Generic Drug Immunosuppression in Thoracic Transplantation: An ISHLT Educational Advisory
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CONSENSUS STATEMENT
Generic Drug Immunosuppression in Thoracic Transplantation:
An ISHLT Educational Advisory
Patricia A. Uber, PharmD,a Heather J. Ross, MD,b Andreas O. Zuckermann, MD,c Stuart C. Sweet, MD,d
Paul A. Corris, MD,e Keith McNeil, MD,f and Mandeep R. Mehra, MBBSa
The 1990s ushered in approval of several novel immu- in-patient hospitalization or prolongation of existing
nosuppressant drugs, including mycophenolate mofetil, hospitalization, persistent or significant disability or
tacrolimus, cyclosporine microemulsion, everolimus and incapacity and death.4
sirolimus, with consequent improvement in clinical Similar in nature are narrow therapeutic index drugs,
outcomes. Subsequently, the transplant community has which are described as any pharmaceutical agent that
been challenged with the development and introduc- has a less than 2-fold difference between the minimum
tion of generic immunosuppression drugs. These drugs toxic concentration and minimum effective concentra-
represent a narrow therapeutic index and are thus tion in blood. The United States FDA describes these
classified as critical-dose agents. Sengai Gibon, a Japa- products as having a less than a 2-fold difference in median
nese zen monk, wrote “Whether for life, whether for lethal dose and median effective dose values, or a less than
death—(it depends on) the right spoon-measure.”1 The a 2-fold difference in the minimum toxic concentrations
purpose of this educational advisory is to provide an and minimum effective concentrations in the blood,
international perspective on regulatory and clinical and that safe and effective use of the drug products
concerns with generic immunosuppression medica- require careful titration and patient monitoring.5
tions in thoracic transplantation.
INTERNATIONAL REGULATION OF GENERIC MEDICATIONS
DEFINITIONS: CRITICAL-DOSE DRUGS AND NARROW Regulating agencies around the world designate a ge-
THERAPEUTIC INDEX MEDICATIONS neric preparation as either a pharmaceutically equiva-
Canada and the European Union catalog immunosup- lent or pharmaceutical alternative product to the inno-
pression medications as “critical-dose drugs,” character- vator (brand) product. Most countries insist that in
ized as those medications wherein comparatively small order for a generic drug to be deemed pharmaceutically
differences in dose or concentration lead to dose- and equivalent, they must contain the identical active ingre-
concentration-dependent, serious therapeutic failures dient to the innovator drug in the same strength, dose
and/or serious adverse drug reactions.2,3 Such therapeu- form and route of administration, and must be pre-
tic consequences may be persistent, irreversible, slowly scribed for the same therapeutic indication.2,3,5,6 These
reversible or life-threatening, which could result in products may differ in shape, color, inactive ingredi-
ents, release mechanism and packaging. Under these
regulations, a generic drug may be considered thera-
From the aDivision of Cardiology, University of Maryland School of peutically equivalent to the innovator drug if it is
Medicine, Baltimore, Maryland; bDivision of Cardiology, Peter Munk
Cardiac Centre, Toronto General Hospital, Toronto, Ontario, Canada;
prescribed to patients under labeling conditions and
c
Department of Cardiothoracic Surgery, Medical University of Vienna, exhibits similar clinical effect and safety profile, both of
Währinger Gürtel, Vienna, Austria; dDivision of Allergy and Pulmo- which are largely dependent on bioequivalence.
nary Medicine, Department of Pediatrics, Washington University Bioequivalence is based on a comparison of mean
School of Medicine, St. Louis, Missouri; eNewcastle University and pharmacokinetic parameters for brand and generic
Cardiothoracic Centre, Freeman Hospital, Newcastle upon Tyne, UK;
and fQueensland Centre for Thoracic Transplantation, The Prince
drugs, the area under the concentration–time curve
Charles Hospital, Chermside, Brisbane, Queensland, Australia. (AUC), maximum concentration (Cmax) and minimum
Submitted May 1, 2009; revised May 1, 2009; accepted May 1, 2009. concentration (Cmin). The rate and extent of absorption
Presented in part at the 29th annual scientific meeting of the ISHLT, can be determined either in vivo or vitro, depending on
April 2009, Paris, France. This study was commissioned by the Board the regulating agency’s requirements for each com-
of Directors of the ISHLT and approved at all stages by the Education
Committee of the ISHLT.
