Medication Guide App

Tacrolimus (Systemic)



JAN:

Tacrolimus Hydrate.

VA CLASSIFICATION
Primary: IM403

Commonly used brand name(s): Prograf.


Another commonly used name is FK 506.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Immunosuppressant—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Transplant rejection, solid organ (prophylaxis)— Tacrolimus is useful for the prevention of rejection of transplanted [heart]1 {14} {15} {16} {17} {18} {19} {267}, kidney1 {56} {57} {58} {59} {60} {61} {62} {63} {64} {65} {66} {67} {68} {69} {70} {71} {72} {73} {74} {75} {277} {278}, liver {01} {02} {22} {24} {25} {26} {27} {28} {29} {30} {32} {33} {34} {35} {36} {37} {38} {39} {40} {41} {268} {269} {270} {271}, [lung]1 {42} {43} {44} {45} {275} {276}, [pancreas]1 {46} {47} {48} {49} {50} {51} {52} {53} {54} {55} {279}, and [ small bowel]1 {03} {04} {05} {06} {07} {08} {09} {10} {13} {265} {266} allografts.

[Transplant rejection, solid organ (treatment)]—Tacrolimus is useful for the treatment of rejection of transplanted heart1 {14} {15} {16} {17} {18} {19} {76} {267}, kidney1 {98} {99} {100} {101} {102} {103} {104} {105} {106} {114}, liver {02} {77} {78} {79} {80} {81} {82} {83} {84} {85} {86} {87} {88} {89} {90} {91} {92} {93} {272} {273} {274}, lung1 {44} {45} {42} {275} {276}, pancreas1 {94} {95} {96} {97}, and small bowel1 {04} {05} allografts.

[Graft-versus-host disease (prophylaxis)]1 {107} {108} {109} {110} {111} or
[Graft-versus-host disease (treatment) ]1 {112} {113}—Tacrolimus is useful for the prevention and treatment of graft-versus-host disease in patients receiving bone marrow transplants.

[Uveitis, severe, refractory (treatment)]1 {131} {132} {133} {134}—Tacrolimus is useful for the treatment of severe, refractory uveitis.

Acceptance not established
Tacrolimus has been studied for the treatment of atopic dermatitis {115} {116}, nephrotic syndrome {119} {120} {121}, pediatric autoimmune enteropathy {122}, primary sclerosing cholangitis {123}, psoriasis {124} {125} {126} {127} {135} {149}, psoriatic arthritis {128}, and pyoderma gangrenosum {129} {130}. More data are needed to assess the place in therapy of tacrolimus for these indications.

There have been additional reports of the use of tacrolimus for other conditions, including:    • alopecia universalis {290};
   • autoimmune chronic active hepatitis {291};
   • inflammatory bowel disease {117} {264};
   • multiple sclerosis {118};
   • primary biliary cirrhosis {292}; and
   • scleroderma {293}.
The use of tacrolimus for these conditions cannot be assessed at this time.

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Source—
    Tacrolimus is a macrolide immunosuppressant produced by Streptomyces tsukubaensis {01} {136} {137}.
Molecular weight—
    822.05 {01} {137} {295}

Solubility
    Freely soluble in ethanol; very soluble in chloroform and methanol; practically insoluble in water {01} {137}

Mechanism of action/Effect:

Tacrolimus inhibits T-lymphocyte activation {01} {138} {139} {140}. This may occur through formation of a complex with FK 506-binding proteins (FKBPs) {01} {139}. The complex inhibits calcineurin phosphatase {01} {139}. This is believed to inhibit interleukin-2 (IL-2) gene expression in T-helper lymphocytes {139}.

Tacrolimus also binds to the steroid receptor–associated heat-shock protein 56. This ultimately results in inhibition of transcription of proinflammatory cytokines such as granulocyte–macrophage colony-stimulating factor (GM-CSF), interleukin-1 (IL-1), interleukin-3 (IL-3), interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor alpha (TNF alpha) {139}.

Absorption:

Rapid, variable, and incomplete from the gastrointestinal tract {01} {11} {141} {143} {144} {145} {146} {147} {148} {155} {156}; the mean bioavailability of the oral dosage form is 27%, range 5 to 65% {155}; rate of absorption is decreased in the presence of food, but the extent of absorption may or may not be affected, depending on the type of food ingested {155}.

