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|
|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). | | | | |
|The apparent | | | | |
|clearance of | | | | |
|during | | | | |
|n was | | | | |
|significantly| | | | |
|decreased | | | | |
|compared to | | | | |
|alone | | | | |
|(0.430±0.129L| | | | |
|/hr/kg vs. | | | | |
|0.148±0.043L/| | | | |
|hr/kg). | | | | |
|Overall, IV | | | | |
|was not | | | | |
|changed by | | | | |
|co-administra| | | | |
|tion, | | | | |
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