Реферат: Такролимус
БАШКИРСКИЙГОСУДАРСТВЕННЫЙМЕДИЦИНСКИЙУНИВЕРСИТЕТ
КАФЕДРАФАРМАКОЛОГИИ№1, С КУРСОМКЛИНИЧЕСКОЙФАРМАКОЛОГИИ
Зав. кафедры: д.м.н. профессорАлехин Е.К.
Зав. курсом: д.м.н. профессор Зарудий Ф.А.
Преподаватель: к.м.н. доцентШигаев Н.И.
РЕФЕРАТ
«Такролимус»
Выполнил: студент лечебногофакультетагр.№ Л-Б
УФА-2002г.
Prograf Prescribing Information
WARNING
DESCRIPTION:
CLINICAL PHARMACOLOGY:
INDICATIONS AND USAGE:
CONTRAINDICATIONS:
WARNINGS:
PRECAUTIONS:
ADVERSE REACTIONS:
OVERDOSAGE:
DOSAGE AND ADMINISTRATION:
HOW SUPPLIED:
REFERENCE
Fujisawa
Revised: May2002
Prograf®
tacrolimuscapsules
tacrolimus injection (forintravenous infusion only)
WARNING
Increased susceptibility to infection and the possible development of lymphoma may result from immunosupdivssion. Only physicians experienced in immunosupdivssive therapy and management of organ transplant patients should divscribe Prograf. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient.
DESCRIPTION:
Prograf isavailable for oral administration as capsules (tacrolimus capsules)containing the equivalent of 0.5 mg, 1 mg or 5 mg of anhydroustacrolimus. Inactive ingredients include lactose, hydroxypropylmethylcellulose, croscarmellose sodium, and magnesium stearate. The0.5 mg capsule shell contains gelatin, titanium dioxide and ferricoxide, the 1 mg capsule shell contains gelatin and titanium dioxide,and the 5 mg capsule shell contains gelatin, titanium dioxide andferric oxide.
Prograf isalso available as a sterile solution (tacrolimus injection)containing the equivalent of 5 mg anhydrous tacrolimus in 1 mL foradministration by intravenous infusion only. Each mL containspolyoxyl 60 hydrogenated castor oil (HCO-60), 200 mg, and dehydratedalcohol, USP, 80.0% v/v. Prograf injection must be diluted with 0.9%Sodium Chloride Injection or 5% Dextrose Injection before use.
Tacrolimus,divviously known as FK506, is the active ingredient in Prograf.Tacrolimus is a macrolide immunosupdivssant produced by Streptomycestsukubaensis.Chemically, tacrolimus is designated as[3S-[3R*[E(1S*,3S*,4S*)],4S*,5R*,8S*,9E,12R*,14R*,15S*,16R*,18S*,19S*,26aR*]]-5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5, 19-dihydroxy-3-[2-(4-hydroxy-3-methoxycyclohexyl) -1-methylethenyl]-14,16-dimethoxy-4,10,12, 18-tetramethyl-8-(2-propenyl)-15,19-epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclotricosine-1,7,20, 21(4H,23H)-tetrone, monohydrate.
Thechemical structure of tacrolimus is:
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Tacrolimushas an empirical formula of C44H69NO12·H2Oand a formula weight of 822.05. Tacrolimus appears as white crystalsor crystalline powder. It is practically insoluble in water, freelysoluble in ethanol, and very soluble in methanol and chloroform.
CLINICAL PHARMACOLOGY:
Mechanism of Action
Tacrolimusprolongs the survival of the host and transplanted graft in animaltransplant models of liver, kidney, heart, bone marrow, small boweland pancreas, lung and trachea, skin, cornea, and limb.
In animals,tacrolimus has been demonstrated to supdivss some humoral immunityand, to a greater extent, cell-mediated reactions such as allograftrejection, delayed type hypersensitivity, collagen- inducedarthritis, experimental allergic encephalomyelitis, and graft versushost disease.
Tacrolimusinhibits T-lymphocyte activation, although the exact mechanism ofaction is not known. Experimental evidence suggests that tacrolimusbinds to an intracellular protein, FKBP-12. A complex oftacrolimus-FKBP-12, calcium, calmodulin, and calcineurin is thenformed and the phosphatase activity of calcineurin inhibited. Thiseffect may divvent the dephosphorylation and translocation of nuclearfactor of activated T-cells (NF-AT), a nuclear component thought toinitiate gene transcription for the formation of lymphokines (such asinterleukin-2, gamma interferon). The net result is the inhibition ofT-lymphocyte activation (i.e., immunosupdivssion).
Pharmacokinetics
Tacrolimusactivity is primarily due to the parent drug. The pharmacokineticparameters (mean±S.D.) of tacrolimus have been determinedfollowing intravenous (IV) and oral (PO) administration in healthyvolunteers, kidney transplant and liver transplant patients. (Seetable below.)
Population
N
Route
(Dose)
Parameters
Cmax
(ng/mL)
Tmax
(hr)
AUC
(ng·hr/mL)
tЅ
(hr)
Cl
(L/hr/kg)
V
(L/kg)
Healthy
Volunteers
IV
(0.025 mg/kg/4hr)
—
—
598*
± 125
34.2
± 7.7
0.040
±0.009
1.91
±0.31
PO
(5 mg)
29.7
±7.2
1.6
±0.7
243**
±73
34.8
±11.4
0.041†
±0.008
1.94†
±0.53
Kidney
Transplant
Pts
IV
(0.02 mg/kg/12hr)
—
—
294***
±262
18.8
±16.7
0.083
±0.050
1.41
±0.66
PO
(0.2 mg/kg/day)
19.2
±10.3
203***
±42
PO
(0.3 mg/kg/day)
24.2
±15.8
288***
±93
Liver
Transplant
Pts
IV
(0.05 mg/kg/12 hr)
3300***
±2130
11.7
±3.9
0.053
±0.017
0.85
±0.30
PO
(0.3 mg/kg/day)
68.5
±30.0
2.3
±1.5
519***
±179
†Corrected for individual bioavailability *AUC0-120 **AUC0-72*** AUC0-inf —not applicable # not available
Dueto intersubject variability in tacrolimus pharmacokinetics,individualization of dosing regimen is necessary for optimal therapy.(See DOSAGEAND ADMINISTRATION).Pharmacokinetic data indicate that whole blood concentrations ratherthan plasma concentrations serve as the more appropriate samplingcompartment to describe tacrolimus pharmacokinetics.
Absorption
Absorption oftacrolimus from the gastrointestinal tract after oral administrationis incomplete and variable. The absolute bioavailability oftacrolimus was 17±10% in adult kidney transplant patients(N=26), 22±6% in adult liver transplant patients (N=17), and18±5% in healthy volunteers (N=16).
Asingle dose study conducted in 32 healthy volunteers established thebioequivalence of the 1 mg and 5 mg capsules. Another single dosestudy in 32 healthy volunteers established the bioequivalence of the0.5 mg and 1 mg capsules. Tacrolimus maximum blood concentrations(Cmax)and area under the curve (AUC) appeared to increase in adose-proportional fashion in 18 fasted healthy volunteers receiving asingle oral dose of 3, 7 and 10 mg.
In18 kidney transplant patients, tacrolimus trough concentrations from3 to 30 ng/mL measured at 10-12 hours post-dose (Cmin)correlated well with the AUC (correlation coefficient 0.93). In 24liver transplant patients over a concentration range of 10 to 60ng/mL, the correlation coefficient was 0.94.
FoodEffects: Therate and extent of tacrolimus absorption were greatest under fastedconditions. The divsence and composition of food decreased both therate and extent of tacrolimus absorption when administered to 15healthy volunteers.
Theeffect was most pronounced with a high-fat meal (848 kcal, 46% fat):mean AUC and C maxwere decreased 37% and 77%, respectively; Tmaxwas lengthened 5-fold. A high-carbohydrate meal (668 kcal, 85%carbohydrate) decreased mean AUC and mean C maxby 28% and 65%, respectively.
Inhealthy volunteers (N=16), the time of the meal also affectedtacrolimus bioavailability. When given immediately following themeal, mean Cmaxwas reduced 71%, and mean AUC was reduced 39%, relative to the fastedcondition. When administered 1.5 hours following the meal, mean Cmaxwas reduced 63%, and mean AUC was reduced 39%, relative to the fastedcondition.
In11 liver transplant patients, Prograf administered 15 minutes after ahigh fat (400 kcal, 34% fat) breakfast, resulted in decreased AUC(27± 18%) and Cmax(50±19%), as compared to a fasted state.
