БАШКИРСЬКА ДЕРЖАВНИЙ МЕДИЧНИЙ УНІВЕРСИТЕТ
Кафедра фармакології № 1, з курсом клінічної фармакології
Зав. кафедри: д.м.н. професор Альохін Є.К.
Зав. курсом: д.м.н. професор Заруддя Ф.А.
Викладач: к.м.н. доцент Шигаєв Н.І.
РЕФЕРАТ
«такролімус»
Виконав: студент лікувального факультету гр. № Л-Б
УФА -2002р.
Prograf Prescribing Information
WARNING
DESCRIPTION:
CLINICAL PHARMACOLOGY:
INDICATIONS AND USAGE:
CONTRAINDICATIONS:
WARNINGS:
PRECAUTIONS:
ADVERSE REACTIONS:
OVERDOSAGE:
DOSAGE AND ADMINISTRATION:
HOW SUPPLIED:
REFERENCE
Fujisawa
Revised: May 2002
Prograf ®
tacrolimus capsules
tacrolimus injection (for intravenous infusion only)
| | | |
| | WARNING | |
| | | |
| | Increased susceptibility to infection and the possible | |
| | Development of lymphoma may result from immunosuppression. Only | |
| | Physicians experienced in immunosuppressive therapy and | |
| | Management of organ transplant patients should prescribe | |
| | 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 is available for oral administration as capsules (tacrolimuscapsules) containing the equivalent of 0.5 mg, 1 mg or 5 mg of anhydroustacrolimus. Inactive ingredients include lactose, hydroxypropylmethylcellulose, croscarmellose sodium, and magnesium stearate. The 0.5 mgcapsule shell contains gelatin, titanium dioxide and ferric oxide, the 1 mgcapsule shell contains gelatin and titanium dioxide, and the 5 mg capsuleshell contains gelatin, titanium dioxide and ferric oxide.
Prograf is also 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 contains polyoxyl 60hydrogenated castor oil (HCO-60), 200 mg, and dehydrated alcohol, USP,
80.0% v/v. Prograf injection must be diluted with 0.9% Sodium Chloride
Injection or 5% Dextrose Injection before use.
Tacrolimus, previously known as FK506, is the active ingredient in Prograf.
Tacrolimus is a macrolide immunosuppressant 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, 13,14,15,16,17,18,19,24,25,26,26 a-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.
The chemical structure of tacrolimus is:
Tacrolimus has an empirical formula of C44H69NO12 · H2O and a formula weightof 822.05. Tacrolimus appears as white crystals or crystalline powder. Itis practically insoluble in water, freely soluble in ethanol, and verysoluble in methanol and chloroform.
CLINICAL PHARMACOLOGY:
Mechanism of Action
Tacrolimus prolongs the survival of the host and transplanted graft inanimal transplant models of liver, kidney, heart, bone marrow, small boweland pancreas, lung and trachea, skin, cornea, and limb.
In animals, tacrolimus has been demonstrated to suppress some humoralimmunity and, to a greater extent, cell-mediated reactions such asallograft rejection, delayed type hypersensitivity, collagen-inducedarthritis, experimental allergic encephalomyelitis, and graft versus hostdisease.
Tacrolimus inhibits T-lymphocyte activation, although the exact mechanismof action is not known. Experimental evidence suggests that tacrolimusbinds to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-
12, calcium, calmodulin, and calcineurin is then formed and the phosphataseactivity of calcineurin inhibited. This effect may prevent thedephosphorylation and translocation of nuclear factor of activated T-cells
(NF-AT), a nuclear component thought to initiate gene transcription for theformation of lymphokines (such as interleukin-2, gamma interferon). The netresult is the inhibition of T-lymphocyte activation (ie,immunosuppression).
