Experience With Generic Tacrolimus Conversion

McDevitt-Potter, Lisa M.1,6; Sadaka, Basma2; Tichy, Eric M.3; Rogers, Christin C.2; Gabardi, Steven4,5

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doi: 10.1097/TP.0b013e31822a79ad
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Abstract

Tacrolimus is a macrolide-derivative, calcineurin inhibitor immunosuppressant that was first discovered in 1984. It was initially approved by the Food and Drug Administration (FDA) for prophylaxis against rejection in liver transplant recipients in 1994 and has subsequently received approval in both renal and heart transplantation. In the 21st century, tacrolimus is considered the primary immunosuppressant of choice by most transplant centers in the United States (1). Brand name tacrolimus (Prograf, Astellas Pharma US, Deerfield, IL) lost patent protection in April 2008, but the first generic tacrolimus product was not FDA-approved until August 10, 2009.

To gain FDA approval, a generic drug must be pharmaceutically equivalent and bioequivalent to the reference drug (2). To be pharmaceutically equivalent, the generic product must contain the same amount of the same active ingredient(s) in the same dosage form and route of administration, and must be manufactured according to the same standards of strength, quality, purity, and identity. Generic drugs are allowed to differ in some characteristics, such as shape, release mechanisms, packaging, excipients, expiration time, and within certain limits, labeling. To be bioequivalent, the rate (i.e., maximum concentration [Cmax]) and extent (i.e., area under the concentration-time curve [AUC]) of absorption of the generic product must not differ significantly from the reference drug. Specifically, the 90% confidence interval of the geometric mean generic/reference Cmax and AUC ratios must fall within the bioequivalence limits of 80% to 125%. In most cases, the average Cmax and AUC between generic and reference products differ by less than 5% (3). A typical bioequivalence study is a single-dose, two-way crossover study in 24 to 36 healthy volunteers. For drugs whose absorption is affected by food, such as tacrolimus, bioequivalence studies must be replicated in both fed and fasting states and the FDA has issued specific recommendations for tacrolimus bioequivalence testing (4).

There is concern whether these stipulations are adequate for drugs such as tacrolimus where effective and toxic concentrations are not different and where therapeutic drug monitoring is essential. In May 2006, the Canadian Ministry of Health established unique bioequivalence criteria for a category of such drugs titled “Critical Dose Drugs.” For these drugs, the 90% confidence interval of the relative mean AUC of the generic to reference formulation should be within 90% to 112% of the reference drug. The 90% confidence interval of the relative mean Cmax can remain between 80% and 125% of the reference drug (5). In January 2010, the European Medicines Agency followed suit and adopted tighter bioequivalence standards for drugs considered “Narrow Therapeutic Index” drugs. Their recently revised guideline requires the confidence interval of the AUC for the generic product to be between 90% and 111% of the reference drug (6). The FDA has defended its current bioequivalence standards. However, in April 2010, the FDA Advisory Committee for Pharmaceutical Science and Clinical Pharmacology agreed that critical dose drugs are a distinct group of products, that the FDA should develop a list of drugs considered “critical dose” drugs, and that current bioequivalence standards may not be sufficient for critical dose drugs (7).

Generic tacrolimus' entry to the market may allow for cost savings. However, drug cost savings must be balanced against potential risk associated with their use. Although the efficacy of generic tacrolimus is not in doubt, clinically relevant risks of altered drug exposure may exist when converting patients from one product to another (i.e., brand-to-generic or generic-to-generic). This article reports our multicenter effort to prospectively track patients converting from brand tacrolimus (Prograf, Astellas Pharma US) to generic tacrolimus (Sandoz, Princeton, NJ), focusing on the need for postconversion tacrolimus dose titrations and cost outcomes.

RESULTS

A total of 94 brand-to-generic conversions were evaluated between four transplant centers. These 94 subjects met study inclusion and exclusion criteria for the time of generic conversion but only 70 subjects also met inclusion and exclusion criteria for the control time point of 6 months before generic conversion. Data are presented for the group with control data only.

Demographic data are presented in Table 1. At the time of generic conversion, subjects were an average of 70±51 months from transplant and 20±18 months from their most recent tacrolimus dose change.

TABLE 1
TABLE 1:
Demographic data

Mean daily tacrolimus doses before and after generic conversion were 4.4±3.2 mg and 4.5±2.9 mg, respectively (P=0.89). Fifteen patients (21%) required dose adjustments; 7 were upward and 8 were downward. Mean daily tacrolimus doses before and after the control time point were 4.6±3.4 mg and 4.6±3.4 mg, respectively (P=0.16). Five patients (7%) required dose adjustments; four were downward and one was upward. Significantly, more patients in the study arm required dose adjustments compared with the control arm (P=0.028).

The magnitude of dose changes are shown in Figures 1 and 2. The mean change in dose was 0.4±0.8 mg/d and 0.1±0.4 mg/d, whereas the mean percent change in dose was 8.6%±21.1% and 0.0%±0.1% for the study and control time points, respectively.

