Tacrolimus Contraindications and Precautions
- breast-feeding
- ocular exposure
- polyoxyethylated castor oil hypersensitivity
- acute bronchospasm
- Black patients
- cardiac disease
- cardiomyopathy
- children
- diabetes mellitus
- electrolyte imbalance
- exfoliative dermatitis
- fungal infection
- heart failure
- hepatic disease
- herpes infection
- hyperglycemia
- hyperkalemia
- hypertension
- hypotension
- ichthyosis
- immunosuppression
- infants
- infection
- intravenous administration
- lymphoma
- mononucleosis
- neoplastic disease
- occlusive dressing
- oliguria
- pregnancy
- QT prolongation
- renal disease
- renal failure
- renal impairment
- seizure disorder
- seizures
- skin cancer
- sunlight (UV) exposure
- vaccination
- varicella
- viral infection
Tacrolimus Contraindications and Precautions
Only physicians experienced in immunosuppressant therapy and organ transplantation should use systemic tacrolimus. Patients initiating systemic tacrolimus therapy should be managed in facilities equipped and staffed with adequate laboratory and supportive medical services. Increased susceptibility to infection may occur with either systemic or topical use. Bacterial, viral, protozoal, and fungal infection occur commonly during immunosuppressive therapy and can be fatal. Reactivation of a latent viral infection, especially herpes infection, can occur with immunosuppressive therapy. Treatment with topical tacrolimus may be associated with an increased risk of varicella zoster infection (chickenpox or shingles) and herpes simplex infection. In the presence of these infections, the balance of risk and benefits associated with topical tacrolimus therapy should be evaluated. Patients should be instructed to report signs of infection promptly.
Immunosuppression from the use of tacrolimus (systemically or topically) may have an influence on the possible development of neoplastic disease, especially skin cancer, lymphoma, or other lymphoproliferative disorders (see Adverse Reactions). Protopic (tacrolimus) should only be prescribed as directed and only after other eczema treatments have failed due to a possible increase in the risk of neoplastic disease (cancer). The FDA has added a black box warning to the professional labeling and a Medication Guide for patients is under development. To date, there have been reports of cancer in three different animal species. The risk increased as the drug dosage increased. There have also been a small number of cancers reported in adult and pediatric patients using tacrolimus topical. The manufacturer will begin conducting research to determine the risk of cancers to humans. Patients who receive topical tacrolimus and develop a new or changed skin lesion or lymphadenopathy should have the lesion or etiology of their lymphadenopathy investigated due to the risk of cancer or lymphoproliferative disorders. In the absence of a clear etiology of the lymphadenopathy or in the presence of cancer or acute infectious mononucleosis, discontinuation of tacrolimus ointment should be considered. Tacrolimus ointment is not approved for use in children less than 2 years old. The long-term effect of tacrolimus ointment on the developing immune system in infants and children is not known.
Systemic tacrolimus therapy is associated with significant nephrotoxicity. Patients with preexisting renal disease or renal impairment should be carefully monitored for further deterioration in renal function while receiving tacrolimus. In renal transplant patients, tacrolimus therapy should be delayed up to 48 hours or longer in patients with post-operative oliguria or renal failure (i.e., serum creatinine >= 4 mg/dl). Monitor these patients carefully; lower tacrolimus doses may be warranted. In patients who develop renal failure while receiving tacrolimus, echocardiographic evaluation should be considered. Avoid concurrent use of nephrotoxic drugs, especially cyclosporine (see Drug Interactions). Whole blood levels of tacrolimus should be monitored frequently in these patients.
Patients with hepatic disease or impairment and those receiving other drugs that may affect the metabolism of tacrolimus (see Drug Interactions) are at risk tacrolimus toxicity. In patients with severe hepatic dysfunction (Pugh score > 10), the mean clearance of tacrolimus is substantially lower, irrespective of the route of administration, compared to normal volunteers or patients with mild hepatic dysfunction (mean Pugh score 6.2). Use of tacrolimus in liver transplant patients experiencing post-transplant hepatic impairment may be associated with increased risk of developing renal insufficiency related to high whole blood levels of tacrolimus.
Systemic tacrolimus should be used cautiously in patients with pre-existing hypertension. Tacrolimus therapy is associated with mild or moderate hypertension, but can also cause severe hypertension. Antihypertensive therapy may be required. Potassium-sparing diuretics should be avoided since tacrolimus can cause hyperkalemia. Additionally, use calcium-channel blockers cautiously because some may interfere with tacrolimus metabolism (see Drug Interactions). To prevent electrolyte imbalance, serum potassium as well as other serum electrolytes should be monitored during tacrolimus therapy.
