Tacrograf Special Precautions

Management: Only health care providers experienced in immunosuppressive therapy and management of organ transplant patients should prescribe tacrolimus. Manage patients receiving the drug in facilities equipped and staffed with adequate laboratory and supportive medical resources. The health care provider responsible for maintenance therapy should have complete information requisite for the follow-up of the patient.
Based on immunosuppressive effects of tacrolimus, inhalation or direct contact with skin or mucous membrane of powder contained in tacrolimus products should be avoided. If such contact occurs, wash the skin and eyes.
Lymphomas and other malignancies: Patients receiving tacrolimus are at an 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.
As usual for patients with increased risk of skin cancer, exposure to sunlight and ultraviolet (UV) light should be avoided or limited by wearing protective clothing and using a sunscreen with a high protection factor.
Post-transplant lymphoproliferative disorder (PTLD) has been reported in immunosuppressed organ transplant recipients. The majority of PTLD events appear related to Epstein-Barr virus (EBV) infection. The risk of PTLD appears greatest in those individuals who are EBV seronegative, a population that includes many young children.
Infections: Immunosuppressant agents, including tacrolimus, increase the risk of infection; the risk of developing bacterial, viral (including cytomegalovirus (CMV)), fungal, and protozoal infections, including opportunistic infections, is increased. Infections may result in serious and fatal outcomes. Latent viral infections may be activated, including BK virus (associated with polyomavirus-associated nephropathy (PVAN)) and JC virus (associated with progressive multifocal leukoencephalopathy (PML)); may result in serious adverse effects. Immunosuppression increases the risk for CMV viremia and/or CMV disease; the risk of CMV disease is increased for patients who are CMV-seronegative prior to transplant and receive a graft from a CMV-seropositive donor. Monitor for development of infection; consider reduction in immunosuppression if PVAN, PML, CMV viremia and/or CMV disease occurs.
Medication errors: Tacrolimus ER is not interchangeable or substitutable with tacrolimus immediate release. Medication and dispensing errors, including inadvertent or unintentional substitution between tacrolimus immediate release and ER, have been observed. This has led to serious adverse events, including graft rejection, or other adverse reactions, which could be a consequence of either under or overexposure to tacrolimus.
New-onset diabetes: Tacrolimus caused new-onset diabetes mellitus after kidney and liver transplantation. New-onset diabetes after transplantation may be reversible in some patients. Black and Hispanic kidney transplant patients are at an increased risk. Closely monitor blood glucose concentrations in patients using tacrolimus.
Nephrotoxicity: Tacrolimus can cause acute or chronic nephrotoxicity, particularly when used in high doses. Acute nephrotoxicity is most often related to vasoconstriction of the afferent renal arteriole, is characterized by increasing serum creatinine, hyperkalemia, and/or a decrease in urine output, and is typically reversible. Chronic calcineurin-inhibitor nephrotoxicity is associated with increased serum creatinine, decreased kidney graft life, and characteristic histologic changes observed on renal biopsy; the changes associated with chronic calcineurin-inhibitor nephrotoxicity are typically progressive. Closely monitor patients with impaired renal function because the dosage of tacrolimus may need to be reduced. In patients with persistent elevations of serum creatinine who are unresponsive to dosage adjustments, consider changing to another immunosuppressive therapy.
Based on reported adverse reactions terms related to decreased renal function, nephrotoxicity was reported in approximately 52% of kidney transplantation patients and in 40% and 36% of liver transplantation patients receiving tacrolimus in the US and European randomized trials, respectively.
Due to the potential for additive or synergistic impairment of renal function, take care when administering tacrolimus with drugs that may be associated with renal dysfunction. Similarly, exercise care when administering with CYP3A4 inhibitors that will result in increased tacrolimus whole blood concentrations due to inhibition of tacrolimus metabolism. (See Interactions).
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, seizure, 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, maintain blood pressure control; 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.
Less severe neurotoxicities include tremors, paresthesia, headache, and other changes in motor function, mental status, and sensory function. Tremor and headache have been associated with high whole blood concentrations of tacrolimus and may respond to dosage adjustment.