Pediatric patients may have decreased bioavailability as compared to adult patients.

Distribution:

The volume of distribution (Vol D) when based on plasma obtained from blood samples at 37 °C (98.6 °F) is 5 to 65 L per kg of body weight (L/kg) {141} {142} {144}. The Vol D based on plasma concentration is much higher than the Vol D based on whole blood concentrations, the difference reflecting the binding of tacrolimus to the red blood cells {145} {155}. The mean Vol D for patients with liver allografts when measured in whole blood is 0.9 L/kg {156}.

Protein binding:

High to very high (75 to 99%), primarily to albumin and alpha 1-acid glycoprotein {01} {145}.

Biotransformation:

Hepatic, extensive, primarily by the cytochrome P450 3A enzymes {01} {157} {158} {283} {284}.

Half-life:


Distribution:

0.9 hour {147}.



Elimination:

Biphasic, variable: Terminal—11.3 hours (range, 3.5 to 40.5 hours) {141} {148}.


Time to peak concentration:

0.5 to 4 hours after oral administration {141} {148} {155} {156}.

Note: The rate of absorption is reduced when tacrolimus is given with food {145}.


Peak serum concentration:

Plasma or blood—Whole blood concentrations may be 12 to 67 times the plasma concentrations {01} {155} {156}.

Elimination:
    Tacrolimus is eliminated by metabolism. Less than 1% of the dose is eliminated unchanged in urine.
    Pediatric patients may have increased clearance as compared with adult patients {153} {154}.


In dialysis—
        Tacrolimus is not removed by dialysis {141}.



Precautions to Consider

Cross-sensitivity and/or related problems

Patients allergic to castor oil derivatives may be allergic to the injectable dosage form of tacrolimus also, since the injection contains a polyoxyl 60 hydrogenated castor oil vehicle {01}.

Carcinogenicity

Tacrolimus is associated with an increased risk of malignancy, especially lymphomas and skin malignancies {01}. The increased risk is attributed to the intensity and duration of immunosuppression. The incidence of lymphomas is comparable to that observed with cyclosporine-based immunosuppressive regimens {01} {28} {282}.

Tumorigenicity



Studies in mice and rats did not show a relationship between the dose of tacrolimus and the incidence of tumors {01}.

Mutagenicity

Mutagenicity was not observed in bacterial or Chinese hamster cell in vitro testing, or in vivo tests performed in mice or rat hepatocytes {01}.

Pregnancy/Reproduction
Fertility—
Adequate and well-controlled studies have not been done in humans {01}.

Pregnancy—
Tacrolimus crosses the placenta {01} {162}. Pregnancy in patients treated with tacrolimus is possible, with low incidences of hypertension and pre-eclampsia. The use of tacrolimus during pregnancy is associated with premature birth, and hyperkalemia and reversible renal function impairment in neonates {01} {160} {161} {162}. One case of intrauterine growth retardation has been reported {161}. In one series, 27 pregnancies in 21 liver transplant recipients managed with tacrolimus did not result in the loss of any allografts. Prenatal growth and postnatal infant growth for postpartum age were normal. Two of the 27 infants died after being delivered at 23 and 24 weeks gestation. The unsuccessful pregnancies were conceived a few weeks and 11.7 months following the liver transplantations {162}.

Studies in rats showed that tacrolimus use during organogenesis was associated with an increase in late fetal resorptions and a decrease in the number of live births {01}.

FDA Pregnancy Category C {01}.

Breast-feeding

Tacrolimus is distributed into breast milk {01} {162}. Breast-feeding should be avoided during tacrolimus therapy {01}.

Pediatrics

Pediatric patients require higher doses of tacrolimus per kg of body weight to maintain trough concentrations similar to those of adult patients {01} {35} {146} {153} {154}. Pediatric patients may have decreased bioavailability and increased clearance as compared with adult patients.

Post-transplant lymphoproliferative disorder (PTLD) may be more common in pediatric patients than in adult patients, especially in pediatric patients up to 3 years of age {159} {282}.