pound. Because immunosuppressant medications are
Reprint requests: Mandeep R. Mehra, MBBS, Department of Cardi- characterized as critical-dose drugs or narrow therapeu-
ology, University of Maryland Medical Center, 22 South Greene Street, tic index medications, generic manufacturers must per-
S3B06, Baltimore, MD 21030. Telephone: 410-328-7716. Fax: 410-328- form in vivo studies, often utilizing healthy volun-
4382. E-mail: mmehra@medicine.umaryland.edu teers.2,6,7
J Heart Lung Transplant 2009;28:655– 60.
Copyright © 2009 by the International Society for Heart and Lung
The pharmacokinetic studies commonly performed
Transplantation. 1053-2498/09/$–see front matter. doi:10.1016/ consist of a two-treatment crossover study design in 24
j.healun.2009.05.001 to 36 normal, healthy adults. Usually, both a single dose
655656 Uber et al. The Journal of Heart and Lung Transplantation
July 2009
Table 1. Pharmacokinetic Parameters and Study Conditions That Determine Drug Bioequivalence by Country
Log-transformed Met in fasted
AUC Cmax parameters and fed state Steady-state required?
Canada 90% CI of relative 90% CI of the Must be met, calculated Yes Not unless warranted by exceptional
mean AUC of relative mean from measured data circumstances; if required, the 90%
test to measured Cmax and data corrected for CI of the relative mean measured
reference of the test to measured drug Cmin of the test to reference should
should be reference content (percent also be between 80.0% and
between 90% should be potency of label claim) 125.0%
and 112% between 80.0%
and 125.0%
United 90% CI of relative 90% CI of the Data are log-transformed May be required, For controlled released drugs or drugs
States mean AUC of relative mean prior to conducting standard high- with low levels with one dose;
test to measured Cmax statistical testing by fat diet is patients may be studied if the drug
reference of the test to ANOVA and calculating utilized; same is considered dangerous with
should be reference a 90% CI for each parameters repeat doses in healthy volunteers;
between 80.0% should be pharmacokinetic apply log-transformation Cmin, Cmax and
and 125.0% between 80.0% parameter; CI must be AUC CI must be entirely within the
and 125.0% entirely within the 80% to 125% boundaries
80% to 125%
boundaries
EMEA 90% CI for test/ 90% CI for test/ Data are log-transformed Either (depending Under special circumstances: 90% CI
zone reference ratio reference ratio prior to conducting on drug) for test/reference ratio should be
(Europe) should be should be statistical testing by within 80% to 125%; however, if
within 80% to within 80% to ANOVA and calculating the single-dose study shows a very
125% 125% a 90% CI for each similar pharmacokinetic profile for
pharmacokinetic test and reference (the 90%
parameter; CI must be confidence interval for AUC is
entirely within the within 90 to 111), the requirement
80% to 125% for steady-state data may be
boundaries waived
Australia 90% CI of relative 90% CI of the Data is log-transformed No specific Not unless warranted by exceptional
mean AUC of relative mean prior to conducting requirements circumstances, such as controlled
test to measured Cmax statistical testing by release drugs
reference of the test to ANOVA and calculating
should be reference a 90% CI for each
between 80.0% should be pharmacokinetic
and 125.0% between 80.0% parameter. CI must be
and 125.0% entirely within the
80% to 125%
boundaries
Japan 90% CI of relative 90% CI of relative Data are log-transformed No specific No specific requirements
mean AUC of mean AUC of prior to conducting requirements
test to test to statistical testing by
reference reference ANOVA and calculating
should be should be a 90% CI for each
between 80.0% between 80.0% pharmacokinetic
and 125.0% and 125.0% parameter; CI must be
entirely within the
80% to 125%
boundaries
CI, confidence interval; AUC, area under the curve; Cmax, maximum concentration; Cmin, minimum concentration.