Pharmacokinetics
Tacrolimus activity is primarily due to the parent drug. Thepharmacokinetic parameters (mean ± SD) of tacrolimus have been determinedfollowing intravenous (IV) and oral (PO) administration in healthyvolunteers, kidney transplant and liver transplant patients. (See tablebelow.)
| Popula | N | Route | Parame | | | | | |
| tion | | (Dose) | ters | | | | | |
| | | | Cmax | Tmax | AUC | tЅ | Cl | V |
| | | | (Ng/mL | (hr) | (ng · hr/m | (hr) | (L/hr/kg | (L/kg) |
| | | |) | | L) | |) | |
| Health | 8 | IV | | | 598 * | 34.2 | 0.040 | 1.91 |
| y | | (0.025 | - | - | 125 ± | ± 7.7 | ± 0.009 | ± 0.31 |
| Volunt | | mg/kg/4hr) | | | | | | |
| eers | | | | | | | | |
| | 16 | PO | 29.7 | 1.6 | 243 ** | 34.8 | 0.041 † | 1.94 † |
| | | (5 mg) | ± 7.2 | ± 0.7 | ± 73 | ± 11.4 | ± 0.008 | |
| | | | | | | | | ± 0.53 |
| Kidney | 26 | IV | | | 294 *** | 18.8 | 0.083 | 1.41 |
| | | (0.02 | - | - | 262 ± | ± 16.7 | ± 0.050 | ± 0.66 |
| Transp | | mg/kg/12hr) | | | | | | |
| lant | | | | | | | | |
| Pts | | | | | | | | |
| | | PO | 19.2 | 3.0 | 203 *** | # | # | # |
| | | (0.2 | ± 10.3 | | ± 42 | | | |
| | | Mg/kg/day) | | | | | | |
| | | PO | 24.2 | 1.5 | 288 *** | # | # | # |
| | | (0.3 | ± 15.8 | | ± 93 | | | |
| | | Mg/kg/day) | | | | | | |
| Liver | 17 | IV | - | - | 3300 *** | 11.7 | 0.053 | 0.85 |
| Transp | | (0.05 | | | | ± 3.9 | ± 0.017 | ± 0.30 |
| lant | | mg/kg/12 | | | ± 2130 | | | |
| Pts | | hr) | | | | | | |
| | | PO | 68.5 | 2.3 | 519 *** | # | # | # |
| | | (0.3 | ± 30.0 | ± 1.5 | ± 179 | | | |
| | | Mg/kg/day) | | | | | | |
† Corrected for individual bioavailability * AUC0-120 ** AUC0-72 *** AUC0-inf - not applicable # not available
Due to intersubject variability in tacrolimus pharmacokinetics,individualization of dosing regimen is necessary for optimal therapy. (See
DOSAGE AND ADMINISTRATION). Pharmacokinetic data indicate that whole bloodconcentrations rather than plasma concentrations serve as the moreappropriate sampling compartment to describe tacrolimus pharmacokinetics.
Absorption
Absorption of tacrolimus from the gastrointestinal tract after oraladministration is incomplete and variable. The absolute bioavailability oftacrolimus was 17 ± 10% in adult kidney transplant patients (N = 26), 22 ± 6% inadult liver transplant patients (N = 17), and 18 ± 5% in healthy volunteers
(N = 16).
A single dose study conducted in 32 healthy volunteers established thebioequivalence of the 1 mg and 5 mg capsules. Another single dose study in
32 healthy volunteers established the bioequivalence of the 0.5 mg and 1 mgcapsules. Tacrolimus maximum blood concentrations (Cmax) and area under thecurve (AUC) appeared to increase in a dose-proportional fashion in 18fasted healthy volunteers receiving a single oral dose of 3, 7 and 10 mg.
In 18 kidney transplant patients, tacrolimus trough concentrations from 3to 30 ng/mL measured at 10-12 hours post-dose (Cmin) correlated well withthe AUC (correlation coefficient 0.93). In 24 liver transplant patientsover a concentration range of 10 to 60 ng/mL, the correlation coefficientwas 0.94.
Food Effects: The rate and extent of tacrolimus absorption were greatestunder fasted conditions. The presence and composition of food decreasedboth the rate and extent of tacrolimus absorption when administered to 15healthy volunteers.
The effect was most pronounced with a high-fat meal (848 kcal, 46% fat):mean AUC and C max were decreased 37% and 77%, respectively; Tmax waslengthened 5-fold. A high-carbohydrate meal (668 kcal, 85% carbohydrate)decreased mean AUC and mean C max by 28% and 65%, respectively.