Geriatrics


No information is available on the relationship of age to the effects of tacrolimus in geriatric patients {01}. Tacrolimus has been used in geriatric patients undergoing transplantation {19}; however, information has not been published on the age-related effects of tacrolimus in these patients. Elderly patients are more likely to have age-related renal function impairment, which may require adjustment of dosage.


Dental

The immunosuppressive effects of tacrolimus may result in an increased incidence of certain microbial infections and delayed healing. Dental work, whenever possible, should be completed prior to initiation of therapy and undertaken with caution during therapy. Patients should be instructed in proper oral hygiene.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.
The drug interactions between tacrolimus and clarithromycin, clotrimazole, danazol, erythromycin, fluconazole, hyperkalemia-causing medications, nephrotoxic medications, and rifampin have been observed clinically in patients. The drug interactions between tacrolimus and aluminum hydroxide gel, bromocriptine, cimetidine, cyclosporine, dexamethasone, diltiazem, ethinyl estradiol, itraconazole, ketoconazole, magnesium oxide, nifedipine, omeprazole, sodium bicarbonate, and verapamil have been demonstrated in vitro or in experimental animal models {283}.
The extent of induction or inhibition of cytochrome P450 enzymes may depend on the dose of the inducer or inhibitor {285}.

Aluminum hydroxide gel{163}    (adsorbs tacrolimus; may lead to reduced blood concentrations of tacrolimus)


Bromocriptine{164}{165} or
Cimetidine{167} or
Clarithromycin{169} or
Clotrimazole{170} or
» Danazol{167}{171} or
Diltiazem{167}{175}{177} or
Ethinyl estradiol{165}{177} or
» Erythromycin{164}{165}{167}{177}{179}{182}{183}{184} or
» Fluconazole{122}{166}{167}{176}{177}{186} or
» Itraconazole{167}{176}{177} or
» Ketoconazole{164}{167}{165}{176}{177} or
Nifedipine{165}{177} or
Omeprazole{165} or
Verapamil{164}{165}{167}    (may inhibit the metabolism of tacrolimus, leading to increased tacrolimus blood concentrations and toxicity; some agents inhibiting the metabolism of tacrolimus [e.g., azole antifungal agents and calcium channel blocking agents] may be used therapeutically so that lower doses of tacrolimus can be used {01} {11})


Note: No interaction between fluconazole and tacrolimus was noted in one study in which the medications were administered intravenously to patients receiving bone marrow transplantation {185}. The mechanism of this interaction may be inhibition of metabolism of tacrolimus in the gut, leading to increased absorption {185}. This interaction may not occur to the same extent when tacrolimus is given intravenously as when it is given orally {185}.


Dexamethasone{155}{176}{177}{283} or
» Rifampin{155}{153}{189}{190}    (may induce cytochrome P450 3A enzymes, leading to increased metabolism of tacrolimus and lower blood concentrations {01} {153} {155})


» Cyclosporine{01}{11}    (increased immunosuppression; tacrolimus may increase the bioavailability of cyclosporine {194}, or may inhibit the metabolism of cyclosporine {165} {195} {196}, leading to increased cyclosporine blood concentrations and toxicity; increased risk of nephrotoxicity with concurrent use)


Hyperkalemia-causing medications{01} (see Appendix II ), especially:
» Diuretics, potassium-sparing    (concurrent use with tacrolimus may result in hyperkalemia {01})


Magnesium oxide{163} or
Sodium bicarbonate{155}{163}    (tacrolimus is degraded by an alkaline environment, resulting in decreased bioavailability of tacrolimus; the same interaction may occur with other antacids; a single-dose study examining the effect of magnesium oxide did not show decreased bioavailability {296})


Muromonab-CD3    (increased incidence of post-transplant lymphoproliferative disorder [PTLD] with concurrent use {12})


Nephrotoxic medications{172} (see Appendix II ), such as:
Aminoglycosides or
Amphotericin B or
Anti-inflammatory drugs, nonsteroidal or
Vancomycin    (may be additive or synergistic impairment of renal function {01} {11} {22} {187})


Vaccines, killed virus    (immune response to vaccines may be decreased {01} {191})


» Vaccines, live virus    (the immunosuppressive effect of tacrolimus may potentiate the replication of the vaccine virus, may increase the side/adverse effect of the vaccine, and/or may decrease the immune response to the vaccine {01} {191})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Alanine aminotransferase (ALT [SGPT]) and
Alkaline phosphatase and
Aspartate aminotransferase (AST [SGOT])    (values may be increased {01}; may indicate hepatotoxicity {01})