of the test and innovator drug product are administered of interest are plasma AUC, calculated to the last
and blood or plasma concentrations are measured over measured concentration [AUC(0 ⫺ t)] and extrapolated
time to determine the rate (Cmax) and extent (AUC) of to infinity [AUC(0 ⫺ infinity)], and the maximum or
absorption of both products in a fasting or, occasion- peak drug concentrations (Cmax). Table 1 contains the
ally, in a fed state as well. Pharmacokinetic parameters pharmacokinetic parameters and regulatory require-The Journal of Heart and Lung Transplantation Uber et al. 657
Volume 28, Number 7
ments by various countries for consideration of bio- smoking and chronologic factors.8 Bioavailability may
equivalence.2,5,6 –9 A difference of ⬎20% for each of the also be altered by co-administration with food and the
tests is considered to be significant and, therefore, effect may be largely formulation-dependent. A single-
undesirable for all drug products. Numerically, this is dose strategy may be inadequate to characterize all of
expressed as a limit of test-product average/reference- these factors in medications that are considered critical-
product average of 80% for the first statistical test (less dose drugs or narrow therapeutic index medications
bioavailable) and a limit of reference-product average/ with a large day-to-day variability in pharmacokinetic
test-product average of 80% for the second statistical parameters even at steady state.
test (more bioavailable). By convention, all data are In addition thoracic transplant patients, who may be
expressed as a ratio of the average response (AUC and particularly vulnerable to adverse consequences of ge-
Cmax) for test/reference, so the limit expressed in the neric drug substitution, we must include those with
second statistical test is 125% (reciprocal of 80%). For high immunologic risk and history of treated allograft
statistical reasons, all data are log-transformed prior to rejection. As in any condition, those who have traveled
conducting statistical testing. In practice, these statisti- the less-than-desirable path secondary to frequent com-
cal tests are carried out using an analysis of variance plications, such as rejection episodes or serious infec-
(ANOVA) procedure and calculating a 90% confidence tions, are not patients in whom destabilization of a
interval for each pharmacokinetic parameter (Cmax and delicate balance is welcomed. These patients require a
AUC). The confidence interval for both pharmacoki- heightened vigilance to any change in their physical
netic parameters, AUC and Cmax, must be entirely condition or changes in concurrent medication and
within the 80% to 125% boundaries just cited. immunosuppression once an appropriate cocktail of
Regulatory agencies may require multiple-dose steady- medications has been successfully established.
state studies when controlled release dose forms are Unique clinical situations that deserve close attention
investigated or if the drug concentration from a single- are described in what follows.
dose study is too low to be measured by the available
assays. Multiple-dose studies may, however, be consid- Disease States Affecting Drug Absorption
ered too high risk for healthy volunteers in which case Many patients who undergo thoracic organ transplant
patients who have the underlying disease for which the have gastrointestinal factors that alter the absorption of
medication was intended may be used. The same phar- medications. For example, in patients with diabetes
macokinetic methods and standards are applied. mellitus, cyclosporine absorption is decreased or de-
Some countries may allow for in vitro testing if more layed as compared with non-diabetic transplant pa-
than a single strength of the innovator product is available tients, reflecting differences in gastric emptying.11,12
for generic manufacturing. The vitro dissolution testing The gastrointestinal manifestations of cystic fibrosis
uses a specific methodology based on the solubility of the also impede post-transplant management by causing
products, which is determined by the dose and intestinal significant variation in the rate and extent of absorption
permeability of that drug.10 For example, tacrolimus 5 mg of orally administered immunosuppressive medications.