In healthy volunteers (N = 16), the time of the meal also affected tacrolimusbioavailability. When given immediately following the meal, mean Cmax wasreduced 71%, and mean AUC was reduced 39%, relative to the fastedcondition. When administered 1.5 hours following the meal, mean Cmax wasreduced 63%, and mean AUC was reduced 39%, relative to the fastedcondition.
In 11 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 plasma protein binding of tacrolimus is approximately 99% and isindependent of concentration over a range of 5-50 ng/mL. Tacrolimus isbound mainly to albumin and alpha-1-acid glycoprotein, and has a high levelof association with erythrocytes. The distribution of tacrolimus betweenwhole blood and plasma depends on several factors, such as hematocrit,temperature at the time of plasma separation, drug concentration, andplasma protein concentration. In a U.S. study, the ratio of whole bloodconcentration to plasma concentration averaged 35 (range 12 to 67).
Metabolism
Tacrolimus is extensively metabolized by the mixed-function oxidase system,primarily the cytochrome P-450 system (CYP3A). A metabolic pathway leadingto the formation of 8 possible metabolites has been proposed. Demethylationand hydroxylation were identified as the primary mechanisms ofbiotransformation in vitro. The major metabolite identified in incubationswith human liver microsomes is 13-demethyl tacrolimus. In in vitro studies,a 31-demethyl metabolite has been reported to have the same activity astacrolimus.
Excretion
The mean clearance following IV administration of tacrolimus is 0.040,
0.083 and 0.053 L/hr/kg in healthy volunteers, adult kidney transplantpatients and adult liver transplant patients, respectively. In man, lessthan 1% of the dose administered is excreted unchanged in urine.
In a mass balance study of IV administered radiolabeled tacrolimus to 6healthy volunteers, the mean recovery of radiolabel was 77.8 ± 12.7%. Fecalelimination accounted for 92.4 ± 1.0% and the elimination half-life based onradioactivity was 48.1 ± 15.9 hours whereas it was 43.5 ± 11.6 hours based ontacrolimus concentrations. The mean clearance of radiolabel was 0.029 ± 0.015
L/hr/kg and clearance of tacrolimus was 0.029 ± 0.009 L/hr/kg. Whenadministered PO, the mean recovery of the radiolabel was 94.9 ± 30.7%. Fecalelimination accounted for 92.6 ± 30.7%, urinary elimination accounted for
2.3 ± 1.1% and the elimination half-life based on radioactivity was 31.9 ± 10.5hours whereas it was 48.4 ± 12.3 hours based on tacrolimus concentrations.
The mean clearance of radiolabel was 0.226 ± 0.116 L/hr/kg and clearance oftacrolimus 0.172 ± 0.088 L/hr/kg.
Special Populations
Pediatric
Pharmacokinetics of tacrolimus have been studied in liver transplantationpatients, 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 ofdistribution 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 9patients, mean AUC and Cmax were 337 ± 167 ng • hr/mL and 43.4 ± 27.9 ng/mL,respectively. The absolute bioavailability was 31 ± 21%.
Whole blood trough concentrations from 31 patients less than 12 years oldshowed that pediatric patients needed higher doses than adults to achievesimilar tacrolimus trough concentrations. (See DOSAGE AND ADMINISTRATION).
Renal and Hepatic Insufficiency
The mean pharmacokinetic parameters for tacrolimus following singleadministrations to patients with renal and hepatic impairment are given inthe following table.
