associated with clinically manifested ventricular dysfunction in patients
receiving Prograf therapy (see PRECAUTIONS-Myocardial Hypertrophy).
Post Marketing
The following have been reported: increased amylase including pancreatitis,
hearing loss including deafness, leukoencephalopathy, thrombocytopenic
purpura, hemolytic-uremia syndrome, acute renal failure, Stevens-Johnson
syndrome, stomach ulcer, glycosuria, cardiac arrhythmia and
gastroenteritis.
OVERDOSAGE:
Limited overdosage experience is available. Acute overdosages of up to 30
times the intended dose have been reported. Almost all cases have been
asymptomatic and all patients recovered with no sequelae. Occasionally,
acute overdosage has been followed by adverse reactions consistent with
those listed in the ADVERSE REACTIONS section except in one case where
transient urticaria and lethargy were observed. Based on the poor aqueous
solubility and extensive erythrocyte and plasma protein binding, it is
anticipated that tacrolimus is not dialyzable to any significant extent;
there is no experience with charcoal hemoperfusion. The oral use of
activated charcoal has been reported in treating acute overdoses, but
experience has not been sufficient to warrant recommending its use. General
supportive measures and treatment of specific symptoms should be followed
in all cases of overdosage.
In acute oral and IV toxicity studies, mortalities were seen at or above
the following 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 area corrections).
DOSAGE AND ADMINISTRATION:
Prograf injection (tacrolimus injection)
For IV Infusion Only
NOTE: Anaphylactic reactions have occurred with injectables containing
castor oil derivatives. See WARNINGS.
In patients unable to take oral Prograf capsules, therapy may be initiated
with Prograf injection. The initial dose of Prograf should be administered
no sooner than 6 hours after transplantation. The recommended starting dose
of Prograf injection is 0.03-0.05 mg/kg/day as a continuous IV infusion.
Adult patients should receive doses at the lower end of the dosing range.
Concomitant adrenal corticosteroid therapy is recommended early post-
transplantation. Continuous IV infusion of Prograf injection should be
continued only until the patient can tolerate oral administration of
Prograf capsules.
Preparation for Administration/Stability
Prograf injection must be diluted with 0.9% Sodium Chloride Injection or 5%
Dextrose Injection to a concentration between 0.004 mg/mL and 0.02 mg/mL
prior to use. Diluted infusion solution should be stored in glass or
polyethylene containers and should be discarded after 24 hours. The diluted
infusion solution should not be stored in a PVC container due to decreased
stability and the potential for extraction of phthalates. In situations
where more dilute solutions are utilized (e.g., pediatric dosing, etc.),
PVC-free tubing should likewise be used to minimize the potential for
significant drug adsorption onto the tubing. Parenteral drug products
should be inspected visually for particulate matter and discoloration prior
to administration, whenever solution and container permit. Due to the
chemical instability of tacrolimus in alkaline media, Prograf injection
should not be mixed or co-infused with solutions of pH 9 or greater (e.g.,
ganciclovir or acyclovir).
Prograf capsules (tacrolimus capsules)
Summary of Initial Oral Dosage Recommendations and Typical Whole Blood
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.
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.
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.
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