Distribution
The plasmaprotein binding of tacrolimus is approximately 99% and is independentof concentration over a range of 5-50 ng/mL. Tacrolimus is boundmainly to albumin and alpha-1-acid glycoprotein, and has a high levelof association with erythrocytes. The distribution of tacrolimusbetween whole blood and plasma depends on several factors, such ashematocrit, temperature at the time of plasma separation, drugconcentration, and plasma protein concentration. In a U.S. study, theratio of whole blood concentration to plasma concentration averaged35 (range 12 to 67).
Metabolism
Tacrolimus isextensively metabolized by the mixed-function oxidase system,primarily the cytochrome P-450 system (CYP3A). A metabolic pathwayleading to the formation of 8 possible metabolites has been proposed.Demethylation and hydroxylation were identified as the primarymechanisms of biotransformation in vitro. The major metaboliteidentified in incubations with human liver microsomes is 13-demethyltacrolimus. In in vitro studies, a 31-demethyl metabolite has beenreported to have the same activity as tacrolimus.
Excretion
The meanclearance following IV administration of tacrolimus is 0.040, 0.083and 0.053 L/hr/kg in healthy volunteers, adult kidney transplantpatients and adult liver transplant patients, respectively. In man,less than 1% of the dose administered is excreted unchanged in urine.
In a massbalance study of IV administered radiolabeled tacrolimus to 6 healthyvolunteers, the mean recovery of radiolabel was 77.8±12.7%.Fecal elimination accounted for 92.4±1.0% and the eliminationhalf-life based on radioactivity was 48.1±15.9 hours whereasit was 43.5±11.6 hours based on tacrolimus concentrations. Themean clearance of radiolabel was 0.029±0.015 L/hr/kg andclearance of tacrolimus was 0.029±0.009 L/hr/kg. Whenadministered PO, the mean recovery of the radiolabel was 94.9±30.7%.Fecal elimination accounted for 92.6±30.7%, urinaryelimination accounted for 2.3±1.1% and the eliminationhalf-life based on radioactivity was 31.9±10.5 hours whereasit was 48.4±12.3 hours based on tacrolimus concentrations. Themean clearance of radiolabel was 0.226±0.116 L/hr/kg andclearance of tacrolimus 0.172±0.088 L/hr/kg.
SpecialPopulations
Pediatric
Pharmacokineticsof tacrolimus have been studied in liver transplantation patients,0.7 to 13.2 years of age. Following IV administration of a 0.037mg/kg/day dose to 12 pediatric patients, mean terminal half-life,volume of distribution and clearance were 11.5±3.8 hours,2.6±2.1 L/kg and 0.138±0.071 L/hr/kg, respectively.Following oral administration to 9 patients, mean AUC and Cmaxwere 337±167 ng•hr/mL and 43.4±27.9 ng/mL,respectively. The absolute bioavailability was 31± 21%.
Wholeblood trough concentrations from 31 patients less than 12 years oldshowed that pediatric patients needed higher doses than adults toachieve similar tacrolimus trough concentrations. (See DOSAGEAND ADMINISTRATION).
Renal andHepatic Insufficiency
The meanpharmacokinetic parameters for tacrolimus following singleadministrations to patients with renal and hepatic impairment aregiven in the following table.
Population
(No. of Patients)
Dose
AUC 0-t
(ng·hr/mL)
tЅ
(hr)
V
(L/kg)
Cl
(L/hr/kg)
Renal
Impairment
(n=12)
0.02
mg/kg/4hr
IV
393±123
(t = 60hr)
26.3±9.21.07
±0.20
0.038
±0.014
Mild Hepatic
Impairment
(n=6)
0.02
mg/kg/4hr
IV
367±107
(t=72hr)
60.6±43.8
Range: 27.8 — 141
3.1
±1.6
0.042
±0.02
7.7 mg
PO
488±320
(t = 72hr)
66.1±44.8
Range: 29.5 — 138
3.7
±4.7*
0.034
±0.019*
Severe Hepatic
Impairment
(n=6, IV)
0.02
mg/kg/4hr
IV (n=2)
762±204
(t=120hr)
198±158
Range: 81-436
3.9
±1.0
0.017
±0.013
0.01
mg/kg/8hr
IV (n=4)
289±117
(t=144hr)
Severe Hepatic
Impairment
(n=5, PO)†
8 mg PO
(n=1)
658
(t=120hr)
119±35
Range: 85-178
3.1
±3.4*
0.016
±0.011*
5mg PO
(n=4)
533±156
(t=144hr)
4 mg PO
(n=1)
* corrected for bioavailability
† 1 patient did not receive the PO dose
RenalInsufficiency:
Tacrolimuspharmacokinetics following a single IV administration were determinedin 12 patients (7 not on dialysis and 5 on dialysis, serum creatinineof 3.9±1.6 and 12.0±2.4 mg/dL, respectively) prior totheir kidney transplant. The pharmacokinetic parameters obtained weresimilar for both groups.
The meanclearance of tacrolimus in patients with renal dysfunction wassimilar to that in normal volunteers (see divvious table).
HepaticInsufficiency:
Tacrolimuspharmacokinetics have been determined in six patients with mildhepatic dysfunction (mean Pugh score: 6.2) following single IV andoral administrations. The mean clearance of tacrolimus in patientswith mild hepatic dysfunction was not substantially different fromthat in normal volunteers (see divvious table). Tacrolimuspharmacokinetics were studied in 6 patients with sever hepaticdysfunction (mean Pugh score: >10). The mean clearance wassubstantially lower in patients with severe hepatic dysfunction,irrespective of the route of administration.
Race
Aformal study to evaluate the pharmacokinetic disposition oftacrolimus in Black transplant patients has not been conducted.However, a retrospective comparison of Black and Caucasian kidneytransplant patients indicated that Black patients required highertacrolimus doses to attain similar trough concentrations. (See DOSAGEAND ADMINISTRATION).
Gender
A formalstudy to evaluate the effect of gender on tacrolimus pharmacokineticshas not been conducted, however, there was no difference in dosing bygender in the kidney transplant trial. A retrospective comparison ofpharmacokinetics in healthy volunteers, and in kidney and livertransplant patients indicated no gender-based differences.
Clinical Studies
Liver Transplantation
The safetyand efficacy of Prograf-based immunosupdivssion following orthotopicliver transplantation were assessed in two prospective, randomized,non-blinded multicenter studies. The active control groups weretreated with a cyclosporine-based immunosupdivssive regimen. Bothstudies used concomitant adrenal corticosteroids as part of theimmunosupdivssive regimens. These studies were designed to evaluatewhether the two regimens were therapeutically equivalent, withpatient and graft survival at 12 months following transplantation asthe primary endpoints. The Prograf-based immunosupdivssive regimenwas found to be equivalent to the cyclosporine-basedimmunosupdivssive regimens.
Inone trial, 529 patients were enrolled at 12 clinical sites in theUnited States; prior to surgery, 263 were randomized to thePrograf-based immunosupdivssive regimen and 266 to acyclosporine-based immunosupdivssive regimen (CBIR). In 10 of the 12sites, the same CBIR protocol was used, while 2 sites used differentcontrol protocols. This trial excluded patients with renaldysfunction, fulminant hepatic failure with Stage IV encephalopathy,and cancers; pediatric patients (12 years old) were allowed.
In the secondtrial, 545 patients were enrolled at 8 clinical sites in Europe;prior to surgery, 270 were randomized to the Prograf-basedimmunosupdivssive regimen and 275 to CBIR. In this study, each centerused its local standard CBIR protocol in the active-control arm. Thistrial excluded pediatric patients, but did allow enrollment ofsubjects with renal dysfunction, fulminant hepatic failure in StageIV encephalopathy, and cancers other than primary hepatic withmetastases.
One-yearpatient survival and graft survival in the Prograf-based treatmentgroups were equivalent to those in the CBIR treatment groups in bothstudies. The overall one-year patient survival (CBIR andPrograf-based treatment groups combined) was 88% in the U.S. studyand 78% in the European study. The overall one-year graft survival(CBIR and Prograf-based treatment groups combined) was 81% in theU.S. study and 73% in the European study. In both studies, the mediantime to convert from IV to oral Prograf dosing was 2 days.
Because ofthe nature of the study design, comparisons of differences insecondary endpoints, such as incidence of acute rejection, refractoryrejection or use of OKT3 for steroid-resistant rejection, could notbe reliably made.
Kidney Transplantation
Prograf-basedimmunosupdivssion following kidney transplantation was assessed in aPhase III randomized, multicenter, non-blinded, prospective study.There were 412 kidney transplant patients enrolled at 19 clinicalsites in the United States. Study therapy was initiated when renalfunction was stable as indicated by a serum creatinine 4 mg/dL (median of 4 days after transplantation, range 1 to 14 days).Patients less than 6 years of age were excluded.
