5.8 Neurotoxicity
Tacrolimus may cause a spectrum of neurotoxicities, particularly when used in high doses. The most severe neurotoxicities include posterior reversible encephalopathy syndrome (PRES), delirium, and coma. Patients treated with Tacrolimus have been reported to develop 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.

Coma and delirium, in the absence of PRES, have also been associated with high plasma concentrations of Tacrolimus. Seizures have occurred in adult and pediatric patients receiving Tacrolimus [see AdverseReactions (6.1)].

Less severe neurotoxicities, include tremors, parathesias, headache, and other changes in motor function, mental status, and sensory function [see Adverse Reactions (6.1)]. Tremor and headache have been associated with high whole-blood concentrations of Tacrolimus and may respond to dosage adjustment.

5.9 Hyperkalemia
Hyperkalemia has been reported with Tacrolimus use. Serum potassium levels should be monitored. Careful consideration should be given prior to use of other agents also associated with hyperkalemia (e.g., potassium-sparing diuretics, ACE inhibitors, angiotensin receptor blockers) during Tacrolimus therapy[see Adverse Reactions (6.1)].

5.10 Hypertension
Hypertension is a common adverse effect of Tacrolimus therapy and may require antihypertensive therapy [see Adverse Reactions (6.1)]. The control of blood pressure can be accomplished with any of the common antihypertensive agents, though careful consideration should be given prior to use of antihypertensive agents associated with hyperkalemia (e.g., potassium-sparing diuretics, ACE inhibitors, angiotensin receptor blockers) [see Warnings and Precautions (5.9)].

Calcium-channel blocking agents may increase Tacrolimus blood concentrations and therefore require dosage reduction of Tacrolimus [see Drug Interactions (7.5)].

5.11 Anaphylactic Reactions with Tacrolimus Injection
Anaphylactic reactions have occurred with injectables containing castor oil derivatives, including Tacrolimus, in a small percentage of patients (0.6%). The exact cause of these reactions is not known. Tacrolimus injection should be reserved for patients who are unable to take Tacrolimus capsules.

Patients receiving Tacrolimus 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.

5.12 Use with Sirolimus
The safety and efficacy of Tacrolimus with sirolimus has not been established in kidney transplant patients.

Use of sirolimus with Tacrolimus in studies of de novo liver transplant patients was associated with an excess mortality, graft loss, and hepatic artery thrombosis (HAT) and is not recommended [see Indi