may be studied in vivo but the 0.5-mg and 1-mg doses may Both tacrolimus and cyclosporine absorption are al-
undergo in vitro dissolution testing for bioequivalence. tered due to fat malabsorption, leading to a potential for
Generally, 12 dose units of all strengths are tested to rejection, and this has lead to the need for finding
ascertain the rate and extent of availability during various alternative ways to administer medications.13,14
testing scenarios that assimilate in vivo conditions. Lactose intolerance affects about 70% of the world’s
population and can be seen in concert with inflamma-
SPECIAL CONSIDERATIONS tory bowel diseases such as Crohn’s disease. This may
The use of healthy volunteers does not adequately create altered absorption of drugs due to the presence
represent the challenges faced in dosing immunosup- of reduced transit time from diarrhea. The content of
pression in transplant recipients. Patients who have lactose, a readily used excipient in medications, can
undergone transplantation exhibit challenges of vary between innovator and generic formulations. Of-
chronic disease, experience effects of drug therapy on ten the total amount of lactose in medications is not
non-transplanted organs, are exposed to several medi- known and can actually reach a critical amount that
cations that have interactions that alter the pharmaco- may lead to symptoms in patients at risk. This was
kinetic profile and have demonstrated extreme intrapa- confirmed in a recent study that determined the milli-
tient variability of immunosuppressive medications. gram content of lactose in various medications used to
Other potential sources of intrapatient variation in treat gastrointestinal disorders. The investigators in that
bioequivalence include genetic factors, physiologic fac- study discovered that some medications taken as pre-
tors such as gastrointestinal transit time and pH, age, scribed could result in as much as 1-g or higher lactose
body composition, hormonal balance, non-compliance, ingestion.15658 Uber et al. The Journal of Heart and Lung Transplantation
July 2009
Ethnicity ics. They performed a single-dose crossover study of 28
African Americans and other populations with altered healthy subjects who were randomized to receive siroli-
immunosuppression absorption patterns are typically mus 5 mg as an oral solution with 250 mg Neoral
underrepresented in bioequivalence studies and their cyclosporine as the innovator product versus the ge-
differences marginalized with the use of healthy volun- neric product, Gengraf cyclosporine. Gengraf signifi-
teers and statistical strategies that employ averages. cantly reduced the peak sirolimus blood concentration
This patient population has a highly variable immuno- by 17% compared with Neoral cyclosporine (p ⫽
suppression drug absorption and exposure pattern, 0.0003). The AUC of sirolimus was significantly de-
governed due to intestinal P-glycoprotein or polymor- creased by 11% in the presence of Gengraf as compared
phisms of the cytochrome P450 system or other phar- with Neoral cyclosporine (p ⫽ 0.041).
macogenetic factors that await discovery. Drug interac- Children
tions of coexisting medications may also alter the
Much of the concern regarding the use of generic
pharmacokinetics in these special populations. There-
immunosuppression in adults is heightened in pediatric
fore, the use of single-dose studies in volunteers not
transplant recipients because of age and developmental
taking concomitant drugs that interfere with absorp-
effects on medication pharmacokinetics. Most commer-
tion, metabolism and clearance of immunosuppression
cially available immunosuppressants do not currently
may greatly underestimate the needs of this popula-
have a labeled indication for pediatric use and safety,
tion.16,17
and efficacy data for young children are limited or
Genetic polymorphisms that affect drug absorp-
absent. As such, it is unlikely that any bioequivalence
tion, metabolism and clearance have also been re-
testing in children is included in the generic approval
ported in various Asian populations. The presence of
process. Moreover, there are many developmental
the CYP3A5(*)1 allele may be responsible for patients
changes in physiologic factors that influence drug dis-
requiring a significantly higher dose of sirolimus or tacroli-
position in healthy infants, children and adolescents.
mus to achieve adequate trough concentrations.18,19 These include the level and maturity of many enzymes
Dietary Interactions involved in drug metabolism, such as cytochrome P450
enzymes, which may be reduced in infancy and later
Differing food interactions with innovator and generic reach the level of activity seen in adults. Gastrointesti-
products may have potentially serious consequences. nal pH and body composition change significantly from
Although specific product labeling may instruct patients early infancy into childhood, thereby affecting drug
to take the drug with or without food, considering the absorption, distribution and degradation. Renal func-
potential consequences of differing food interactions with tion and the capacity for tubular secretion do not reach
products containing such drugs, bioequivalence should the level of an adult until the child reaches 6 months to
ideally be demonstrated under both fasting and fed 1 year of age.24 Thus, even without the added complex-
conditions.2 For example, the SangCya generic cyclo- ity of a generic preparation, age- and transplant-related
sporine formulation initially demonstrated regulatory changes in pharmacokinetics mandate close monitoring
bioequivalence to Neoral; however, the product was of immunosuppressive medications with narrow thera-
recalled in the United States (in 2000) because cyclo- peutic indices.