There were205 patients randomized to Prograf-based immunosupdivssion and 207patients were randomized to cyclosporine-based immunosupdivssion. Allpatients received prophylactic induction therapy consisting of anantilymphocyte antibody divparation, corticosteroids andazathioprine. Overall one year patient and graft survival was 96.1%and 89.6%, respectively and was equivalent between treatment arms.
Because ofthe nature of the study design, comparisons of differences insecondary endpoints, such as incidence of acute rejection, refractoryrejection or use of OKT3 for steroid-resistant rejection, could notbe reliably made.
INDICATIONS AND USAGE:
Prograf isindicated for the prophylaxis of organ rejection in patientsreceiving allogeneic liver or kidney transplants. It is recommendedthat Prograf be used concomitantly with adrenal corticosteroids.Because of the risk of anaphylaxis, Prograf injection should bereserved for patients unable to take Prograf capsules orally.
CONTRAINDICATIONS:
Prograf iscontraindicated in patients with a hypersensitivity to tacrolimus.Prograf injection is contraindicated in patients with ahypersensitivity to HCO-60 (polyoxyl 60 hydrogenated castor oil).
WARNINGS:
(Seeboxed WARNING.)
Insulin-dependentpost-transplant diabetes mellitus (PTDM) was reported in 20% ofPrograf-treated kidney transplant patients without divtransplanthistory of diabetes millitus in the Phase III study below (See TablesBelow). The median time to onset of PTDM was 68 days. Insulindependence was reversible in 15% of these PTDM patients at one yearand in 50% at two years post transplant. Black and Hispanic kidneytransplant patients were at an increased risk of development of PTDM.
Incidenceof Post Transplant Diabetes Mellitus
and Insulin Use at 2 years inKidney Transplant Recipients in the Phase III Study
--PAGE_BREAK--
Status of PTDM*
Prograf
CBIR
Patients without divtransplant history of diabetes mellitus.
151
151
New onset PTDM*, 1st Year
30/151 (20%)
6/151 (4%)
Still insulin dependent at one year in those without prior
history of diabetes.
25/151(17%)
5/151 (3%)
New onset PTDM* post 1 year
1
0
Patients with PTDM* at 2 years
16/151 (11%)
5/151 (3%)
*use of insulin for 30 or more consecutive days, with
Developmentof Post Transplant Diabetes Mellitus by Race
and by TreatmentGroup during First Year Post Kidney Transplantation in the Phase IIIStudy
Patient Race
Prograf
CBIR
No. of Patients
at Risk
Patients Who
Developed PTDM*
No. of Patients
at Risk
Patients Who
Developed PTDM*
Black
41
15 (37%)
36
3 (8%)
Hispanic
17
5 (29%)
18
1 (6%)
Caucasian
82
10 (12%)
87
1 (1%)
Other
11
0 (0%)
10
1 (10%)
Total
151
30 (20%)
151
6 (4%)
* use of insulin for 30 or more consecutive days, with
Insulin-dependentpost-transplant diabetes mellitus was reported in 18% and 11% ofPrograf-treated liver transplant patients and was reversible in 45%and 31% of these patients at one year post transplant, in the U.S.and European randomized studies, respectively (See Table below).Hyperglycemiawas associated with the use of Prograf in 47% and 33% of livertransplant recipients in the U.S. and European randomized studies,respectively, and may require treatment (see ADVERSEREACTIONS).
Incidenceof Post Transplant Diabetes Mellitus and Insulin Use
at One Yearin Liver Transplant Recipients
Status of PTDM*
US Study
European Study
Prograf
CBIR
Prograf
CBIR
Patients at risk **
239
236
239
249
New Onset PTDM*
42 (18%)
30 (13%)
26 (11%)
12(5%)
Patients still on insulin at 1 year
23 (10%)
19 (8%)
18 (8%)
6 (2%)
* use ofinsulin for 30 or more consecutive days, with **Patients without divtransplanthistory of diabetes mellitus.
Prografcan cause neurotoxicity and nephrotoxicity, particularly when used inhigh doses. Nephrotoxicity was reported in approximately 52% ofkidney transplantation patients and in 40% and 36% of livertransplantation patients receiving Prograf in the U.S. and Europeanrandomized trials, respectively (see ADVERSEREACTIONS).More overt nephrotoxicity is seen early after transplantation,characterized by increasing serum creatinine and a decrease in urineoutput. Patients with impaired renal function should be monitoredclosely as the dosage of Prograf may need to be reduced. In patientswith persistent elevations of serum creatinine who are unresponsiveto dosage adjustments, consideration should be given to changing toanother immunosupdivssive therapy. Care should be taken in usingtacrolimus with other nephrotoxic drugs. Inparticular, to avoid excess nephrotoxicity, Prograf should not beused simultaneously with cyclosporine. Prograf or cyclosporine shouldbe discontinued at least 24 hours prior to initiating the other. Inthe divsence of elevated Prograf or cyclosporine concentrations,dosing with the other drug usually should be further delayed.
Mildto severe hyperkalemia was reported in 31% of kidney transplantrecipients and in 45% and 13% of liver transplant recipients treatedwith Prograf in the U.S. and European randomized trials,respectively, and may require treatment (see ADVERSEREACTIONS).Serum potassium levels should be monitored and potassium-sparingdiuretics should not be used during Prograf therapy (seePRECAUTIONS).
Neurotoxicity,including tremor, headache, and other changes in motor function,mental status, and sensory function were reported in approximately55% of liver transplant recipients in the two randomized studies.Tremor occurred more often in Prograf-treated kidney transplantpatients (54%) compared to cyclosporine-treated patients. Theincidence of other neurological events in kidney transplant patientswas similar in the two treatment groups (see ADVERSEREACTIONS).Tremor and headache have been associated with high whole-bloodconcentrations of tacrolimus and may respond to dosage adjustment.Seizures have occurred in adult and pediatric patients receivingPrograf (see ADVERSEREACTIONS).Coma and delirium also have been associated with high plasmaconcentrations of tacrolimus.
As inpatients receiving other immunosupdivssants, patients receivingPrograf are at increased risk of developing lymphomas and othermalignancies, particularly of the skin. The risk appears to berelated to the intensity and duration of immunosupdivssion ratherthan to the use of any specific agent. A lymphoproliferative disorder(LPD) related to Epstein-Barr Virus (EBV) infection has been reportedin immunosupdivssed organ transplant recipients. The risk of LPDappears greatest in young children who are at risk for primary EBVinfection while immunosupdivssed or who are switched to Prograffollowing long-term immunosupdivssion therapy. Because of the dangerof oversupdivssion of the immune system which can increasesusceptibility to infection, combination immunosupdivssant therapyshould be used with caution.
A fewpatients receiving Prograf injection have experienced anaphylacticreactions. Although the exact cause of these reactions is not known,other drugs with castor oil derivatives in the formulation have beenassociated with anaphylaxis in a small percentage of patients.Because of this potential risk of anaphylaxis, Prograf injectionshould be reserved for patients who are unable to take Prografcapsules.
Patientsreceiving Prograf injection should be under continuous observationfor at least the first 30 minutes following the start of the infusionand at frequent intervals thereafter. If signs or symptoms ofanaphylaxis occur, the infusion should be stopped. An aqueoussolution of epinephrine should be available at the bedside as well asa source of oxygen.
PRECAUTIONS:
General
Hypertensionis a common adverse effect of Prograf therapy (see ADVERSEREACTIONS).Mild or moderate hypertension is more frequently reported than severehypertension. Antihypertensive therapy may be required; the controlof blood divssure can be accomplished with any of the commonantihypertensive agents. Since tacrolimus may cause hyperkalemia,potassium-sparing diuretics should be avoided. While calcium-channelblocking agents can be effective in treating Prograf-associatedhypertension, care should be taken since interference with tacrolimusmetabolism may require a dosage reduction (see DrugInteractions).
Renally and Hepatically Impaired Patients
Forpatients with renal insufficiency some evidence suggests that lowerdoses should be used (see CLINICALPHARMACOLOGYand DOSAGEAND ADMINISTRATION).
Theuse of Prograf in liver transplant recipients experiencingpost-transplant hepatic impairment may be associated with increasedrisk of developing renal insufficiency related to high whole-bloodlevels of tacrolimus. These patients should be monitored closely anddosage adjustments should be considered. Some evidence suggests thatlower doses should be used in these patients (see DOSAGEAND ADMINISTRATION).