Use systemic tacrolimus cautiously in patients with pre-existing cardiomyopathy or other cardiac disease associated with left ventricular dysfunction (e.g., heart failure). Tacrolimus-induced myocardial hypertrophy has been reported in infants, children, and adults and appears to be 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, echocardiographic evaluation should be considered. If myocardial hypertrophy is diagnosed, dosage reduction or discontinuation of tacrolimus should be considered. Although causality has not been established, a few case reports of QT prolongation and torsade de pointes have been reported during therapy with tacrolimus. Until further data are available, use tacrolimus with caution in patients at risk for QT prolongation (e.g., congenital long QT syndrome).
High blood levels of tacrolimus are associated with neurotoxicity including seizures. Tacrolimus whole blood levels should be carefully monitored in patients with a seizure disorder, especially in patients with concurrent renal or hepatic dysfunction.
Insulin-dependent post-transplant diabetes mellitus has been reported in tacrolimus-treated renal transplant patients. Black patients and Hispanic patients post-renal transplant were at an increased risk of development of post-transplant diabetes mellitus. The risk of development of post-transplant diabetes mellitus increased with increasing whole blood trough concentrations of tacrolimus and increasing doses of corticosteroids. Patients with pre-existing hyperglycemia may require alterations in hypoglycemic therapy.
The intravenous formulation of tacrolimus contains polyoxyl 60 hydrogenated castor oil, and it should be avoided in patients with polyoxyethylated castor oil hypersensitivity because anaphylaxis can occur during intravenous administration of tacrolimus. Patients should be under constant observation for at least the first 30 minutes following the start of the infusion and at frequent intervals thereafter. If signs and symptoms of anaphylaxis occur (e.g., acute bronchospasm or hypotension), the infusion should be stopped.
Tacrolimus is classified as FDA pregnancy risk category C. Tacrolimus crosses the placenta and passes into breast milk. Adequate studies in pregnant women have not been conducted, but use of tacrolimus in during pregnancy has been associated with neonatal hyperkalemia and renal dysfunction. The experience with topical tacrolimus in pregnant women is too limited to permit assessment of safety of its use during pregnancy. Tacrolimus should be used during pregnancy only when clearly needed. Breast-feeding should be discontinued while patients are receiving tacrolimus.
Patients receiving any vaccination during immunosuppressive therapy or in the 2 weeks prior to starting systemic therapy should be considered unimmunized and should be revaccinated at least 3 months after discontinuation of therapy. Those undergoing immunosuppressive therapy should not be exposed to others who have recently received the oral poliovirus vaccine (OPV). Measles-mumps-rubella (MMR) vaccination is not contraindicated for the close contacts of immunocompromised patients, including health care professionals. Passive immunoprophylaxis with immune globulins may be indicated for immunocompromised persons instead of or in addition to vaccination. When exposed to a vaccine-preventable disease such as measles, severely immunocompromised children should be considered susceptible regardless of their vaccination history.
Patients should minimize or avoid phototherapy or sunlight (UV) exposure (natural or artificial) during topical tacrolimus therapy. Despite the absence of observed phototoxicity in humans, tacrolimus ointment shortened the time to skin tumor formation in an animal photocarcinogenicity study.
Tacrolimus ointment is for dermatologic use only. Avoid ocular exposure of tacrolimus ointment. Avoid use of any occlusive dressing. The safety of tacrolimus ointment has not been established with occlusive dressings, which may increase the systemic absorption of tacrolimus.
The safety of tacrolimus ointment has not been established for patients with generalized erythroderma, a widespread reddening of the skin often associated with exfoliative dermatitis. The use of tacrolimus ointment in those with ichthyosis, specifically Netherton’s syndrome (congenital ichthyosiform erythroderma), is not recommended due to the potential for increased systemic absorption of tacrolimus.
[ Last revised: 3/12/2005 3:04:00 PM ]
References
. Hodak SP, Moubarak JB, Rodriguez I, et al. QT Prolongation and near fatal cardiac arrhythmia after intravenous tacrolimus administration: a case report. Transplantation 1998;66:535 - 7.
. Johnson MC, So S, Marsh JW, et al. QT prolongation and Torsades de Pointes after administration of FK506. Transplantation 1992;53:929 - 30.
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