sporine concentrations were significantly affected by
co-administration with apple juice, an interaction that PRACTICAL CONSIDERATIONS: NOTIFICATION OF
was not seen with Neoral.20 –22 SWITCHING AND SURVEILLANCE
Notification of Generic Substitution
Interactions With Concomitant Immunosuppressive Drugs
Most countries have rules in place allowing dispensing
The current definition of bioequivalence does not re- authorities to substitute a bioequivalent generic prod-
quire any testing on the impact of common drug uct for the innovator drug (Table 2). This could create
interactions on drug levels or efficacy. The importance multiple problems, as there may be more than one
of concurrent medications in post-transplant patients generic formulation available. Therefore, the patient
should not be underestimated. There are multiple drug may be exposed to several different preparations during
interactions that occur in this population, which in- the course of therapy and each product may exhibit its
volve the effect of one immunosuppressive agent on all own potentially different pharmacokinetic effects in
other medications, including other immunosuppres- concert with other medications that could create ad-
sants. The use of generic medications may or may not verse outcomes.
upset the fine balance currently in effect. Kovarik and Currently, no country has a system in place to notify
colleagues23 investigated the effect of two different the prescribing authority of the change from brand to
cyclosporine preparations on sirolimus pharmacokinet- generic medication, or generic to a different genericThe Journal of Heart and Lung Transplantation Uber et al. 659
Volume 28, Number 7
Table 2. Prescribing and Dispensing Regulations Regarding Bioequivalent Generic Product Substitution by Country
Principal Principal
prescribing prescribing Notification of change
authority for first authority after 1 Automatic generic Ability to specify “brand in manufacturer of
Geographic year post- year post- substitution for medications medically necessary” on immunosuppressive
location transplant transplant allowed prescription medication required
Canada Any licensed MD Any licensed MD Pharmacy may automatically Yes, however, under most Not required
can prescribe can prescribe substitute without drug plans, the patient
notification; it is would be responsible
customary, but not for paying the
obligatory, to inform the difference between the
patient if a medication is brand and generic cost
being substituted
United Any licensed MD Any licensed MD Pharmacy may automatically Yes, however, under most Not required
States can prescribe; can prescribe substitute for drugs that drug plans, the patient
however, are rated as would be responsible
many therapeutically equivalent for paying the
transplant difference between the
centers brand and generic cost
provided full
care for first
year
UK Any licensed MD Any licensed MD Pharmacy may automatically Not required
can prescribe can prescribe substitute for drugs that
are rated as
therapeutically equivalent
EU Depending on Depending on Pharmacy may automatically Yes (however, it might be Not required
country and country and substitute for drugs that questioned by
center center are rated as insurance and
therapeutically equivalent confirmed by
prescribing doctor)
Australia Any licensed MD Any licensed MD Pharmacy may automatically Yes, however, under most Not required
can prescribe can prescribe substitute for drugs that drug plans, the patient
are rated as would be responsible
therapeutically equivalent for paying the
difference between the
brand and generic cost
product. Due to the lack of such a systematic approach, nosuppression should be performed until stability is
the clinician’s ability to monitor any changes depends reached. Rejection surveillance, as well as monitoring
on the patient’s self-declaration to the health-care team. for over-immunosuppression, should be initiated and
Often, as Table 2 demonstrates, the health-care team continued until a new steady state has been established.
performing the transplant is not always responsible for On the surface, it is perceived that use of generic
writing the prescription, and this adds another layer of immunosuppression would yield significant cost sav-
complexity to the problem. Surveys of physicians have ings to the medical system. However, the direct savings
shown that there is little understanding of what deter- potentially ensuing from such a strategy could be easily
mines bioequivalency of generic drugs.25 It is therefore offset by additional surveillance therapeutic monitoring
imperative that clinicians be required to educate them- costs. Therefore, the cost-vs-benefit of generic medica-
selves and develop programmatic direction on the use tion in thoracic transplantation should be ascertained,
of generic drugs. keeping in mind the increased need for supplementary
testing and monitoring to prevent adverse allograft-
Surveillance Strategies
related outcomes.
If the clinician changes the drug regimen of an estab-
lished post-transplant patient to include a generic for-
mulation, a heightened surveillance strategy is sug- SUMMARY RECOMMENDATIONS
gested. Pharmacokinetic monitoring of the generic Generic immunosuppression medications may offer an
medication and monitoring of levels of the other immu- economic advantage, but it is imperative that clinicians660 Uber et al. The Journal of Heart and Lung Transplantation
July 2009
educate themselves about their pitfalls. We offer the 6. Birkett DJ. Generics— equal or not? Austral Prescriber 3003;26:
following recommendations: 85–7.