FIGURE 1.
FIGURE 1.:
Number of patients per absolute change in dose. This figure shows the variance in dose (mg/d) before and after generic conversion (study arm) and 6 months before generic conversion (control arm).
FIGURE 2.
FIGURE 2.:
Number of patients per percent change in dose. This figure shows the variance in dose (% change in mg/d) before and after generic conversion (study arm) and 6 months before generic conversion (control arm).

Mean tacrolimus trough concentrations before and after generic conversion were 5.8±2.1 ng/mL and 5.9±2.7 ng/mL, respectively (P=0.81). Mean tacrolimus trough concentrations before and after the control time point were 6.1±1.6 ng/mL and 5.9±2.0 ng/mL, respectively (P=0.40).

The magnitude of fluctuation in tacrolimus trough concentrations is shown in Figures 3 and 4. The mean change in tacrolimus trough concentration was 1.6±1.5 ng/mL and 1.2±1.0 ng/mL, whereas the mean percent change in tacrolimus trough concentration was 26.7%±22.0% and 19.5%±15.0% for the study and control study time points, respectively.

FIGURE 3.
FIGURE 3.:
Number of patients per absolute change in tacrolimus trough. This figure shows the variance in tacrolimus trough (ng/mL) before and after generic conversion (study arm) and 6 months before generic conversion (control arm).
FIGURE 4.
FIGURE 4.:
Number of patients per percent change in tacrolimus trough. This figure shows the variance in tacrolimus trough (% change in ng/mL) before and after generic conversion (study arm) and 6 months before generic conversion (control arm).

Monthly drug costs were calculated two ways: “actual drug cost” was based on average wholesale price and “cost to patient” was based on actual patient copays. The mean monthly cost of brand-name drug was $645±$465. The mean monthly cost of generic drug was $593±$429 based on a mg:mg dose conversion and $595±$393 after dose titration. This is an average overall savings of approximately $50 per patient per month. Mean monthly patient copays were $38±$108 for brand and $15±$47 for generic. Patient copays varied according to the type of insurance coverage as illustrated in Table 2.

TABLE 2
TABLE 2:
Monthly patient copays for tacrolimus

Four spontaneous adverse events were reported in four subjects: nausea, mouth sores, rash, and vision changes. Three of the four elected to convert back to the branded product. No biopsies were performed and there were no episodes of allograft rejection.

DISCUSSION

It was not a surprise that the tacrolimus dose requirements and tacrolimus trough concentrations were similar between subjects on branded and generic products. The bell curve appearance of Figures 1 to 4 suggest that the variation seen may reflect standard dose-dose variation in the same patient. It is interesting to note, however, that three times as many patients underwent a dose change after conversion to generic compared with the proportion of patients who underwent a dose change at a random moment under routine posttransplant care.

The expenses described in this study include drug cost only. Additional costs to consider for patients remaining on brand-name product include time required for transplant staff to obtain prior authorizations and ensure prescriptions include the state-specific wording that mandates dispensing of brand-name product by the pharmacy. Additional costs to consider for patients converting to generic products include obtaining and following up on one or more additional tacrolimus trough concentrations on product conversion. At our centers, tacrolimus trough concentrations cost an average of $76±$18 each.

The insurance copay data reflect significant variance. Medicare is a federally funded public insurance plan; eligibility is determined by age (65 years or older), disability, or the presence of end-stage renal disease. Medicaid is a state funded public insurance plan; eligibility is income based. Private insurance is generally obtained through one's employment. For patients with Medicare, copays varied depending on whether immunosuppressants were billable to Part B (i.e., patients who had Medicare at the time of their transplant) or Part D (i.e., patients who have Medicare now but did not have it at the time of their transplant). For those whose drug cost was billable to Part B, copays varied depending on whether they carried a Medicare supplement (i.e., no copay for those with a supplement and 20% of cost copays for those without a supplement). For those whose drug cost was billable to Part D, copays varied depending on which phase of coverage patients were in at the time of their refill (i.e., deductible, coinsurance, coverage gap, or catastrophic coverage). For patients with private insurance only, copays varied depending on the state where patients reside. Copay coupons that allow copays to be waived for patients taking branded product are permitted in all states except Massachusetts.

It is important to note that, at the time of this study, only one generic tacrolimus product was available on the US market (Sandoz). Because all subjects used the same manufacturer's generic tacrolimus product, this experience may not apply to generic-to-generic substitution. Four generic tacrolimus products are currently available in the United States: Dr. Reddy's Labs, Ltd. (Bridgewater, NJ), Mylan (Canonsburg, PA), Sandoz, and Watson (Corona, CA) (8). Although the arrival of multiple generic products may further impact drug cost, the cost associated with postconversion monitoring must also be considered. Postconversion monitoring is relevant not only when converting from brand-to-generic product but also when converting from one manufacturer's generic product to another manufacturer's generic. A change in appearance of the drug will suggest to a patient that the manufacturer may have changed and could prompt a call for conversion monitoring. Alternately, state pharmacy laws such as those in North Carolina may require a dispensing pharmacist to obtain provider and patient approval before substituting one generic for another for drugs declared as narrow therapeutic index drugs (9).

