| | | |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 used
in high doses. Nephrotoxicity was reported in approximately 52% of kidney
transplantation patients and in 40% and 36% of liver transplantation
patients receiving Prograf in the U.S. and European randomized trials,
respectively (see ADVERSE REACTIONS). More overt nephrotoxicity is seen
early after transplantation, characterized by increasing serum creatinine
and a decrease in urine output. Patients with impaired renal function
should be monitored closely as the dosage of Prograf may need to be
reduced. In patients with persistent elevations of serum creatinine who are
unresponsive to dosage adjustments, consideration should be given to
changing to another immunosuppressive therapy. Care should be taken in
using tacrolimus with other nephrotoxic drugs. In particular, to avoid
excess nephrotoxicity, Prograf should not be used simultaneously with
cyclosporine. Prograf or cyclosporine should be discontinued at least 24
hours prior to initiating the other. In the presence of elevated Prograf or
cyclosporine concentrations, dosing with the other drug usually should be
further delayed.
Mild to severe hyperkalemia was reported in 31% of kidney transplant
recipients and in 45% and 13% of liver transplant recipients treated with
Prograf in the U.S. and European randomized trials, respectively, and may
require treatment (see ADVERSE REACTIONS). Serum potassium levels should be
monitored and potassium-sparing diuretics should not be used during Prograf
therapy (see PRECAUTIONS).
Neurotoxicity, including tremor, headache, and other changes in motor
function, mental status, and sensory function were reported in
approximately 55% of liver transplant recipients in the two randomized
studies. Tremor occurred more often in Prograf-treated kidney transplant
patients (54%) compared to cyclosporine-treated patients. The incidence of
other neurological events in kidney transplant patients was similar in the
two treatment groups (see ADVERSE REACTIONS). Tremor and headache have been
associated with high whole-blood concentrations of tacrolimus and may
respond to dosage adjustment. Seizures have occurred in adult and pediatric
patients receiving Prograf (see ADVERSE REACTIONS). Coma and delirium also
have 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 other
malignancies, particularly of the skin. The risk appears to be related to
the intensity and duration of immunosuppression rather than to the use of
any specific agent. A lymphoproliferative disorder (LPD) related to Epstein-
Barr Virus (EBV) infection has been reported in immunosuppressed organ
transplant recipients. The risk of LPD appears greatest in young children
who are at risk for primary EBV infection while immunosuppressed or who are
switched to Prograf following long-term immunosuppression therapy. Because
of the danger of oversuppression of the immune system which can increase
susceptibility to infection, combination immunosuppressant therapy should
be used with caution.
A few patients receiving Prograf injection have experienced anaphylactic
reactions. Although the exact cause of these reactions is not known, other
drugs with castor oil derivatives in the formulation have been associated
with anaphylaxis in a small percentage of patients. Because of this
potential risk of anaphylaxis, Prograf injection should be reserved for
patients who are unable to take Prograf capsules.
Patients receiving Prograf injection should be under continuous observation
for at least the first 30 minutes following the start of the infusion and
at frequent intervals thereafter. If signs or symptoms of anaphylaxis
occur, the infusion should be stopped. An aqueous solution of epinephrine
should 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 than
severe hypertension. Antihypertensive therapy may be required; the control
of blood pressure can be accomplished with any of the common
antihypertensive agents. Since tacrolimus may cause hyperkalemia, potassium-
sparing diuretics should be avoided. While calcium-channel blocking agents
can be effective in treating Prograf-associated hypertension, care should
be taken since interference with tacrolimus metabolism may require a dosage
reduction (see Drug Interactions).
Renally and Hepatically Impaired Patients
For patients with renal insufficiency some evidence suggests that lower
doses 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 of
developing renal insufficiency related to high whole-blood levels of
tacrolimus. These patients should be monitored closely and dosage
adjustments should be considered. Some evidence suggests that lower doses
should be used in these patients (see DOSAGE AND ADMINISTRATION).