MyocardialHypertrophy
Myocardialhypertrophy has been reported in association with the administrationof Prograf, and is generally manifested by echocardiographicallydemonstrated concentric increases in left ventricular posterior walland interventricular septum thickness. Hypertrophy has been observedin infants, children and adults. This condition appears reversible inmost cases following dose reduction or discontinuance of therapy. Ina group of 20 patients with div- and post-treatment echocardiogramswho showed evidence of myocardial hypertrophy, mean tacrolimus wholeblood concentrations during the period prior to diagnosis ofmyocardial hypertrophy ranged from 11 to 53 ng/mL in infants (N=10,age 0.4 to 2 years), 4 to 46 ng/mL in children (N=7, age 2 to 15years) and 11 to 24 ng/mL in adults (N=3, age 37 to 53 years).
In patientswho develop renal failure or clinical manifestations of ventriculardysfunction while receiving Prograf therapy, echocardiographicevaluation should be considered. If myocardial hypertrophy isdiagnosed, dosage reduction or discontinuation of Prograf should beconsidered.
Information for Patients
Patientsshould be informed of the need for repeated appropriate laboratorytests while they are receiving Prograf. They should be given completedosage instructions, advised of the potential risks during divgnancy,and informed of the increased risk of neoplasia. Patients should beinformed that changes in dosage should not be undertaken withoutfirst consulting their physician.
Patientsshould be informed that Prograf can cause diabetes mellitus andshould be advised of the need to see their physician if they developfrequent urination, increased thirst or hunger.
Laboratory Tests
Serumcreatinine, potassium, and fasting glucose should be assessedregularly. Routine monitoring of metabolic and hematologic systemsshould be performed as clinically warranted.
Drug Interactions
Due to thepotential for additive or synergistic impairment of renal function,care should be taken when administering Prograf with drugs that maybe associated with renal dysfunction. These include, but are notlimited to, aminoglycosides, amphotericin B, and cisplatin. Initialclinical experience with the co-administration of Prograf andcyclosporine resulted in additive/synergistic nephrotoxicity.Patients switched from cyclosporine to Prograf should receive thefirst Prograf dose no sooner than 24 hours after the lastcyclosporine dose. Dosing may be further delayed in the divsence ofelevated cyclosporine levels.
Drugs That May AlterTacrolimus Concentrations
Sincetacrolimus is metabolized mainly by the CYP3A enzyme systems,substances known to inhibit these enzymes may decrease the metabolismor increase bioavailability of tacrolimus as indicated by increasedwhole blood or plasma concentrations. Drugs known to induce theseenzyme systems may result in an increased metabolism of tacrolimus ordecreased bioavailability as indicated by decreased whole blood orplasma concentrations. Monitoring of blood concentrations andappropriate dosage adjustments are essential when such drugs are usedconcomitantly.
*Drugs That May Increase Tacrolimus Blood Concentrations:
Calcium
Channel
Blockers
Antifungal
Agents
Macrolide
Antibiotics
clotrimazole
clarithromycin nicardipine
fluconazole
erythromycin nifedipine
itraconazole
troleandomycin verapamil
ketoconazole
Gastrointestinal
Prokinetic
Agents
Other
Drugs
cisapride
bromocriptine
metoclopramide
cimetidine
cyclosporine
danazol
ethinyl estradiol
methyldivdnisolone
omeprazole
protease inhibitors
nefazodone
In a study of 6 normal volunteers, a significant increase in tacrolimus oral bioavailability (14±5% vs. 30±8%) was observed with concomitant ketoconazole administration (200 mg). The apparent oral clearance of tacrolimus during ketoconazole administration was significantly decreased compared to tacrolimus alone (0.430±0.129L/hr/kg vs. 0.148±0.043L/hr/kg). Overall, IV clearance of tacrolimus was not significantly changed by ketoconazole co-administration, although it was highly variable between patients.
*Drugs That May Decrease Tacrolimus Blood Concentrations:
Anticonvulsants
Antibiotics
Herbal Preparations
carbamazepinerifabutin
St. John's Wort phenobarbital
rifampin
phenytoin
*This tableis not all inclusive.
St.John's Wort (Hypericumperforatum)induces CYP3A4 and P-glycoprotein. Since tacrolimus is a substratefor CYP3A4, there is the potential that the use of St. John's Wort inpatients receiving Prograf could result in reduced tacrolimus levels.
In a study of6 normal volunteers, a significant decrease in tacrolimus oralbioavailability (14±6% vs. 7±3%) was observed withconcomitant rifampin administration (600 mg). In addition, there wasa significant increase in tacrolimus clearance (0.036±0.008L/hr/kgvs. 0.053±0.010L/hr/kg) with concomitant rifampinadministration.
Interactionstudies with drugs used in HIV therapy have not been conducted.However, care should be exercised when drugs that are nephrotoxic(e.g., ganciclovir) or that are metabolized by CYP3A (e.g.,ritonavir) are administered concomitantly with tacrolimus. Tacrolimusmay effect the pharmacokinetics of other drugs (e.g. phenytoin) andincrease their concentration. Grapefruit juice affects CYP3A-mediatedmetabolism and should be avoided (see DOSAGEAND ADMINISTRATION).
Other Drug Interactions
Immunosupdivssantsmay affect vaccination. Therefore, during treatment with Prograf,vaccination may be less effective. The use of live vaccines should beavoided; live vaccines may include, but are not limited to measles,mumps, rubella, oral polio, BCG, yellow fever, and TY 21a typhoid.1
Carcinogenesis, Mutagenesis and Impairment ofFertility
An increasedincidence of malignancy is a recognized complication ofimmunosupdivssion in recipients of organ transplants. The most commonforms of neoplasms are non-Hodgkin's lymphomas and carcinomas of theskin. As with other immunosupdivssive therapies, the risk ofmalignancies in Prograf recipients may be higher than in the normal,healthy population. Lymphoproliferative disorders associated withEpstein-Barr Virus infection have been seen. It has been reportedthat reduction or discontinuation of immunosupdivssion may cause thelesions to regress.
Noevidence of genotoxicity was seen in bacterial (Salmonellaand E. coli)or mammalian (Chinese hamster lung-derived cells) in vitro assays ofmutagenicity, the in vitro CHO/HGPRT assay of mutagenicity, or invivo clastogenicity assays performed in mice; tacrolimus did notcause unscheduled DNA synthesis in rodent hepatocytes.
Carcinogenicitystudies were carried out in male and female rats and mice. In the80-week mouse study and in the 104-week rat study no relationship oftumor incidence to tacrolimus dosage was found. The highest dosesused in the mouse and rat studies were 0.8 — 2.5 times (mice) and 3.5- 7.1 times (rats) the recommended clinical dose range of 0.1 — 0.2mg/kg/day when corrected for body surface area.
No impairmentof fertility was demonstrated in studies of male and female rats.Tacrolimus, given orally at 1.0 mg/kg (0.7 — 1.4X the recommendedclinical dose range of 0.1 — 0.2 mg/kg/day based on body surface areacorrections) to male and female rats, prior to and during mating, aswell as to dams during gestation and lactation, was associated withembryolethality and with adverse effects on female reproduction.Effects on female reproductive function (parturition) andembryolethal effects were indicated by a higher rate ofdiv-implantation loss and increased numbers of undelivered andnonviable pups. When given at 3.2 mg/kg (2.3 — 4.6X the recommendedclinical dose range based on body surface area correction),tacrolimus was associated with maternal and paternal toxicity as wellas reproductive toxicity including marked adverse effects on estruscycles, parturition, pup viability, and pup malformations.
Pregnancy: Category C
Inreproduction studies in rats and rabbits, adverse effects on thefetus were observed mainly at dose levels that were toxic to dams.Tacrolimus at oral doses of 0.32 and 1.0 mg/kg during organogenesisin rabbits was associated with maternal toxicity as well as anincrease in incidence of abortions; these doses are equivalent to 0.5- 1X and 1.6 — 3.3X the recommended clinical dose range (0.1 — 0.2mg/kg) based on body surface area corrections. At the higher doseonly, an increased incidence of malformations and developmentalvariations was also seen. Tacrolimus, at oral doses of 3.2 mg/kgduring organogenesis in rats, was associated with maternal toxicityand caused an increase in late resorptions, decreased numbers of livebirths, and decreased pup weight and viability. Tacrolimus, givenorally at 1.0 and 3.2 mg/kg (equivalent to 0.7 — 1.4X and 2.3 — 4.6Xthe recommended clinical dose range based on body surface areacorrections) to divgnant rats after organogenesis and duringlactation, was associated with reduced pup weights.
No reductionin male or female fertility was evident.
There are noadequate and well-controlled studies in divgnant women. Tacrolimus istransferred across the placenta. The use of tacrolimus duringdivgnancy has been associated with neonatal hyperkalemia and renaldysfunction. Prograf should be used during divgnancy only if thepotential benefit to the mother justifies potential risk to thefetus.
