Prograf: Package Insert and Label Information (Page 4 of 7)

Hyperkalemia

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 in 8% of heart transplant recipients in a European randomized trial 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

Prograf can cause neurotoxicity, particularly when used in high doses. 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%) and heart transplant patients (15%) compared to cyclosporine-treated patients. The incidence of other neurological events in kidney transplant and heart 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.

Patients treated with tacrolimus have been reported to develop posterior reversible encephalopathy syndrome (PRES). Symptoms indicating PRES include headache, altered mental status, seizures, visual disturbances and hypertension. Diagnosis may be confirmed by radiological procedure. If PRES is suspected or diagnosed, blood pressure control should be maintained and immediate reduction of immunosuppression is advised. This syndrome is characterized by reversal of symptoms upon reduction or discontinuation of immunosuppression.

Malignancy and Lymphoproliferative Disorders

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.

Latent Viral Infections

Immunosuppressed patients are at increased risk for opportunistic infections, including activation of latent viral infections. These include BK virus associated nephropathy and JC virus associated progressive multifocal leukoencephalopathy (PML) which have been observed in patients receiving tacrolimus. These infections may lead to serious, including fatal, outcomes.

Prograf in Combination with Sirolimus

The use of full-dose Prograf with sirolimus (2 mg per day) in heart transplant recipients was associated with increased risk of wound healing complications, renal function impairment, and insulin-dependent post-transplant diabetes mellitus, and is not recommended (see CLINICAL STUDIES).

Anaphylactic Reactions

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.

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.

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 Concentrations
*
This table is not all inclusive.
In a study of 6 normal volunteers, a significant increase in tacrolimus oral bioavailability (14±5% vs. 30±8%) was observed with concomitant ketoconazole administration (200 mg). The apparent oral clearance of tacrolimus during ketoconazole administration was significantly decreased compared to tacrolimus alone (0.430±0.129 L/hr/kg vs. 0.148±0.043 L/hr/kg). Overall, IV clearance of tacrolimus was not significantly changed by ketoconazole co-administration, although it was highly variable between patients.
Lansoprazole (CYP2C19, CYP3A4 substrate) may potentially inhibit CYP3A4-mediated metabolism of tacrolimus and thereby substantially increase tacrolimus whole blood concentrations, especially in transplant patients who are intermediate or poor CYP2C19 metabolizers, as compared to those patients who are efficient CYP2C19 metabolizers.

Calcium

Channel Blockers

Antifungal

Agents

Macrolide

Antibiotics
diltiazem clotrimazole clarithromycin
nicardipine fluconazole erythromycin
nifedipine itraconazole troleandomycin
verapamil ketoconazole
voriconazole
Gastrointestinal Prokinetic Agents

Other

Drugs
cisapride bromocriptine
metoclopramide chloramphenicol
cimetidine
cyclosporine
danazol
ethinyl estradiol
methylprednisolone
lansoprazole
omeprazole
protease inhibitors
nefazodone
magnesium-aluminum-hydroxide
*Drugs That May Decrease Tacrolimus Blood Concentrations
*
This table is not all inclusive.
Anticonvulsants Antimicrobials
carbamazepine rifabutin
phenobarbital caspofungin
phenytoin rifampin
Herbal Preparations Other Drugs
St. John’s Wort sirolimus

St. John’s Wort (Hypericum perforatum) induces CYP3A4 and P-glycoprotein. Since tacrolimus is a substrate for CYP3A4, there is the potential that the use of St. John’s Wort in patients receiving Prograf could result in reduced tacrolimus levels.

In a single-dose crossover study in healthy volunteers, co-administration of tacrolimus and magnesium-aluminum-hydroxide resulted in a 21% increase in the mean tacrolimus AUC and a 10% decrease in the mean tacrolimus Cmax relative to tacrolimus administration alone.

In a study of 6 normal volunteers, a significant decrease in tacrolimus oral bioavailability (14±6% vs. 7±3%) was observed with concomitant rifampin administration (600 mg). In addition, there was a significant increase in tacrolimus clearance (0.036±0.008 L/hr/kg vs. 0.053±0.010 L/hr/kg) with concomitant rifampin administration.

Interaction studies with drugs used in HIV therapy have not been conducted. However, care should be exercised when drugs that are nephrotoxic (e.g., ganciclovir) or that are metabolized by CYP3A (e.g., nelfinavir, ritonavir) are administered concomitantly with tacrolimus. Based on a clinical study of 5 liver transplant recipients, co-administration of tacrolimus with nelfinavir increased blood concentrations of tacrolimus significantly and, as a result, a reduction in the tacrolimus dose by an average of 16-fold was needed to maintain mean trough tacrolimus blood concentrations of 9.7 ng/mL. Thus, frequent monitoring of tacrolimus blood concentrations and appropriate dosage adjustments are essential when nelfinavir is used concomitantly. Tacrolimus may affect the pharmacokinetics of other drugs (e.g., phenytoin) and increase their concentration. Grapefruit juice affects CYP3A-mediated metabolism and should be avoided (see DOSAGE AND ADMINISTRATION).

Following co-administration of tacrolimus and sirolimus (2 or 5 mg/day) in stable renal transplant patients, mean tacrolimus AUC0-12 and Cmin decreased approximately by 30% relative to tacrolimus alone. Mean tacrolimus AUC0-12 and Cmin following co-administration of 1 mg/day of sirolimus decreased approximately 3% and 11%, respectively. The safety and efficacy of tacrolimus used in combination with sirolimus for the prevention of graft rejection has not been established and is not recommended.

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