Bilirubin, serum    (concentrations may be increased {01}; may indicate hepatotoxicity {01})


Blood urea nitrogen (BUN) and
» Creatinine, serum{01}    (concentrations may be increased {01}; may indicate nephrotoxicity {01} {27} {28})


Calcium and
» Magnesium, serum    (concentrations may be decreased {01})


Cholesterol, serum    (values may be increased {01} {192} {193})


» Glucose, blood and
Triglycerides, serum    (concentrations may be increased {01} {192} {193})


Hematocrit value and
Hemoglobin concentration    (may be decreased {01})


Leukocytes (neutrophils [WBC])    (blood counts may be increased or decreased {01})


Platelets    (blood counts may be decreased {01})


Phosphate and
» Potassium{01}    (serum concentrations may be increased {01} {28})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist:
» Allergy to polyoxyl 60 hydrogenated castor oil    (patients with an allergy to castor oil derivatives may be allergic to tacrolimus injection also, since tacrolimus injection has a castor oil vehicle; intravenous administration of castor oil derivatives has been associated with anaphylactic reactions; the use of tacrolimus injection in patients with an allergy to castor oil derivatives is contraindicated {01})


» Allergy to tacrolimus, history of{01}
» Malignancy, current    (Tacrolimus use is associated with an increased susceptibility to malignancies {01})


Risk-benefit should be considered when the following medical problems exist
» Chickenpox, existing or recent (including recent exposure) or
» Herpes zoster    (risk of severe generalized disease)


Diabetes mellitus    (risk of loss of glucose control)


Hepatic function impairment or
Hepatitis B or C infection, chronic or
» Renal function impairment    (dosage reduction may be required {01} {280} {281}; patients with post-transplant hepatic function impairment may have an increased risk of renal toxicity when taking tacrolimus {197})


Hyperkalemia{01}    (tacrolimus may exacerbate hyperkalemia)


» Infection    (immunosuppression may exacerbate infections {01})


Neurologic function impairment    (dosage reduction may be required {01})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):


Note: Monitoring intervals may need to be altered based on the condition of the patient.

Alanine aminotransferase (ALT [SGPT]) and
Alkaline phosphatase and
Aspartate aminotransferase (AST [SGOT]) and
Bilirubin, serum    (recommended periodically to monitor hepatic function; more frequent monitoring required in the early post-transplant period)


Blood urea nitrogen (BUN) and
» Creatinine, serum    (recommended to monitor for nephrotoxicity; nephrotoxicity occurs most often in the early post-transplant period, especially if intravenous tacrolimus is administered)


» Blood pressure measurements    (frequent measurements recommended)


Calcium and
» Magnesium and
Phosphate and
» Potassium    (frequent monitoring recommended in the early post-transplant period; periodic monitoring recommended thereafter)


Cholesterol, serum and
Triglycerides, serum    (periodic monitoring recommended)


Complete blood counts (CBCs)    (monitoring of CBC recommended to detect tacrolimus-induced blood dyscrasias; changes in the neutrophil count may also indicate infection)


» Glucose, blood    (frequent monitoring recommended in the early post-transplant period; periodic monitoring recommended thereafter)


» Tacrolimus concentrations, whole blood, trough    (target blood concentrations vary depending on the indication and the transplant center protocol; trough whole blood concentrations of 10 to 20 mcg per mL [mcg/mL] [12.2 to 24.4 micromoles per L (micromoles/L)] are used by some centers in the first month following transplantation {172}; for the subsequent 2 months, lower blood concentrations [i.e., 5 to 15 mcg/mL (6.1 to 18.3 micromoles/L)] are often recommended {172} {198}; after 3 months some centers lower the target blood concentrations to 5 to 10 mcg/mL [6.1 to 12.2 micromoles/L] {172}; higher concentrations are used in intestinal transplantation)