Nursing Mothers
Sincetacrolimus is excreted in human milk, nursing should be avoided.
Pediatric Patients
Experiencewith Prograf in pediatric kidney transplant patients is limited.Successful liver transplants have been performed in pediatricpatients (ages up to 16 years) using Prograf. The two randomizedactive-controlled trials of Prograf in primary liver transplantationincluded 56 pediatric patients. Thirty-one patients were randomizedto Prograf-based and 25 to cyclosporine-based therapies.Additionally, a minimum of 122 pediatric patients were studied in anuncontrolled trial of tacrolimus in living related donor livertransplantation. Pediatric patients generally required higher dosesof Prograf to maintain blood trough concentrations of tacrolimussimilar to adult patients (see DOSAGEAND ADMINISTRATION).
ADVERSE REACTIONS:
Liver Transplantation
The principaladverse reactions of Prograf are tremor, headache, diarrhea,hypertension, nausea, and renal dysfunction. These occur with oraland IV administration of Prograf and may respond to a reduction indosing. Diarrhea was sometimes associated with other gastrointestinalcomplaints such as nausea and vomiting.
Hyperkalemiaand hypomagnesemia have occurred in patients receiving Prograftherapy. Hyperglycemia has been noted in many patients; some mayrequire insulin therapy (see WARNINGS).
Theincidence of adverse events was determined in two randomizedcomparative liver transplant trials among 514 patients receivingtacrolimus and steroids and 515 patients receiving acyclosporine-based regimen (CBIR). The proportion of patientsreporting more than one adverse event was 99.8% in the tacrolimusgroup and 99.6% in the CBIR group. Precautions must be taken whencomparing the incidence of adverse events in the U.S. study to thatin the European study. The 12-month posttransplant information fromthe U.S. study and from the European study is divsented below. Thetwo studies also included different patient populations and patientswere treated with immunosupdivssive regimens of differingintensities. Adverse events reported in >15% in tacrolimus patients (combined study results) are divsentedbelow for the two controlled trials in liver transplantation:
LIVERTRANSPLANTATION: ADVERSE EVENTS OCCURRING IN >15% OF PROGRAF-TREATED PATIENTS
продолжение
--PAGE_BREAK--U.S. STUDY (%) EUROPEAN STUDY (%)
Prograf
(N=250)
CBIR
(N=250)
Prograf
(N=264)
CBIR
(N=265)
Nervous System
Headache (see WARNINGS)
64 60 37 26Tremor (see WARNINGS)
56 46 48 32 Insomnia 64 68 32 23 Paresthesia 40 30 17 17Gastrointestinal
Diarrhea 72 47 37 27 Nausea 46 37 32 27 Constipation 24 27 23 21 LFT Abnormal 36 30 6 5 Anorexia 34 24 7 5 Vomiting 27 15 14 11
Cardiovascular
Hypertension (see PRECAUTIONS)
47 56 38 43Urogenital
Kidney Function Abnormal (see WARNINGS)
40 27 36 23Creatinine Increased (see WARNINGS)
39 25 24 19BUN Increased (see WARNINGS)
30 22 12 9 Urinary Tract Infection 16 18 21 19 Oliguria 18 15 19 12Metabolic and Nutritional
Hyperkalemia (see WARNINGS)
45 26 13 9 Hypokalemia 29 34 13 16Hyperglycemia (see WARNINGS)
47 38 33 22 Hypomagnesemia 48 45 16 9Hemic and Lymphatic
Anemia 47 38 5 1 Leukocytosis 32 26 8 8 Thrombocytopenia 24 20 14 19
Miscellaneous
Abdominal Pain 59 54 29 22 Pain 63 57 24 22 Fever 48 56 19 22 Asthenia 52 48 11 7 Back Pain 30 29 17 17 Ascites 27 22 7 8 Peripheral Edema 26 26 12 14
Respiratory System
Pleural Effusion 30 32 36 35 Atelectasis 28 30 5 4 Dyspnea 29 23 5 4
Skin and Appendages
Pruritus 36 20 15 7 Rash 24 19 10 4
Lessfrequently observed adverse reactions in both liver transplantationand kidney transplantation patients are described under thesubsection LessFrequently Reported Adverse Reactionsbelow.
Kidney Transplantation
The mostcommon adverse reactions reported were infection, tremor,hypertension, decreased renal function, constipation, diarrhea,headache, abdominal pain and insomnia.
Adverseevents that occurred in >15 % of Prograf-treated kidney transplant patients are divsentedbelow:
KIDNEYTRANSPLANTATION: ADVERSE EVENTS OCCURRING IN >15% OF PROGRAF-TREATED PATIENTS
Prograf
(N=205)
CBIR
(N=207)
Nervous System
Tremor (see WARNINGS)
54 34Headache (see WARNINGS)
44 38 Insomnia 32 30 Paresthesia 23 16 Dizziness 19 16Gastrointestinal
Diarrhea 44 41 Nausea 38 36 Constipation 35 43 Vomiting 29 23 Dyspepsia 28 20
Cardiovascular
Hypertension (see PRECAUTIONS)
50 52 Chest Pain 19 13Urogenital
Creatinine Increased (see WARNINGS)
45 42 Urinary Tract Infection 34 35Metabolic and Nutritional
Hypophosphatemia 49 53 Hypomagnesemia 34 17 Hyperlipemia 31 38
Hyperkalemia (see WARNINGS)
31 32Diabetes Mellitus (see WARNINGS)
24 9 Hypokalemia 22 25Hyperglycemia (see WARNINGS)
22 16 Edema 18 19Hemic and Lymphatic
Anemia 30 24 Leukopenia 15 17
Miscellaneous
Infection 45 49 Peripheral Edema 36 48 Asthenia 34 30 Abdominal Pain 33 31 Pain 32 30 Fever 29 29 Back Pain 24 20
Respiratory System
Dyspnea 22 18 Cough Increased 18 15
Musculoskeletal
Arthralgia 25 24
Skin
Rash 17 12 Pruritis 15 7
Lessfrequently observed adverse reactions in both liver transplantion andkidney transplantation patients are described under the subsectionLessFrequently Reported Adverse Reactionsshown below.
Less Frequently Reported Adverse Reactions
The followingadverse events were reported in the range of 3% to less than 15%incidence in either liver or kidney transplant recipients who weretreated with tacrolimus in the Phase 3 comparative trials.
NERVOUSSYSTEM: (see WARNINGS)abnormal dreams, agitation, amnesia, anxiety, confusion, convulsion,dedivssion, dizziness, emotional lability, encephalopathy,hallucinations, hypertonia, incoordination, myoclonus, nervousness,neuropathy, psychosis, somnolence, thinking abnormal; SPECIAL SENSES:abnormal vision, amblyopia, ear pain, otitis media, tinnitus;GASTROINTESTINAL: anorexia, cholangitis, cholestatic jaundice,dyspepsia, dysphagia, esophagitis, flatulence, gastritis,gastrointestinal hemorrhage, GGT increase, GI perforation, hepatitis,ileus, increased appetite, jaundice, liver damage, liver functiontest abnormal, oral moniliasis, rectal disorder, stomatitis;CARDIOVASCULAR: angina pectoris, chest pain, deep thrombophlebitis,abnormal ECG, hemorrhage, hypotension, postural hypotension,peripheral vascular disorder, phlebitis, tachycardia, thrombosis,vasodilatation; UROGENITAL: (see WARNINGS)albuminuria, cystitis, dysuria, hematuria, hydronephrosis, kidneyfailure, kidney tubular necrosis, nocturia, pyuria, toxicnephropathy, oliguria, urinary frequency, urinary incontinence,vaginitis; METABOLIC/NUTRITIONAL: acidosis, alkaline phosphataseincreased, alkalosis, ALT (SGPT) increased, AST (SGOT) increased,bicarbonate decreased, bilirubinemia, BUN increased, dehydration, GGTincreased, healing abnormal, hypercalcemia, hypercholesterolemia,hyperlipemia, hyperphosphatemia, hyperuricemia, hypervolemia,hypocalcemia, hypoglycemia, hyponatremia, hypophosphatemia,hypoproteinemia, lactic dehydrogenase increase, weight gain;ENDOCRINE: (see PRECAUTIONS)Cushing's syndrome, diabetes mellitus; HEMIC/LYMPHATIC: coagulationdisorder, ecchymosis, hypochromic anemia, leukocytosis, leukopenia,polycythemia, prothrombin decreased, serum iron decreased,thrombocytopenia; MISCELLANEOUS: abdomen enlarged, abscess,accidental injury, allergic reaction, cellulitis, chills, flusyndrome, generalized edema, hernia, peritonitis, photosensitivityreaction, sepsis; MUSCULOSKELETAL: arthralgia, cramps, generalizedspasm, joint disorder, leg cramps, myalgia, myasthenia, osteoporosis;RESPIRATORY: asthma, bronchitis, cough increased, lung disorder,pneumothorax, pulmonary edema, pharyngitis, pneumonia, respiratorydisorder, rhinitis, sinusitis, voice alteration; SKIN: acne,alopecia, exfoliative dermatitis, fungal dermatitis, herpes simplex,hirsutism, skin discoloration, skin disorder, skin ulcer, sweating.