Myocardial Hypertrophy
Myocardial hypertrophy has been reported in association with the
administration of Prograf, and is generally manifested by
echocardiographically demonstrated concentric increases in left ventricular
posterior wall and interventricular septum thickness. Hypertrophy has been
observed in infants, children and adults. This condition appears reversible
in most cases following dose reduction or discontinuance of therapy. In a
group of 20 patients with pre- and post-treatment echocardiograms who
showed evidence of myocardial hypertrophy, mean tacrolimus whole blood
concentrations during the period prior to diagnosis of myocardial
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 15 years) and 11 to 24
ng/mL in adults (N=3, age 37 to 53 years).
In patients who develop renal failure or clinical manifestations of
ventricular dysfunction while receiving Prograf therapy, echocardiographic
evaluation 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 laboratory
tests while they are receiving Prograf. They should be given complete
dosage instructions, advised of the potential risks during pregnancy, and
informed of the increased risk of neoplasia. Patients should be informed
that changes in dosage should not be undertaken without first consulting
their physician.
Patients should be informed that Prograf can cause diabetes mellitus and
should be advised of the need to see their physician if they develop
frequent urination, increased thirst or hunger.
Laboratory Tests
Serum creatinine, potassium, and fasting glucose should be assessed
regularly. Routine monitoring of metabolic and hematologic systems should
be performed as clinically warranted.
Drug Interactions
Due to the potential for additive or synergistic impairment of renal
function, care should be taken when administering Prograf with drugs that
may be associated with renal dysfunction. These include, but are not
limited to, aminoglycosides, amphotericin B, and cisplatin. Initial
clinical experience with the co-administration of Prograf and cyclosporine
resulted in additive/synergistic nephrotoxicity. Patients switched from
cyclosporine to Prograf should receive the first Prograf dose no sooner
than 24 hours after the last cyclosporine dose. Dosing may be further
delayed 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 or
increase bioavailability of tacrolimus as indicated by increased whole
blood or plasma concentrations. Drugs known to induce these enzyme systems
may result in an increased metabolism of tacrolimus or decreased
bioavailability as indicated by decreased whole blood or plasma
concentrations. Monitoring of blood concentrations and appropriate dosage
adjustments are essential when such drugs are used concomitantly.
|*Drugs That | | | | |
|May Increase | | | | |
|Tacrolimus | | | | |
|Blood | | | | |
|Concentration| | | | |
|s: | | | | |
|Calcium | |Antifungal | |Macrolide |
|Channel | |Agents | |Antibiotics |
|Blockers | | | | |
|diltiazem | |clotrimazole | |clarithromyci|
| | | | |n |
|nicardipine | |fluconazole | |erythromycin |
|nifedipine | |itraconazole | |troleandomyci|
| | | | |n |
|verapamil | |ketoconazole | | |
| | | | | |
|Gastrointesti| |Other | | |
|nal | |Drugs | | |
|Prokinetic | | | | |
|Agents | | | | |
|cisapride | |bromocriptine| | |
|metoclopramid| |cimetidine | | |
|e | | | | |
| | |cyclosporine | | |
| | |danazol | | |
| | |ethinyl | | |
| | |estradiol | | |
| | |methylprednis| | |
| | |olone | | |
| | |omeprazole | | |
| | |protease | | |
| | |inhibitors | | |
| | |nefazodone | | |
| | | | | |
|In a study of| | | | |
|6 normal | | | | |
|volunteers, a| | | | |
|significant | | | | |
|increase in | | | | |
|tacrolimus | | | | |
|oral | | | | |
|bioavailabili| | | | |
|ty (14±5% vs.| | | | |
|30±8%) was | | | | |
|observed with| | | | |
|concomitant | | | | |
|ketoconazole | | | | |
|administratio| | | | |
|n (200 mg). | | | | |
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