| Population | Dose | AUC 0-t | tЅ | V | Cl |
| (No. of | | (ng · hr/mL | (hr) | (L/kg | (L/hr/kg) |
| Patients) | |) | |) | |
| Renal | 0.02 | 393 ± 123 | 26.3 ± 9.2 | 1.07 | 0.038 |
| Impairment | mg/kg/4h | (t = | | | ± 0.014 |
| (n = 12) | r | 60hr) | | ± 0.20 | |
| | IV | | | | |
| Mild Hepatic | 0.02 | 367 ± 107 | 60.6 ± 43.8 | 3.1 | 0.042 |
| Impairment | mg/kg/4h | (t = 72hr) | Range: 27.8 - | ± 1.6 | ± 0.02 |
| (n = 6) | r | | 141 | | |
| | IV | | | | |
| | 7.7 mg | 488 ± 320 | 66.1 ± 44.8 | 3.7 | 0.034 |
| | PO | (t = | Range: 29.5 - | ± 4.7 * | ± 0.019 * |
| | | 72hr) | 138 | | |
| Severe Hepatic | 0.02 | 762 ± 204 | 198 ± 158 | 3.9 | 0.017 |
| Impairment | mg/kg/4h | (t = 120hr) | Range: 81-436 | ± 1.0 | ± 0.013 |
| (n = 6, IV) | r | | | | |
| | IV (n = 2) | | | | |
| | | | | | |
| | 0.01 | 289 ± 117 | | | |
| | Mg/kg/8h | (t = 144hr) | | | |
| | R | | | | |
| | IV (n = 4) | | | | |
| | | | | | |
| Severe Hepatic | 8 mg PO | 658 | 119 ± 35 | 3.1 | 0.016 |
| Impairment | (n = 1) | (t = 120hr) | Range: 85-178 | ± 3.4 * | ± 0.011 * |
| (n = 5, PO) † | | | | | |
| | 5mg PO | 533 ± 156 | | | |
| | (N = 4) | (t = 144hr) | | | |
| | 4 mg PO | | | | |
| | (N = 1) | | | | |
| * corrected for bioavailability |
| † 1 patient did not receive the PO dose |
Renal Insufficiency:
Tacrolimus pharmacokinetics following a single IV administration weredetermined in 12 patients (7 not on dialysis and 5 on dialysis, serumcreatinine of 3.9 ± 1.6 and 12.0 ± 2.4 mg/dL, respectively) prior to theirkidney transplant. The pharmacokinetic parameters obtained were similar forboth groups.
The mean clearance of tacrolimus in patients with renal dysfunction wassimilar to that in normal volunteers (see previous table).
Hepatic Insufficiency:
Tacrolimus pharmacokinetics have been determined in six patients with mildhepatic dysfunction (mean Pugh score: 6.2) following single IV and oraladministrations. The mean clearance of tacrolimus in patients with mildhepatic dysfunction was not substantially different from that in normalvolunteers (see previous table). Tacrolimus pharmacokinetics were studiedin 6 patients with sever hepatic dysfunction (mean Pugh score:> 10). Themean clearance was substantially lower in patients with severe hepaticdysfunction, irrespective of the route of administration.
Race
A formal study to evaluate the pharmacokinetic disposition of tacrolimus in
Black transplant patients has not been conducted. However, a retrospectivecomparison of Black and Caucasian kidney transplant patients indicated that
Black patients required higher tacrolimus doses to attain similar troughconcentrations. (See DOSAGE AND ADMINISTRATION).
Gender
A formal study to evaluate the effect of gender on tacrolimuspharmacokinetics has not been conducted, however, there was no differencein dosing by gender in the kidney transplant trial. A retrospectivecomparison of pharmacokinetics in healthy volunteers, and in kidney andliver transplant patients indicated no gender-based differences.
Clinical Studies
Liver Transplantation
The safety and efficacy of Prograf-based immunosuppression followingorthotopic liver transplantation were assessed in two prospective,randomized, non-blinded multicenter studies. The active control groups weretreated with a cyclosporine-based immunosuppressive regimen. Both studiesused concomitant adrenal corticosteroids as part of the immunosuppressiveregimens. These studies were designed to evaluate whether the two regimenswere therapeutically equivalent, with patient and graft survival at 12months following transplantation as the primary endpoints. The Prograf -based immunosuppressive regimen was found to be equivalent to thecyclosporine-based immunosuppressive regimens.
In one trial, 529 patients were enrolled at 12 clinical sites in the United
States; prior to surgery, 263 were randomized to the Prograf-basedimmunosuppressive regimen and 266 to a cyclosporine-based immunosuppressiveregimen (CBIR). In 10 of the 12 sites, the same CBIR protocol was used,while 2 sites used different control protocols. This trial excludedpatients with renal dysfunction, fulminant hepatic failure with Stage IVencephalopathy, and cancers; pediatric patients (<12 years old) wereallowed.