Bioequivalence data for the tacrolimus product used by study subjects have been published (10). Each of the fasting and fed-state bioequivalence studies were performed in a population consisting of 40 healthy volunteers. This is the second published experience using this drug product in transplant recipients (11). Transplant centers in India (12), South Korea (13, 14), and Chile (15) have also reported experience with generic tacrolimus. However, the tacrolimus products used in the Indian and Korean experience do not have FDA approval. The Chilean paper did not describe which manufacturer's product was used.

The perception of generic tacrolimus in the transplant community has been partially shaped by previous experience with cyclosporine which has shown both positive and negative results (16–18). With these concerns in mind, transplant groups have voiced opinions on the use of generic immunosuppressants (19–22). Although the recommendations of these groups are numerous, they universally advise blood level monitoring during transition points between products to avoid deleterious outcomes that might be associated with acute variation in drug levels that may result from the transition. Our experience described in this article would seem to demonstrate a practical approach for managing tacrolimus generic substitution in stable organ transplant recipients consistent with the above recommendations.

Tacrolimus dose requirements and trough concentrations are similar between brand and generic tacrolimus. Generic substitution allows for savings. However, additional drug monitoring postconversion would be prudent as patients may require dose titration. Additional studies are needed to evaluate the potential for variation in tacrolimus levels when switching between generic tacrolimus products and to determine the impact of generic tacrolimus on complications such as changes in serum creatinine, adverse events and allograft rejection.

MATERIALS AND METHODS

This study was a prospective, observational trial conducted at four transplant centers. Institutional review board (IRB) approval was obtained at each center (Tufts IRB no. 9405; Beth Israel IRB no. 2009-P-000381/1, Yale IRB no. 0912006049, Brigham and Women's IRB no. 2009-P-000979/1).

Each center used their own criteria to decide which patients to convert and when. Criteria included offering patients the choice between brand and generic, converting to generic only when mandated by an insurer per formulary or copay reasons, or capturing inadvertent conversions pursuant to prescriptions missing the required “dispense as written” language. Once a patient converted from brand to generic tacrolimus, all centers followed a consistent plan for handling the conversion. Doses were converted on a mg:mg basis, and patients were instructed to return for a tacrolimus trough 4 to 7 days after starting the generic product. Doses were titrated, if needed, per the center's standard of care.

The objective of our analysis was to determine the need for dose titrations and measure drug cost savings on conversion from brand to generic tacrolimus. The primary endpoint was the number of patients requiring dose titration. Secondary endpoints included the impact of generic conversion on tacrolimus trough concentrations, dose requirements, drug expense, and patient copay.

All subjects converting to generic tacrolimus at the participating centers were considered for study participation. To be included in the data analysis, subjects must have met study inclusion and exclusion criteria for two time points: (1) the time of conversion to generic tacrolimus (study group) and (2) a time point exactly 6 months before generic conversion (control group).

Subjects were included if the date of conversion to generic tacrolimus was known, the tacrolimus dose was stable for at least 4 weeks before each time point, and the patient returned for follow-up trough monitoring after each time point. Subjects were excluded if they underwent tacrolimus dose titration within 4 weeks before either time point, if they started or stopped drugs known to interact with tacrolimus around either time point, if their target tacrolimus trough range changed at either time point, or if they were taking a mix of brand and generic products.

Demographic data, data relevant to dose and trough fluctuations, and cost and copay data were collected. Demographic data included age at conversion, gender, race, transplant center, type of organ transplanted, time from transplant, and type of insurance coverage. Data relevant to tacrolimus dosing included time on a stable tacrolimus dose before generic conversion, daily tacrolimus dose before each time point, daily tacrolimus dose after dose titration (if needed), and generic product manufacturer. Data relevant to tacrolimus trough concentrations included the three troughs before and one trough after each time point. For comparison, the median of the three most recent tacrolimus troughs before the time point was compared with the first tacrolimus trough after the time point. The median of the three most recent preconversion troughs was chosen because this most closely reflects actual clinical practice where a new result is interpreted in the context of the few most recent trough results taken while a patient continues on a stable dose.

Cost data were based on average wholesale price as of April 1, 2010 (Prograf $4.84 per 1 mg capsule and tacrolimus $4.46 per 1 mg capsule) (23). Monthly copay data was obtained from patients, their dispensing pharmacy, and their insurance provider. Spontaneous reports of adverse events were collected. Each subject served as his/her own control. Descriptive statistics and paired t tests were used to analyze the data. A Fisher's exact test was used to compare the number of patients requiring tacrolimus dose titration in the study versus control arms.

ACKNOWLEDGMENT

The authors acknowledge the contributions of Robin Ruthazer in the Clinical and Translational Research Center at Tufts Medical Center in Boston, MA.

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Keywords:

Tacrolimus; Pharmacotherapy; Immunosuppression; Generic

© 2011 Lippincott Williams & Wilkins, Inc.