Prograf Special Precautions

Hypertension: 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 Interactions).
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.
Gastrointestinal perforation: Gastrointestinal perforation has been reported in patients treated with tacrolimus, although all cases were considered a complication of transplant surgery or accompanied by infection, diverticulum, or malignant neoplasm. As gastrointestinal perforation is a medically important event that may lead to a life-threatening or serious condition, adequate treatments including surgery should be considered immediately after a suspect symptom occurs.
Thrombotic microangiopathy (TMA) (including haemolytic uraemic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP)): Thrombotic microangiopathies may have a multifactorial etiology. Risk factors for TMA that can occur in transplant patients include, for example, severe infections, graft-versus-host disease (GVHD), Human Leukocyte Antigen (HLA) mismatch, the use of calcineurin inhibitors, and mammalian target of rapamycin (mTOR) inhibitors. These risk factors may either alone or as a combination effect contribute to the risk of TMA.
Concurrent use of tacrolimus and mTOR inhibitors may contribute to the risk of TMA.
QT prolongation and Torsades de pointes: Tacrolimus may prolong the QT interval and may cause Torsades de pointes. Caution should be exercised in patients with risk factors for QT prolongation (including but not limited to, congenital or acquired QT prolongation, concomitant medications known to prolong the QT interval or known to increase tacrolimus exposure).
Patients with Lupus nephritis: Patients with lupus nephritis need special attention because the renal disorder may become aggravated as the lupus nephritis progresses.
Patients with lupus nephritis are more likely to suffer from hyperlipidemia or hypertension, etc., which are considered to be risk factors for the development of the coronary artery disease associated with systemic erythematosus, the underlying disease, patients being treated with Prograf should also receive appropriate therapy for these corollary diseases.
In patients with lupus nephritis, creatinine clearance decreased after 28 weeks of treatment. There are only a few results from clinical trials in patients with lupus nephritis lasting longer than 28 weeks, and therefore the long-term safety of this product has not been established.
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.
As with other immunosuppressive agents, owing to the potential risk of malignant skin changes, exposure to sunlight and ultraviolet (UV) light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.
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.
Others: Medication errors, including inadvertent, unintentional or unsupervised substitution of immediate- or prolonged-release tacrolimus formulations, have been observed. This has led to serious adverse reactions, including graft rejection, or other adverse reactions which could be a consequence of either under- or over-exposure to tacrolimus. Patients should be maintained on a single formulation of tacrolimus with the corresponding daily dosing regimen; alterations in formulation or regimen should only take place under the close supervision of a transplant specialist.
The combined administration of cyclosporine and tacrolimus should be avoided and care should be taken when administering tacrolimus to patients who have previously received cyclosporine.
Renally and Hepatically Impaired Patients: For patients with renal insufficiency some evidence suggests that lower doses should be used (see Pharmacology under Actions and Dosage & 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 & Administration).
Effects on Ability to Drive and Use Machines: Tacrolimus may cause visual and neurological disturbances. No studies on the effects of tacrolimus on the ability to drive and use machines have been performed.
Use in Children: Experience with Prograf in pediatric kidney transplant patients is limited. Successful liver transplants have been performed in pediatric patients (ages up to 16 years) using Prograf. The two randomized active-controlled trial of Prograf in primary liver transplantation included 56 pediatric patients. Thirty-one patients were randomized to Prograf-based and 25 to cyclosporine-based therapies. Additionally, a minimum of 122 pediatric patients were studied in an uncontrolled trial of tacrolimus in living related donor liver transplantation. Pediatric patients generally required higher doses of Prograf to maintain blood trough concentrations of tacrolimus similar to adult patients (see Dosage & Administration).
The safety of this product in pediatric patient has not been established in lupus nephritis (no clinical experiences in lupus nephritis).