In the second trial, 545 patients were enrolled at 8 clinical sites in
Europe; prior to surgery, 270 were randomized to the Prograf-basedimmunosuppressive regimen and 275 to CBIR. In this study, each center usedits local standard CBIR protocol in the active-control arm. This trialexcluded pediatric patients, but did allow enrollment of subjects withrenal dysfunction, fulminant hepatic failure in Stage IV encephalopathy,and cancers other than primary hepatic with metastases.
One-year patient 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 and Prograf-basedtreatment groups combined) was 88% in the U.S. study and 78% in the
European study. The overall one-year graft survival (CBIR and Prograf-basedtreatment groups combined) was 81% in the U.S. study and 73% in the
European study. In both studies, the median time to convert from IV to oral
Prograf dosing was 2 days.
Because of the 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 not bereliably made.
Kidney Transplantation
Prograf-based immunosuppression following kidney transplantation wasassessed in a Phase III randomized, multicenter, non-blinded, prospectivestudy. There were 412 kidney transplant patients enrolled at 19 clinicalsites in the United States. Study therapy was initiated when renal functionwas stable as indicated by a serum creatinine <4 mg/dL (median of 4 daysafter transplantation, range 1 to 14 days). Patients less than 6 years ofage were excluded.
There were 205 patients randomized to Prograf-based immunosuppression and
207 patients were randomized to cyclosporine-based immunosuppression. Allpatients received prophylactic induction therapy consisting of anantilymphocyte antibody preparation, corticosteroids and azathioprine.
Overall one year patient and graft survival was 96.1% and 89.6%,respectively and was equivalent between treatment arms.
Because of the 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 not bereliably made.
INDICATIONS AND USAGE:
Prograf is indicated for the prophylaxis of organ rejection in patientsreceiving allogeneic liver or kidney transplants. It is recommended that
Prograf be used concomitantly with adrenal corticosteroids. Because of therisk of anaphylaxis, Prograf injection should be reserved for patientsunable to take Prograf capsules orally.
CONTRAINDICATIONS:
Prograf is contraindicated in patients with a hypersensitivity totacrolimus. Prograf injection is contraindicated in patients with ahypersensitivity to HCO-60 (polyoxyl 60 hydrogenated castor oil).
WARNINGS:
(See boxed WARNING.)
Insulin-dependent post-transplant diabetes mellitus (PTDM) was reported in
20% of Prograf-treated kidney transplant patients without pretransplanthistory of diabetes millitus in the Phase III study below (See Tables
Below). The median time to onset of PTDM was 68 days. Insulin dependencewas reversible in 15% of these PTDM patients at one year and in 50% at twoyears post transplant. Black and Hispanic kidney transplant patients wereat an increased risk of development of PTDM.
Incidence of Post Transplant Diabetes Mellitus
and Insulin Use at 2 years in Kidney Transplant Recipients in the Phase III
Study
| Status of PTDM * | Prograf | CBIR |
| Patients without pretransplant history of | 151 | 151 |
| diabetes mellitus. | | |
| New onset PTDM *, 1st Year | 30/151 | 6/151 |
| | (20%) | (4%) |
| Still insulin dependent at one year in those | 25/151 (17 | 5/151 |
| without prior |%) | (3%) |
| history of diabetes. | | |
| New onset PTDM * post 1 year | 1 | 0 |
| Patients with PTDM * at 2 years | 16/151 | 5/151 |
| | (11%) | (3%) |
| * use of insulin for 30 or more consecutive days, with <5 day gap, |
| without a prior history of insulin dependent diabetes mellitus or |
| non insulin dependent diabetes mellitus. |
Development of Post Transplant Diabetes Mellitus by Race
and by Treatment Group during First Year Post Kidney Transplantation in the
Phase III Study < p> | Patient | Prograf | | CBIR | |
| Race | | | | |
| | No. of | Patients Who | No. of | Patients Who |
| | Patients | Developed | Patients | Developed |
| | At Risk | PTDM * | at Risk | 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 <5 day gap, |
| without a prior history of insulin dependent diabetes mellitus or |
| non insulin dependent diabetes mellitus. |
Insulin-dependent post-transplant diabetes mellitus was reported in 18% and
11% of Prograf-treated liver transplant patients and was reversible in 45% and 31% of these patients at one year post transplant, in the US and
European randomized studies, respectively (See Table below). Hyperglycemia was associated with the use of Prograf in 47% and 33% of liver transplant recipients in the US and European randomized studies, respectively, and may require treatment (see ADVERSE REACTIONS).