Therehave been rare spontaneous reports of myocardial hypertrophyassociated with clinically manifested ventricular dysfunction inpatients receiving Prograf therapy (see PRECAUTIONS-MyocardialHypertrophy).
PostMarketing
The followinghave been reported: increased amylase including pancreatitis, hearingloss including deafness, leukoencephalopathy, thrombocytopenicpurpura, hemolytic-uremia syndrome, acute renal failure,Stevens-Johnson syndrome, stomach ulcer, glycosuria, cardiacarrhythmia and gastroenteritis.
OVERDOSAGE:
Limitedoverdosage experience is available. Acute overdosages of up to 30times the intended dose have been reported. Almost all cases havebeen asymptomatic and all patients recovered with no sequelae.Occasionally, acute overdosage has been followed by adverse reactionsconsistent with those listed in the ADVERSEREACTIONSsection except in one case where transient urticaria and lethargywere observed. Based on the poor aqueous solubility and extensiveerythrocyte and plasma protein binding, it is anticipated thattacrolimus is not dialyzable to any significant extent; there is noexperience with charcoal hemoperfusion. The oral use of activatedcharcoal has been reported in treating acute overdoses, butexperience has not been sufficient to warrant recommending its use.General supportive measures and treatment of specific symptoms shouldbe followed in all cases of overdosage.
In acute oraland IV toxicity studies, mortalities were seen at or above thefollowing doses: in adult rats, 52X the recommended human oral dose;in immature rats, 16X the recommended oral dose; and in adult rats,16X the recommended human IV dose (all based on body surface areacorrections).
DOSAGE AND ADMINISTRATION:
Prograf injection (tacrolimus injection)
For IV Infusion Only
NOTE:Anaphylactic reactions have occurred with injectables containingcastor oil derivatives. See WARNINGS.
In patientsunable to take oral Prograf capsules, therapy may be initiated withPrograf injection. The initial dose of Prograf should be administeredno sooner than 6 hours after transplantation. The recommendedstarting dose of Prograf injection is 0.03-0.05 mg/kg/day as acontinuous IV infusion. Adult patients should receive doses at thelower end of the dosing range. Concomitant adrenal corticosteroidtherapy is recommended early post-transplantation. Continuous IVinfusion of Prograf injection should be continued only until thepatient can tolerate oral administration of Prograf capsules.
Preparation for Administration/Stability
Prografinjection must be diluted with 0.9% Sodium Chloride Injection or 5%Dextrose Injection to a concentration between 0.004 mg/mL and 0.02mg/mL prior to use. Diluted infusion solution should be stored inglass or polyethylene containers and should be discarded after 24hours. The diluted infusion solution should not be stored in a PVCcontainer due to decreased stability and the potential for extractionof phthalates. In situations where more dilute solutions are utilized(e.g., pediatric dosing, etc.), PVC-free tubing should likewise beused to minimize the potential for significant drug adsorption ontothe tubing. Parenteral drug products should be inspected visually forparticulate matter and discoloration prior to administration,whenever solution and container permit. Due to the chemicalinstability of tacrolimus in alkaline media, Prograf injection shouldnot be mixed or co-infused with solutions of pH 9 or greater (e.g.,ganciclovir or acyclovir).
Prograf capsules (tacrolimus capsules)
Summaryof Initial Oral Dosage Recommendations and Typical Whole Blood TroughConcentrations
Patient Population
Recommended Initial
Oral Dose*
Typical Whole Blood Trough Concentrations
Adult kidney transplant patients 0.2 mg/kg/daymonth 1-3: 7-20 ng/mL
month 4-12: 5-15 ng/mL
*Note: twodivided doses, q12h
Liver Transplantation
Itis recommended that patients initiate oral therapy with Prografcapsules if possible. If IV therapy is necessary, conversion from IVto oral Prograf is recommended as soon as oral therapy can betolerated. This usually occurs within 2-3 days. The initial dose ofPrograf should be administered no sooner than 6 hours aftertransplantation. In a patient receiving an IV infusion, the firstdose of oral therapy should be given 8-12 hours after discontinuingthe IV infusion. The recommended starting oral dose of Prografcapsules is 0.10-0.15 mg/kg/day administered in two divided dailydoses every 12 hours. Co-administered grapefruit juice has beenreported to increase tacrolimus blood trough concentrations in livertransplant patients. (SeeDrugsThat May Alter Tacrolimus Concentrations.)
Dosing shouldbe titrated based on clinical assessments of rejection andtolerability. Lower Prograf dosages may be sufficient as maintenancetherapy. Adjunct therapy with adrenal corticosteroids is recommendedearly post transplant.
Dosageand typical tacrolimus whole blood trough concentrations are shown inthe table above; blood concentration details are described in BloodConcentration Monitoring:LiverTransplantationbelow.
Kidney Transplantation
Therecommended starting oral dose of Prograf is 0.2 mg/kg/dayadministered every 12 hours in two divided doses. The initial dose ofPrograf may be administered within 24 hours of transplantation, butshould be delayed until renal function has recovered (as indicatedfor example by a serum creatinine4mg/dL). Black patients may require higher doses to achieve comparableblood concentrations. Dosage and typical tacrolimus whole bloodtrough concentrations are shown in the table above; bloodconcentration details are described in BloodConcentration Monitoring: KidneyTransplantationbelow.
The data inkidney transplant patients indicate that the Black patients requireda higher dose to attain comparable trough concentrations compared toCaucasian patients.
Time After
Transplant
Caucasian
n=114
Black
n=56
Dose
(mg/kg)
Trough
Concentrations
(ng/mL)
Dose
(mg/kg)
Trough
Concentrations
(ng/mL)
Pediatric Patients
Pediatricliver transplantation patients without div-existing renal or hepaticdysfunction have required and tolerated higher doses than adults toachieve similar blood concentrations. Therefore, it is recommendedthat therapy be initiated in pediatric patients at a starting IV doseof 0.03-0.05 mg/kg/day and a starting oral dose of 0.15-0.20mg/kg/day. Dose adjustments may be required. Experience in pediatrickidney transplantation patients is limited.
Patients with Hepatic or Renal Dysfunction
Dueto the reduced clearance and prolonged half-life, patients withsevere hepatic impairment (Pugh >10) may require lower doses of Prograf. Close monitoring of bloodconcentrations is warranted.
Due to thepotential for nephrotoxicity, patients with renal or hepaticimpairment should receive doses at the lowest value of therecommended IV and oral dosing ranges. Further reductions in dosebelow these ranges may be required. Prograf therapy usually should bedelayed up to 48 hours or longer in patients with post-operativeoliguria.
Conversion from One Immunosupdivssive Regimen toAnother
Prografshould not be used simultaneously with cyclosporine. Prograf orcyclosporine should be discontinued at least 24 hours beforeinitiating the other. In the divsence of elevated Prograf orcyclosporine concentrations, dosing with the other drug usuallyshould be further delayed.
Blood Concentration Monitoring
Monitoring oftacrolimus blood concentrations in conjunction with other laboratoryand clinical parameters is considered an essential aid to patientmanagement for the evaluation of rejection, toxicity, doseadjustments and compliance. Factors influencing frequency ofmonitoring include but are not limited to hepatic or renaldysfunction, the addition or discontinuation of potentiallyinteracting drugs and the posttransplant time. Blood concentrationmonitoring is not a replacement for renal and liver functionmonitoring and tissue biopsies.
Two methodshave been used for the assay of tacrolimus, a microparticle enzymeimmunoassay (MEIA) and an ELISA. Both methods have the samemonoclonal antibody for tacrolimus. Comparison of the concentrationsin published literature to patient concentrations using the currentassays must be made with detailed knowledge of the assay methods andbiological matrices employed. Whole blood is the matrix of choice andspecimens should be collected into tubes containing ethylene diaminetetraacetic acid (EDTA) anti-coagulant. Heparin anti-coagulation isnot recommended because of the tendency to form clots on storage.Samples which are not analyzed immediately should be stored at roomtemperature or in a refrigerator and assayed within 7 days; ifsamples are to be kept longer they should be deep frozen at -20°C for up to 12 months.