7. Federal Regulations 21 CFR 320. Washington, DC: DHHS; 1998.
1. Clinicians should educate their patients to inform 8. Palylyk-Colwell E, Jamali F, Dryden W, et al. Bioequivalence and
the coordinating center if a change in either the interchangeability of narrow therapeutic range drugs. J Pharm
Pharmaceut Sci 1998;1:2–7.
labeling or appearance of their immunosuppressive
9. Guidelines for bioequivalence studies for generic products [in
medications suggests that a generic drug substitu- Japanese]; 2006. www.nihs.go.jp/drug/be-guide/GL061124_BE.pdf.
tion has occurred. 10. Waiver of in vivo bioavailability and bioequivalence studies for
2. Clinical care coordinating centers must develop immediate-release solid oral dosage forms based on a biopharma-
structured approaches for the education of all per- ceutics classification system. Washington, DC: FDA; 2000. http://
sonnel with regard to use of generic immunosup- www.fda.gov/cder/guidance/3618fnl.pdf.
11. Deierhoi MH, Haug M. Review of select transplant subpopula-
pressants.
tions at high risk of failure from standard immunosuppressive
3. In unique clinical situations, where critical drug therapy. Clin Transplant 2000;14:439 – 48.
dosing represents a fine balance, caution should be 12. Schroeder TJ, Hariharan S, First MR. Variations in bioavailability of
exercised in the use of generic immunosuppres- cyclosporine and relationship to clinical outcome in renal trans-
sion. plant subpopulations. Transplant Proc 1995;27:837–9.
4. Heightened vigilance to adverse sequelae and closer 13. Knoop C, Vervier I, Thiry P, et al. Cyclosporine pharmacokinetics
and dose monitoring after lung transplantation: comparison
therapeutic drug monitoring is indicated until a
between cystic fibrosis and other conditions. Transplantation
stable immunosuppression milieu can be estab- 2003;76:683– 8.
lished. 14. Reams BD, Palmer SM. Sublingual tacrolimus for immunosuppres-
5. International advocacy efforts should be undertaken sion in lung transplantation: a potentially important therapeutic
to develop routine clinical care coordinating center option in cystic fibrosis. J Respir Med 2002;1:91– 8.
notification when generic drug substitution occurs. 15. Eadala P, Waud JP, Matthews SB, et al. Quantifying the ‘hidden’
lactose in drugs used for the treatment of gastro-intestinal condi-
6. International advocacy efforts should be undertaken
tions. Aliment Pharmacol Ther 2009;29:677– 87.
to compel regulating agencies to approve only 16. Girnita DM, Webber SA, Ferrell R, et al. Disparate distribution of
those generic immunosuppressants that have been 16 candidate single nucleotide polymorphisms among racial and
studied under more appropriate circumstances, ethnic groups of pediatric heart transplant patients. Transplanta-
such as with concomitant interacting medications tion 2006;82:1774 – 80.
or in transplant recipients. 17. Girnita DM, Brooks MM, Webber SA, et al. Genetic polymor-
phisms impact the risk of acute rejection in pediatric heart
APPENDIX transplantation: a multi-institutional study. Transplantation 2008;
Relationship disclosures for the authors of this study are as 85:1632–9.
18. Miao LY, Huang CR, Hou JQ, et al. Association study of ABCB1
follows (past 12 months): Patricia Uber—none to disclose;
and CYP3A5 gene polymorphisms with sirolimus trough concen-
Heather Ross—Novartis and Wyeth (consultant, scientific
tration and dose requirements in Chinese renal transplant recip-
advisor); Andreas Zuckermann—Novartis and Wyeth (speaker), ients. Biopharm Drug Dispos 2008;29:1–5.
Roche (research grant), Astellas (consultant, scientific advi- 19. Macphee IA, Fredericks S, Mohamed M, et al. Tacrolimus phar-
sory board), Genzyme (speaker, research grant); Stuart macogenetics: the CYP3A5*1 allele predicts low dose-normalized
Sweet—Astellas (speakers bureau); Paul Corris—Novartis (sci- tacrolimus blood concentrations in whites and South Asians.
entific advisory board member); Keith McNeil—none to dis- Transplantation 2005;79:499 –502.
close; Mandeep Mehra—Roche (research grants, consultant). 20. Department of Health and Human Services, Food and Drug
Administration to SangStat Medical Corp; withdrawal of approval
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