Incidence of Post Transplant Diabetes Mellitus and Insulin Use
at One Year in 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 of insulin for 30 or more consecutive days, with <5 day gap, without a prior history of insulin dependent diabetes mellitus or non insulin dependent diabetes mellitus.
** Patients without pretransplant history of diabetes mellitus.
Prograf can cause neurotoxicity and nephrotoxicity, particularly when usedin high doses. Nephrotoxicity was reported in approximately 52% of kidneytransplantation patients and in 40% and 36% of liver transplantationpatients receiving Prograf in the U.S. and European randomized trials,respectively (see ADVERSE REACTIONS). More overt nephrotoxicity is seenearly after transplantation, characterized by increasing serum creatinineand a decrease in urine output. Patients with impaired renal functionshould be monitored closely as the dosage of Prograf may need to bereduced. In patients with persistent elevations of serum creatinine who areunresponsive to dosage adjustments, consideration should be given tochanging to another immunosuppressive therapy. Care should be taken inusing tacrolimus with other nephrotoxic drugs. In particular, to avoidexcess nephrotoxicity, Prograf should not be used simultaneously withcyclosporine. Prograf or cyclosporine should be discontinued at least 24hours prior to initiating the other. In the presence of elevated Prograf orcyclosporine concentrations, dosing with the other drug usually should befurther delayed.
Mild to severe hyperkalemia was reported in 31% of kidney transplantrecipients and in 45% and 13% of liver transplant recipients treated with
Prograf in the U.S. and European randomized trials, respectively, and mayrequire treatment (see ADVERSE REACTIONS). Serum potassium levels should bemonitored and potassium-sparing diuretics should not be used during Prograftherapy (see PRECAUTIONS).
Neurotoxicity, including tremor, headache, and other changes in motorfunction, mental status, and sensory function were reported inapproximately 55% of liver transplant recipients in the two randomizedstudies. Tremor occurred more often in Prograf-treated kidney transplantpatients (54%) compared to cyclosporine-treated patients. The incidence ofother neurological events in kidney transplant patients was similar in thetwo treatment groups (see ADVERSE REACTIONS). Tremor and headache have beenassociated with high whole-blood concentrations of tacrolimus and mayrespond to dosage adjustment. Seizures have occurred in adult and pediatricpatients receiving Prograf (see ADVERSE REACTIONS). Coma and delirium alsohave been associated with high plasma concentrations of tacrolimus.
As in patients receiving other immunosuppressants, patients receiving
Prograf are at increased risk of developing lymphomas and othermalignancies, particularly of the skin. The risk appears to be related tothe intensity and duration of immunosuppression rather than to the use ofany specific agent. A lymphoproliferative disorder (LPD) related to Epstein-
Barr Virus (EBV) infection has been reported in immunosuppressed organtransplant recipients. The risk of LPD appears greatest in young childrenwho are at risk for primary EBV infection while immunosuppressed or who areswitched to Prograf following long-term immunosuppression therapy. Becauseof the danger of oversuppression of the immune system which can increasesusceptibility to infection, combination immunosuppressant therapy shouldbe used with caution.
A few patients receiving Prograf injection have experienced anaphylacticreactions. Although the exact cause of these reactions is not known, otherdrugs with castor oil derivatives in the formulation have been associatedwith anaphylaxis in a small percentage of patients. Because of thispotential risk of anaphylaxis, Prograf injection should be reserved forpatients who are unable to take Prograf capsules.