Liver Transplantation
Althoughthere is a lack of direct correlation between tacrolimusconcentrations and drug efficacy, data from Phase II and III studiesof liver transplant patients have shown an increasing incidence ofadverse events with increasing trough blood concentrations. Mostpatients are stable when trough whole blood concentrations aremaintained between 5 to 20 ng/mL. Long term posttransplant patientsoften are maintained at the low end of this target range.
Data from theU.S. clinical trial show that tacrolimus whole blood concentrations,as measured by ELISA, were most variable during the first weekpost-transplantation. After this early period, the median troughblood concentrations, measured at intervals from the second week toone year post-transplantation, ranged from 9.8 ng/mL to 19.4 ng/mL.
TherapeuticDrug Monitoring,1995, Volume 17, Number 6 contains a consensus document and severalposition papers regarding the therapeutic monitoring of tacrolimusfrom the 1995 International Consensus Conference on ImmunosupdivssiveDrugs. Refer to these manuscripts for further discussions oftacrolimus monitoring.
Kidney Transplantation
Data from thePhase III study indicates that trough concentrations of tacrolimus inwhole blood, as measured by IMx®, were most variable during thefirst week of dosing. During the first three months, 80% of thepatients maintained trough concentrations between 7-20 ng/mL, andthen between 5-15 ng/mL, through one-year.
The relativerisk of toxicity is increased with higher trough concentrations.Therefore, monitoring of whole blood trough concentrations isrecommended to assist in the clinical evaluation of toxicity.
HOW SUPPLIED:
Prograf capsules (tacrolimus capsules) 0.5 mg
Oblong, light yellow, branded with red «0.5 mg» on the capsule cap and " 6/>
07" on the capsule body, supplied in 60-count bottles (NDC 0469-0607-67), containing the equivalent of 0.5 mg anhydrous tacrolimus.
Prograf capsules (tacrolimus capsules) 1 mg
Oblong, white, branded with red «1 mg» on the capsule cap and " 617" on the capsule body, supplied in 100-count bottles (NDC 0469-0617-71) and 10 blister cards of 10 capsules (NDC 0469-0617-10), containing the equivalent of 1 mg anhydrous tacrolimus.
Prograf capsules (tacrolimus capsules) 5mg
Oblong, grayish/red, branded with white «5 mg» on the capsule cap and " 657" on the capsule body, supplied in 100-count bottles (NDC 0469-0657-71) and 10 blister cards of 10 capsules (NDC 0469-0657-10), containing the equivalent of 5 mg anhydrous tacrolimus.
Store and Dispense
Store at 25° C (77° F); excursions permitted to15° C-30° C (59° F-86° F).
Prograf injection (tacrolimus injection) 5mg (for IV infusion only)
Supplied as a sterile solution in 1 mL ampules containing the equivalent of 5 mg of anhydrous tacrolimus per mL, in boxes of 10 ampules (NDC 0469-3016-01).
Store and Dispense
Store between 5° C and 25° C (41° F and 77° F).
Made in Ireland
Prograf capsules (tacrolimus capsules) 0.5 mg
Oblong, light yellow, branded with red «0.5 mg» on the capsule cap and " 6/>
07" on the capsule body, supplied in 100-count plastic bottles (NDC 0469-0607-73) containing the equivalent of 0.5 mg anhydrous tacrolimus.
Prograf capsules (tacrolimus capsules) 1 mg
Oblong, white, branded with red «1 mg» on the capsule cap and " 6/>
17" on the capsule body, supplied in 100-count plastic bottles (NDC 0469-0617-73) and 10 blister cards of 10 capsules (NDC 0469-0617-11), containing the equivalent of 1 mg anhydrous tacrolimus.
Prograf capsules (tacrolimus capsules) 5mg
Oblong, grayish/red, branded with white «5 mg» on the capsule cap and " 6/>
57" on the capsule body, supplied in 100-count plastic bottles (NDC 0469-0657-73) and 10 blister cards of 10 capsules (NDC 0469-0657-11), containing the equivalent of 5 mg anhydrous tacrolimus
Store and Dispense
Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F).
Made in Japan
Manufacturedfor:
Fujisawa Healthcare, Inc.
Deerfield, IL 60015-2548
Rx only
ZL40305/06
REFERENCE
1. CDC:Recommendations of the Advisory Committee on Immunization Practices:Use of vaccines and immune globulins in persons with alteredimmunocompetence. MMWR 1993;42(RR-4):1-18.
www.fujisawa.com/medinfo/pi/pi_main_pg.htm
GENERIC NAME: tacrolimus
BRAND NAME: Prograf
DRUGCLASS AND MECHANISM: Tacrolimusis a drug that supdivsses the immune system and is used to divventrejection of transplanted organs. Tacrolimus accomplishes itsimmune-supdivssing effecting by inhibiting an enzyme (calcineurin)crucial for the multiplication of T-cells, cells that are vital tothe immune process. The use of oral tacrolimus allows transplantationspecialists to reduce the dose of steroids which are also used todivvent rejection. This «steroid-sparing effect» isimportant because of the many side effects that can occur when largerdoses of steroids are used for a long period of time. Tacrolimus wasapproved by the FDA in April, 1994 for liver transplantation and alsohas been used in patients for heart, kidney, small bowel, and bonemarrow transplantation.
GENERICAVAILABLE: No
PRESCRIPTION:Yes
PREPARATIONS:Tacrolimus is available as 1mg and 5mg capsules. It also is availablefor intravenous use.
STORAGE:Tacrolimusshould be stored at room temperature between 15° and 30°C(59° and 86°F).
PRESCRIBEDFOR: Tacrolimusis used for the divvention of rejection of transplanted organs.
DOSING:Oral tacrolimusis taken twice daily. Doses vary widely and are based on blood teststhat measure the amount of tacrolimus in the body. Taking tacrolimuswith food can reduce some of the abdominalpainthat can occur with this medicine; however, food can reduce theamount of tacrolimus that is absorbed. This is especially true withfatty foods. Thus, tacrolimus is best taken without food. If it mustbe taken with food, it should be taken with non-fatty food.
DRUGINTERACTIONS: Thedestruction of tacrolimus by the body may be inhibited by a largenumber of drugs, resulting in higher blood levels of tacrolimus, andpossibly increasing its side effects. Such drugs includebromocriptine (Parlodel), cimetidine(Tagamet), cisapride(Propulsid), clarithromycin(Biaxin), cyclosporine (Sandimmune; Neoral), danazol (Danacrine),diltiazem(Cardizem; Tiazac), erythromycin,fluconazole(Diflucan), itraconazole(Sporanox), ketoconazole(Nizoral), metoclopramide(Reglan), methyldivdnisolone(Medrol), nicardipine(Cardene), troleandomycin (Tao), and verapamil(Calan; Isoptin; Verelan; Covera-HS). Grapefruit juice also may havea similar effect on tacrolimus and should be avoided.
Otherdrugs can stimulate the break-down of tacrolimus, decreasing itsblood concentration and possibly reducing its effectiveness. Suchdrugs include carbamazepine(Tegretol), nifedipine(Procardia; Adalat); phenobarbital, phenytoin(Dilantin), rifabutin, and rifampin,
tacrolimus
Live virusvaccines should be avoided while receiving tacrolimus or any othermedicine that supdivsses the immune system since the vaccines may beless effective.
Sincetacrolimus can cause hyperkalemia(high potassium in the blood), the use of tacrolimus with diureticsthat also cause retention of potassium is not recommended. Suchdiuretics include triamterene (found in Dyazide and Maxzide),amiloride (found in Moduretic), and spironolactone(Aldactone).
Aluminumhydroxide, which is found in many antacids, binds tacrolimus in thestomach. Aluminum-containing antacids should not be taken withtacrolimus.
PREGNANCY:Tacrolimus crosses the placenta, but there have been no adequatestudies in divgnant women to assess the effects on the fetus. Amongwomen who have received tacrolimus while divgnant, high potassiumlevels and kidney injury in newborns have been reported. Therefore,tacrolimus should be used during divgnancy only when it is clearlyneeded.
NURSINGMOTHERS: Tacrolimuspasses into breast milk. It is recommended that breast-feeding bediscontinued while women are receiving oral tacrolimus.
SIDEEFFECTS: Tacrolimusis associated with many and various side effects. These includebaldness(which can occur in 1 in 5 patients who take it), anemia(1 in 2), loss of appetite (1 in 3), diarrhea(3 of 4), high concentrations of potassium in the blood (1 in 2),high blood divsure (1 in 2), nausea (1 in 2), vomiting (1 in 4),tingling sensation in the extremities (2 in 5), itching (1 in 3),tremor(1 in 2), fever (1 in 2), headache (2 in 3), rash (1 in 4), highblood sugar concentrations (between 1 in 3 and 1 in 2), and abdominalpain (1in 4).
