|
Trough Concentrations
|Patient Population |Recommended |Typical Whole Blood Trough |
| |Initial |Concentrations |
| |Oral Dose* | |
|Adult kidney transplant |0.2 mg/kg/day |month 1-3 : 7-20 ng/mL |
|patients | |month 4-12 : 5-15 ng/mL |
|Adult liver transplant |0.10-0.15 |month 1-12 : 5-20 ng/mL |
|patients |mg/kg/day | |
|Pediatric liver |0.15-0.20 |month 1-12 : 5-20 ng/mL |
|transplant patients |mg/kg/day | |
*Note: two divided doses, q12h
Liver Transplantation
It is recommended that patients initiate oral therapy with Prograf capsules
if possible. If IV therapy is necessary, conversion from IV to oral Prograf
is recommended as soon as oral therapy can be tolerated. This usually
occurs within 2-3 days. The initial dose of Prograf should be administered
no sooner than 6 hours after transplantation. In a patient receiving an IV
infusion, the first dose of oral therapy should be given 8-12 hours after
discontinuing the IV infusion. The recommended starting oral dose of
Prograf capsules is 0.10-0.15 mg/kg/day administered in two divided daily
doses every 12 hours. Co-administered grapefruit juice has been reported to
increase tacrolimus blood trough concentrations in liver transplant
patients. (See Drugs That May Alter Tacrolimus Concentrations.)
Dosing should be titrated based on clinical assessments of rejection and
tolerability. Lower Prograf dosages may be sufficient as maintenance
therapy. Adjunct therapy with adrenal corticosteroids is recommended early
post transplant.
Dosage and typical tacrolimus whole blood trough concentrations are shown
in the table above; blood concentration details are described in Blood
Concentration Monitoring: Liver Transplantation below.
Kidney Transplantation
The recommended starting oral dose of Prograf is 0.2 mg/kg/day administered
every 12 hours in two divided doses. The initial dose of Prograf may be
administered within 24 hours of transplantation, but should be delayed
until renal function has recovered (as indicated for example by a serum
creatinine 10) may require lower doses of Prograf. Close
monitoring of blood concentrations is warranted.
Due to the potential for nephrotoxicity, patients with renal or hepatic
impairment should receive doses at the lowest value of the recommended IV
and oral dosing ranges. Further reductions in dose below these ranges may
be required. Prograf therapy usually should be delayed up to 48 hours or
longer in patients with post-operative oliguria.
Conversion from One Immunosuppressive Regimen to Another
Prograf should not be used simultaneously with cyclosporine. Prograf or
cyclosporine should be discontinued at least 24 hours before initiating the
other. In the presence of elevated Prograf or cyclosporine concentrations,
dosing with the other drug usually should be further delayed.
Blood Concentration Monitoring
Monitoring of tacrolimus blood concentrations in conjunction with other
laboratory and clinical parameters is considered an essential aid to
patient management for the evaluation of rejection, toxicity, dose
adjustments and compliance. Factors influencing frequency of monitoring
include but are not limited to hepatic or renal dysfunction, the addition
or discontinuation of potentially interacting drugs and the posttransplant
time. Blood concentration monitoring is not a replacement for renal and
liver function monitoring and tissue biopsies.
Two methods have been used for the assay of tacrolimus, a microparticle
enzyme immunoassay (MEIA) and an ELISA. Both methods have the same
monoclonal antibody for tacrolimus. Comparison of the concentrations in
published literature to patient concentrations using the current assays
must be made with detailed knowledge of the assay methods and biological
matrices employed. Whole blood is the matrix of choice and specimens should
be collected into tubes containing ethylene diamine tetraacetic acid (EDTA)
anti-coagulant. Heparin anti-coagulation is not recommended because of the
tendency to form clots on storage. Samples which are not analyzed
immediately should be stored at room temperature or in a refrigerator and
assayed within 7 days; if samples are to be kept longer they should be deep
frozen at -20° C for up to 12 months.
Liver Transplantation
Although there is a lack of direct correlation between tacrolimus
concentrations and drug efficacy, data from Phase II and III studies of
liver transplant patients have shown an increasing incidence of adverse
events with increasing trough blood concentrations. Most patients are
stable when trough whole blood concentrations are maintained between 5 to
20 ng/mL. Long term posttransplant patients often are maintained at the low
end of this target range.
Data from the U.S. clinical trial show that tacrolimus whole blood
concentrations, as measured by ELISA, were most variable during the first
week post-transplantation. After this early period, the median trough blood
concentrations, measured at intervals from the second week to one year post-
transplantation, ranged from 9.8 ng/mL to 19.4 ng/mL.
Therapeutic Drug Monitoring, 1995, Volume 17, Number 6 contains a consensus
document and several position papers regarding the therapeutic monitoring
of tacrolimus from the 1995 International Consensus Conference on
Immunosuppressive Drugs. Refer to these manuscripts for further discussions
of tacrolimus monitoring.
Kidney Transplantation
Data from the Phase III study indicates that trough concentrations of
tacrolimus in whole blood, as measured by IMx®, were most variable during
the first week of dosing. During the first three months, 80% of the
patients maintained trough concentrations between 7-20 ng/mL, and then
between 5-15 ng/mL, through one-year.
The relative risk of toxicity is increased with higher trough
concentrations. Therefore, monitoring of whole blood trough concentrations
is recommended 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 "|
|607" 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 "|
|607" 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 " 617" 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 " |
|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 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F). |
|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 altered
immunocompetence. 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 immune
system and is used to prevent rejection of transplanted organs. Tacrolimus
accomplishes its immune-suppressing effecting by inhibiting an enzyme
(calcineurin) crucial for the multiplication of T-cells, cells that are
vital to the immune process. The use of oral tacrolimus allows
transplantation specialists to reduce the dose of steroids which are also
used to prevent rejection. This "steroid-sparing effect" is important
because of the many side effects that can occur when larger doses of
steroids 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 in
patients 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 is
available for intravenous use.
STORAGE: Tacrolimus should be stored at room temperature between 15° and
30°C (59° and 86°F).
PRESCRIBED FOR: Tacrolimus is used for the prevention of rejection of
transplanted organs.
DOSING: Oral tacrolimus is taken twice daily. Doses vary widely and are
based on blood tests that measure the amount of tacrolimus in the body.
Taking tacrolimus with food can reduce some of the abdominal pain that can
occur with this medicine; however, food can reduce the amount of tacrolimus
that is absorbed. This is especially true with fatty foods. Thus,
tacrolimus is best taken without food. If it must be taken with food, it
should be taken with non-fatty food.
DRUG INTERACTIONS: The destruction of tacrolimus by the body may be
inhibited by a large number of drugs, resulting in higher blood levels of
tacrolimus, and possibly increasing its side effects. Such drugs include
bromocriptine (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 be
avoided.
Other drugs can stimulate the break-down of tacrolimus, decreasing its
blood concentration and possibly reducing its effectiveness. Such drugs
include carbamazepine (Tegretol), nifedipine (Procardia; Adalat);
phenobarbital, phenytoin (Dilantin), rifabutin, and rifampin,
tacrolimus
Live virus vaccines should be avoided while receiving tacrolimus or any
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