Patients receiving Prograf injection should be under continuous observationfor at least the first 30 minutes following the start of the infusion andat frequent intervals thereafter. If signs or symptoms of anaphylaxisoccur, the infusion should be stopped. An aqueous solution of epinephrineshould be available at the bedside as well as a source of oxygen.
PRECAUTIONS:
General
Hypertension is a common adverse effect of Prograf therapy (see ADVERSE
REACTIONS). Mild or moderate hypertension is more frequently reported thansevere hypertension. Antihypertensive therapy may be required; the controlof blood pressure can be accomplished with any of the commonantihypertensive agents. Since tacrolimus may cause hyperkalemia, potassium -sparing diuretics should be avoided. While calcium-channel blocking agentscan be effective in treating Prograf-associated hypertension, care shouldbe taken since interference with tacrolimus metabolism may require a dosagereduction (see Drug Interactions).
Renally and Hepatically Impaired Patients
For patients with renal insufficiency some evidence suggests that lowerdoses should be used (see CLINICAL PHARMACOLOGY and DOSAGE AND
ADMINISTRATION).
The use of Prograf in liver transplant recipients experiencing post -transplant hepatic impairment may be associated with increased risk ofdeveloping renal insufficiency related to high whole-blood levels oftacrolimus. These patients should be monitored closely and dosageadjustments should be considered. Some evidence suggests that lower dosesshould be used in these patients (see DOSAGE AND ADMINISTRATION).
Myocardial Hypertrophy
Myocardial hypertrophy has been reported in association with theadministration of Prograf, and is generally manifested byechocardiographically demonstrated concentric increases in left ventricularposterior wall and interventricular septum thickness. Hypertrophy has beenobserved in infants, children and adults. This condition appears reversiblein most cases following dose reduction or discontinuance of therapy. In agroup of 20 patients with pre-and post-treatment echocardiograms whoshowed evidence of myocardial hypertrophy, mean tacrolimus whole bloodconcentrations during the period prior to diagnosis of myocardialhypertrophy ranged from 11 to 53 ng/mL in infants (N = 10, age 0.4 to 2years), 4 to 46 ng/mL in children (N = 7, age 2 to 15 years) and 11 to 24ng/mL in adults (N = 3, age 37 to 53 years).
In patients who develop renal failure or clinical manifestations ofventricular dysfunction while receiving Prograf therapy, echocardiographicevaluation should be considered. If myocardial hypertrophy is diagnosed,dosage reduction or discontinuation of Prograf should be considered.
Information for Patients
Patients should 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 pregnancy, andinformed of the increased risk of neoplasia. Patients should be informedthat changes in dosage should not be undertaken without first consultingtheir physician.
Patients should 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
Serum creatinine, potassium, and fasting glucose should be assessedregularly. Routine monitoring of metabolic and hematologic systems shouldbe performed as clinically warranted.
Drug Interactions
Due to the potential for additive or synergistic impairment of renalfunction, care should be taken when administering Prograf with drugs thatmay be associated with renal dysfunction. These include, but are notlimited to, aminoglycosides, amphotericin B, and cisplatin. Initialclinical experience with the co-administration of Prograf and cyclosporineresulted in additive/synergistic nephrotoxicity. Patients switched fromcyclosporine to Prograf should receive the first Prograf dose no soonerthan 24 hours after the last cyclosporine dose. Dosing may be furtherdelayed in the presence of elevated cyclosporine levels.
Drugs That May Alter Tacrolimus Concentrations
Since tacrolimus is metabolized mainly by the CYP3A enzyme systems,substances known to inhibit these enzymes may decrease the metabolism orincrease bioavailability of tacrolimus as indicated by increased wholeblood or plasma concentrations. Drugs known to induce these enzyme systemsmay result in an increased metabolism of tacrolimus or decreasedbioavailability as indicated by decreased whole blood or plasmaconcentrations. Monitoring of blood concentrations and appropriate dosageadjustments are essential when such drugs are used concomitantly.