Hyperkalemia: Hyperkalemia has been reported. Monitor serum potassium levels. Give careful consideration prior to use of other agents also associated with hyperkalemia (e.g., potassium-sparing diuretics, angiotensin-converting enzyme inhibitors (ACEIs), angiotensin-receptor blockers (ARBs)) during tacrolimus therapy.
Hypertension: Hypertension is a common adverse reaction, and antihypertensive therapy may be required. The control of blood pressure can be accomplished with any of the common antihypertensive agents, though give careful consideration prior to use of antihypertensive agents associated with hyperkalemia (e.g., potassium-sparing diuretics, ACE inhibitors, angiotensin-receptor blockers).
Calcium channel blocking agents may increase tacrolimus blood concentrations and, therefore, require dosage reduction of tacrolimus.
QT prolongation: Prolongation of the QT/QTc interval and torsade de pointes may occur; avoid use in patients with congenital long QT syndrome. In patients with congestive heart failure, bradyarrhythmias, those taking certain antiarrhythmic medications or other medicinal products that lead to QT prolongation, and those with electrolyte disturbances such as hypokalemia, hypocalcemia, or hypomagnesemia, consider obtaining electrocardiograms and monitoring electrolytes (magnesium, potassium, calcium) periodically during treatment.
Myocardial hypertrophy: Myocardial hypertrophy has been reported in infants, children, and adults, particularly those with high tacrolimus trough concentrations, and is generally manifested by echocardiographically demonstrated concentric increases in left ventricular posterior wall and interventricular septum thickness. This condition appears reversible in most cases following dose reduction or discontinuance of therapy. In patients who develop renal failure or clinical manifestations of ventricular dysfunction while receiving tacrolimus, consider echocardiographic evaluation. If myocardial hypertrophy is diagnosed, consider dosage reduction or discontinuation of tacrolimus.
Vaccinations: Patients should be brought up to date with all immunizations before initiating therapy. Patients should not be immunized with live vaccines during or shortly after treatment and should avoid close contact with recently vaccinated (live vaccine) individuals. Inactivated vaccines may be administered (response may be diminished).
Pure red cell aplasia (PRCA): Cases of pure red cell aplasia (PRCA) have been reported. A mechanism for tacrolimus induced PRCA has not been elucidated. All patients reported risk factors for PRCA, such as parvovirus B19 infection, underlying disease, or concomitant medications associated with PRCA. If PRCA is diagnosed, consider discontinuation of tacrolimus.
Gastrointestinal (Gl) perforation: GI perforation may occur, all reported cases were considered to be a complication of transplant surgery or accompanied by infection, diverticulum, or malignant neoplasm. GI perforation may be serious or life-threatening, promptly institute appropriate medical/surgical management.
Hypersensitivity reactions: Hypersensitivity symptoms reported include dyspnea, rash, pruritus, and acute respiratory distress syndrome.
Renal function impairment: Consider dosing tacrolimus at the lower end of the therapeutic dosing range in patients who have received a liver transplant and have pre-existing renal impairment. Further reductions in dose below the targeted range may be required.
Hepatic function impairment: Close monitoring of tacrolimus trough concentrations is warranted in patients with hepatic impairment.
Monitoring: The relative risk of toxicity and efficacy failure are related to tacrolimus whole blood trough concentrations. Therefore, monitoring of whole blood trough concentration is recommended to assist in the clinical evaluation of toxicity and efficacy failure. (See also Therapeutic drug monitoring under Dosage & Administration).
Assess blood pressure, serum creatinine, electrolytes (magnesium, potassium, calcium), and blood glucose regularly.
Closely monitor patients with impaired renal function and/or hepatic impairment. Monitor patients for QT prolongation and consider electrocardiographic evaluation in patients who develop renal failure, electrolyte abnormalities, or clinical manifestations of ventricular dysfunction.
Use in Children: The safety and efficacy of tacrolimus in pediatric kidney transplant patients have not been established. Successful liver transplants have been performed in pediatric patients (up to 16 years) using tacrolimus. Pediatric patients generally required higher doses of tacrolimus to maintain blood trough concentration of tacrolimus similar to those of adult patients.
Use in the Elderly: Use with caution.