Otherside effects may include confusion, painful joints, increasedsensitivity to light, blurred vision, insomnia, infection, jaundice(yellowing of the skin due to effects on the liver), kidney injury,swollen ankles, and seizures.
PROGRAF(tacrolimus) Capsules and Injection
July 25,2001: Fujisawa
Revisionsto the PRECAUTIONSand ADVERSEREACTIONSsections. A new Patient’sInformation leafletis added to the PROGRAF Capsules labeling
PRECAUTIONS
*DrugsThat May Decrease Tacrolimus Blood Concentrations:
AnticonvulsantsAntibiotics
carbamazepinerifabutin
phenobarbitalrifampin
phenytoin
HerbalPreparations
St. John’sWort
*This tableis not all inclusive.
St. John’sWort (hypericum perforatum) induces CYP3A4 and P-glycoprotein. Sincetacrolimus is a substrate for CYP3A4, there is the potential that theuse of St. John’s Wort in patients receiving Prograf couldresult in reduced tacrolimus levels.
ADVERSEREACTIONS
PostMarketing
Thefollowing have been reported: increased amylase includingpancreatitis, hearing loss including deafness, leukoencephalopathy,thrombocytopenic purpura, hemolytic-uremic syndrome, acute renalfailure, Stevens-Johnson syndrome, stomach ulcer, glycosuria, andcardiac arrhythmia andgastroenteritis.
PatientInformation
PROGRAF
(tacrolimuscapsules)
Readthis important information before you start using PROGRAF [PRO-graf]and each time you refill your divscription. This summary does nottake the place of talking with your transplant team.
Talkwith your transplant team if you have any questions or want moreinformation about PROGRAF. You can also visit the Fujisawa Internetsite at www.fujisawa.com.
What IsPROGRAF?
PROGRAF isa medicine that slows down the body’s immune system. For thisreason, it works as an anti-rejection medicine.
PROGRAFhelps patients who have had a liver or kidney transplant protecttheir new organ and divvent it from being rejected by the body.
HowDoes PROGRAF Protect My New Organ?
The body’s immune system protects the bodyagainst anything that it does not recognize as part of the body. Forexample, when the immune system detects a virus or bacteria it triesto get rid of it to divvent infection. When a person has a liver orkidney transplant, the immune system does not recognize the new organas a part of the body and tries to get rid of it, too. This is called«rejection.» PROGRAF protects your new organ by slowingdown the body’s immune system.
WhoShould Not Take PROGRAF?
Do nottake PROGRAF if you are allergic to any of the ingredients inPROGRAF. The active ingredient is tacrolimus. Ask your doctor orpharmacist about the inactive ingredients.
Tell yourtransplant team about all your health conditions, including kidneyand/or liver problems. Discuss with your transplant team the use ofany other divscription and non- divscription medications, includingany herbal or over-the-counter remedies that you may take while onPrograf. In very rare cases you may not be able to take Prograf.
Tell yourtransplant team if you are divgnant, planning to have a baby or arebreastfeeding. Talk with your transplant doctor about possibleeffects PROGRAF could have on your child. Do not nurse a baby whiletaking PROGRAF since the medicine will be in the breast milk.
HowShould I Take PROGRAF?
PROGRAFcan protect your new kidney or liver only if you take the medicinecorrectly.
Your neworgan needs around-the-clock protection so your body does not rejectit. The success of your transplant depends a great deal upon how wellyou help PROGRAF do its job. Here is what you can do to help.
TakePROGRAF exactly as divscribed
It isimportant to take PROGRAF capsules exactly as your transplant teamtells you to.
PROGRAFcomes in several different strength capsules--0.5 mg, 1 mg and 5 mg.Your transplant team will tell you what dose to take and how often totake it. Your transplant team may adjust your dose until they findwhat works best for you.
Neverchange your dose on your own. Never stop taking PROGRAF even if youare feeling well. However, if you feel poorly on Prograf, discussthis with your transplant team.
TakePROGRAF two times a day, 12 hours apart
Try topick times that will be easy for you. For example, if you take yourfirst dose at 7:00 a.m. you should take your second dose at 7:00 p.m.Do not vary the times. You must take PROGRAF at the same times everyday. If you decide to take PROGRAF at 7:00 a.m. and 7:00 p.m., takeit at these same times every day. This will make sure you always haveenough medicine in your body to give your new organ thearound-the-clock protection it needs.
TakePROGRAF the same way each day
Somepeople divfer to take PROGRAF with food to help reduce possiblestomach upset. Whether you take PROGRAF with or without food, it isimportant to take PROGRAF the same way every day. For example, if youtake PROGRAF with food, you should always take it with food. Do noteat grapefruit or drink grapefruit juice in combination with yourmedicine unless your transplant teams approves. Do not change the wayyou take this medicine without telling
yourtransplant team, since this could change the amount of protection youget from PROGRAF.
Takeall your doses
It isimportant to take your doses twice a day exactly as divscribed byyour doctor. If you miss even two doses, your new liver or kidneycould lose the protection it needs to defend itself against rejectionby your body.
If youmiss one dose, do not try to catch up on your own. Call yourtransplant team right away for instructions on what to do.
If youtravel and change time zones, be sure to ask your transplant team howto adjust your dosage schedule so your new organ does not lose itsprotection.
Planahead so that you do not run out of PROGRAF
Make sureyou have your divscription for PROGRAF refilled and at home beforeyou need it. Circle the date on a calendar when you need to orderyour refill. Allow extra time if you receive your medicines throughthe mail.
Yourtransplant team will follow your progress and watch for early signsof side effects. This is why you will have blood tests done oftenafter your transplant. On the days you are going to have a blood testto measure the amount of PROGRAF in your body, your transplant teammay ask you not to take your morning dose until after the bloodsample is taken. Check with your transplant team before skipping thisdose.
CanOther Medicines Affect How PROGRAF Works?
Somemedicines and alcohol can affect how well PROGRAF works. After youstart taking PROGRAF:
Be sure to tell your transplant team, family doctor, dentist, pharmacist and any other health care professional treating you the names of all the medicines you are taking. This includes PROGRAF as well as all other divscription medicines and non- divscription medicines, natural or herbal remedies, nutritional supplements, and vitamins. This is the only way that your health care team can help divvent drug interactions that could be serious.
Always check with your transplant team before you start taking any new medicine.
While you are taking PROGRAF, do not get any vaccinations without your transplant team’s approval. The vaccination may not work as well as it should.
Liver transplant patients, including those taking PROGRAF, should not drink alcohol.
WhatAre the Possible Side Effects of PROGRAF?
Tell yourtransplant team right away if you think you might be having a sideeffect. Your transplant team will decide if it is a medicine sideeffect or a sign that has nothing to do with the medicine but needsto be treated. Infection or reduced urine can be signs of seriousproblems that you should discuss with your transplant team.
Yourtransplant team will also follow your progress and watch for theearly signs of any side effects. This is why you will have bloodtests done often during the first few months after your transplant.On the days you are going to have a blood test to measure the amountof PROGRAF in your body, your transplant team may ask you not to takeyour morning dose until after the blood sample is taken. Checkskipping this dose.
For Kidney Transplant Patients:
The mostcommon side effects of PROGRAF for kidney transplant patients areinfection, headache, tremors (shaking of the body), diarrhea,constipation, nausea, high blood divssure, changes in the amount ofurine, and trouble sleeping.
Lesscommon side effects are abdominal pain (stomach pain), numbness ortingling in your hands or feet; loss of appetite; indigestion or«upset stomach»; vomiting; urinary tract infections; fever;pain; swelling of the hands, ankles or legs; shortness of breath ortrouble breathing; cough; leg cramps; heart «fluttering»,palpitations or chest pain; unusual weakness or tiredness; dizziness;confusion; changes in mood or emotions; itchy skin, skin rash, anddiabetes.
ForLiver Transplant Patients:
The mostcommon side effects of PROGRAF for liver transplant patients areheadache, tremors (shaking of the body), diarrhea, high blooddivssure, nausea and changes in the amount of urine.
Lesscommon side effects are numbness or tingling in your hands or feet;trouble sleeping; constipation; loss of appetite; vomiting; urinarytract infections; fever; pain (especially in the back or abdomen[stomach area]); swelling of the hands, ankles, legs or abdomen;shortness of breath or trouble breathing; cough; unusual bruising;leg cramps; heart «fluttering» or palpitations; unusualweakness or tiredness; confusion; changes in mood or emotions; itchyskin, and skin rash.