    (target blood concentrations vary for pediatric patients, depending on indication and transplant center; for liver transplantation, a consortium of transplant centers recommends trough concentrations of 12 to 15 mcg/L [14.6 to 18.3 micromoles/L] in the first month following transplantation, 10 to 12 mcg/L [12.2 to 14.6 micromoles/L] for the subsequent 2 months, and 5 to 10 mcg/L [6.1 to 12.2 micromoles/L] thereafter {199}; for renal transplantation, one transplant center recommends trough blood concentrations of 20 to 25 mcg/L [24.4 to 30.5 micromoles/L] in the first 2 weeks following transplantation, 15 to 20 mcg/mL [18.3 to 24.4 micromoles/L] for the second 2 weeks following transplantation, 10 to 15 mcg/L [12.2 to 18.3 micromoles/L] for the following 3 months, and 5 to 9 mcg/L [6.1 to 11 micromoles/L] thereafter {61})

    (trough blood concentrations should be measured frequently in the early post-transplant period {172}; tacrolimus blood concentrations often are measured daily until good graft function and good renal function are achieved, and then every other day during the early post-transplant hospitalization {172}; concentrations should be measured after adjustment in the tacrolimus dose, and after the addition or removal of medications that may alter tacrolimus absorption or clearance {172})

    (high tacrolimus blood concentrations are correlated with toxicity {198} {200} {201}; low tacrolimus blood concentrations are not as well-correlated with episodes of rejection {198} {200} {201}; tacrolimus blood concentrations should always be considered in conjunction with the patient's clinical condition when assessing the adequacy of the tacrolimus dose)




Side/Adverse Effects

Note: Hyperglycemia, nephrotoxicity, and neurotoxicity are the most significant adverse effects resulting from the use of tacrolimus. Other adverse effects (e.g., infection, post-transplant lymphoproliferative disorder [PTLD]) result from the degree of immunosuppression, not specifically from the use of tacrolimus.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Asthenia{93} (loss of energy or weakness)
    
blood dyscrasias{28}{93}{103}{202}{203}{204} including red cell aplasia (fever and sore throat; pale skin; unusual bleeding or bruising; unusual tiredness or weakness)
    
gastrointestinal disturbance{28}{33}{50}{55}{67}{70}{78}{79}{85}{93}{101}{214}{217}{218} , including abdominal pain{93}{101}
diarrhea{28}{67}{79}{93}{127}
loss of appetite{28}{79}{93}{217}
nausea{28}{67}{79}{93}{101}{113}
vomiting{28}{67}{93}{113}
    
hyperglycemia{16}{19}{27}{28}{29}{36}{38}{70}{73}{78}{81}{82}{87}{93}{101}{109}{110}{113}{192}{193}{205}{207}{214}{215}{221}{222}{223}{224}{227}{228} (frequent urination)
    
hyperkalemia{28}{38}{93}{101}{113}{205} (abdominal pain; nausea or vomiting; weakness)
    
hypomagnesemia{01} (muscle trembling or twitching)
    
infection{10}{16}{19}{27}{28}{29}{31}{33}{36}{38}{45}{47}{55}{67}{70}{75}{78}{85}{89}{93}{101}{103}{215}{242}{243}{244}{245}{246}{247} (fever or chills)
    
nephrotoxicity{19}{20}{27}{28}{29}{36}{38}{39}{47}{50}{55}{67}{73}{78}{80}{81}{85}{89}{93}{108}{109}{110}{112}{113}{187}{197}{205}{207}{214}{215}{216}{229}{230}{231}{232}{233}{234}{235}{236}{237}{238}{239}
    
neurotoxicity{16}{20}{27}{28}{29}{31}{33}{36}{38}{50}{55}{67}{70}{78}{79}{82}{89}{93}{101}{109}{110}{112}{113}{205}{206}{207}{210}{211}{212}{214}{215}{216} , including abnormal dreams
agitation
anxiety
confusion{211}
depression{217}
dizziness{79}
hallucinations (seeing or hearing things that are not there), headache{28}{79}{93}{101}{109}{110}{113}{211}{215}
insomnia{79}{93}{127}{211}{215} (trouble in sleeping), nervousness
seizures{27}{31}{38}{211}
tremor{27}{28}{36}{79}{93}{101}{113} (trembling and shaking of hands), paresthesia{27}{28}{127}{211}{215} (tingling)
    
peripheral edema{93} (swelling of ankles, feet, or lower legs)
    