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 "|
| 657 "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 25ТАC (77ТАF); excursions permitted to 15ТАC-30ТАC (59ТАF-86ТАF). |
| Made in Japan |
Manufactured for:
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.http://www.fujisawa.com/medinfo/pi/pi_main_pg.htm
GENERIC NAME: tacrolimus
BRAND NAME: Prograf
DRUG CLASS AND MECHANISM: Tacrolimus is a drug that suppresses the immunesystem and is used to prevent rejection of transplanted organs. Tacrolimusaccomplishes its immune-suppressing effecting by inhibiting an enzyme
(calcineurin) crucial for the multiplication of T-cells, cells that arevital to the immune process. The use of oral tacrolimus allowstransplantation specialists to reduce the dose of steroids which are alsoused to prevent rejection. This "steroid-sparing effect" is importantbecause of the many side effects that can occur when larger doses ofsteroids are used for a long period of time. Tacrolimus was approved by the
FDA in April, 1994 for liver transplantation and also has been used inpatients for heart, kidney, small bowel, and bone marrow transplantation.
GENERIC AVAILABLE: No
PRESCRIPTION: Yes
PREPARATIONS: Tacrolimus is available as 1mg and 5mg capsules. It also isavailable for intravenous use.
STORAGE: Tacrolimus should be stored at room temperature between 15ТА and
30ТАC (59ТА and 86ТАF).
PRESCRIBED FOR: Tacrolimus is used for the prevention of rejection oftransplanted organs.
DOSING: Oral tacrolimus is taken twice daily. Doses vary widely and arebased on blood tests that measure the amount of tacrolimus in the body.
Taking tacrolimus with food can reduce some of the abdominal pain that canoccur with this medicine; however, food can reduce the amount of tacrolimusthat is absorbed. This is especially true with fatty foods. Thus,tacrolimus is best taken without food. If it must be taken with food, itshould be taken with non-fatty food.
DRUG INTERACTIONS: The destruction of tacrolimus by the body may beinhibited by a large number of drugs, resulting in higher blood levels oftacrolimus, and possibly 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), methylprednisolone (Medrol), nicardipine (Cardene),troleandomycin (Tao), and verapamil (Calan; Isoptin; Verelan; Covera-HS).
Grapefruit juice also may have a similar effect on tacrolimus and should beavoided.
Other drugs can stimulate the break-down of tacrolimus, decreasing itsblood concentration and possibly reducing its effectiveness. Such drugsinclude carbamazepine (Tegretol), nifedipine (Procardia; Adalat);phenobarbital, phenytoin (Dilantin), rifabutin, and rifampin, tacrolimus
Live virus vaccines should be avoided while receiving tacrolimus or anyother medicine that suppresses the immune system since the vaccines may beless effective.
Since tacrolimus can cause hyperkalemia (high potassium in the blood), theuse of tacrolimus with diuretics that also cause retention of potassium isnot recommended. Such diuretics include triamterene (found in Dyazide and
Maxzide), amiloride (found in Moduretic), and spironolactone (Aldactone).
Aluminum hydroxide, which is found in many antacids, binds tacrolimus inthe stomach. Aluminum-containing antacids should not be taken withtacrolimus.
PREGNANCY: Tacrolimus crosses the placenta, but there have been no adequatestudies in pregnant women to assess the effects on the fetus. Among womenwho have received tacrolimus while pregnant, high potassium levels andkidney injury in newborns have been reported. Therefore, tacrolimus shouldbe used during pregnancy only when it is clearly needed.
NURSING MOTHERS: Tacrolimus passes into breast milk. It is recommended thatbreast-feeding be discontinued while women are receiving oral tacrolimus.
SIDE EFFECTS: Tacrolimus is associated with many and various side effects.
These include baldness (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), highconcentrations of potassium in the blood (1 in 2), high blood presure (1 in
2), nausea (1 in 2), vomiting (1 in 4), tingling sensation in theextremities (2 in 5), itching (1 in 3), tremor (1 in 2), fever (1 in 2),headache (2 in 3), rash (1 in 4), high blood sugar concentrations (between
1 in 3 and 1 in 2), and abdominal pain (1in 4).
Other side effects may include confusion, painful joints, increasedsensitivity to light, blurred vision, insomnia, infection, jaundice
(yellowing of the skin due to effe