pleural effusion (shortness of breath{78})
    
pruritus{28}{79}{93} (itching)
    
skin rash{28}{78}

Incidence less frequent
    
Cardiovascular effects{16}{19}{33}{70}{78} , including cardiomyopathy{250}{253} (shortness of breath), chest pain{79}
hyperlipidemia{192}{257}
hypertension{16}{19}{28}{31}{38}{39}{78}{109}{216}{258}
    
hyperesthesia{79} (increased sensitivity to pain)
    
muscle cramps{79}
    
neuropathy{27} (numbness or pain in legs)
    
osteoporosis{249}
    
sweating{79}
    
tinnitus{79} (ringing in ears)
    
visual disturbance{79} (blurred vision)

Incidence rare
    
Anaphylaxis (flushing of face or neck; shortness of breath; wheezing)—with parenteral use
    
hepatotoxicity{39}{93}{219} (flu-like symptoms)
    
PTLD{09}{10}{16}{38}{39}{55}{75}{78}{101}{103}{259}{260}{261} (fever; general feeling of discomfort and illness; weight loss)
Note: PTLD may be more common in pediatric patients than in adult patients, especially in pediatric patients up to 3 years of age {159}.







Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
Early clinical trials used doses of tacrolimus that were later determined to be overdoses. The patients experienced the same side effects as patients receiving lower doses, but the incidence of these effects was greater in patients receiving higher doses of tacrolimus {01}. The patients receiving the overdoses of tacrolimus experienced more new-onset diabetes, nephrotoxicity, and neurotoxicity as compared to patients receiving lower doses {01}.

There is limited literature on the effects of massive overdoses of tacrolimus in humans {01}. Overdoses of up to 7 mg per kg of body weight (mg/kg) have been reported. Most patients did not develop symptoms associated with the overdose {01} {294}.

In toxicity studies in rats, mortalities first occurred at intravenous doses 16 times the recommended human dose {01}.

Treatment of overdose
Treatment is symptomatic and supportive {01}. Clearance of tacrolimus cannot be enhanced by dialysis because tacrolimus is extensively bound to erythrocytes and plasma proteins {01}.

Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Tacrolimus (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Allergy to tacrolimus or castor oil derivatives



Carcinogenicity—
Use of tacrolimus is associated with an increased incidence of malignancy

Pregnancy—Tacrolimus crosses the placenta; transplant patients should not conceive shortly after transplantation or while being treated for transplant-related complications





Breast-feeding—Tacrolimus is distributed into breast milk; breast-feeding should be avoided





Dental—Dental work should be completed prior to initiation of therapy whenever possible
Other medications, especially cyclosporine, danazol, erythromycin, fluconazole, itraconazole, ketoconazole, potassium-sparing diuretics, or rifampin
Other medical problems, especially allergy to polyoxyl 60 hydrogenated castor oil, chickenpox, current malignancy, herpes zoster infection, or renal function impairment

Proper use of this medication
» Importance of not using more or less medication than the amount prescribed

Getting into the habit of taking at the same time each day and in a consistent relationship to the type and timing of the intake of food to help increase compliance and maintain steady blood concentrations

» Checking with physician before discontinuing or changing medication; possible need for lifelong therapy

» Proper dosing
Missed dose: Taking as soon as possible if remembered within 12 hours; not taking if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
» Importance of close monitoring by physician

Maintaining good dental hygiene and seeing dentist frequently for teeth cleaning

» Not eating raw oysters or other shellfish; making sure they are fully cooked before eating

» Continuing recommended vaccination schedule (except for live vaccines)

» Avoiding exposure to chickenpox, measles, mumps, and rubella; if exposed, seeing physician for prophylactic therapy

Not traveling to another country without making sure a supply of tacrolimus will be available

Not eating grapefruit or drinking grapefruit juice


Side/adverse effects
Signs of potential side effects, especially asthenia, blood dyscrasias, abdominal pain, diarrhea, loss of appetite, nausea, vomiting, hyperglycemia, hyperkalemia, hypomagnesemia, infection, nephrotoxicity, abnormal dreams, agitation, anxiety, confusion, depression, dizziness, hallucinations, headache, insomnia, nervousness, seizures, tremor, paresthesia, peripheral edema, pleural effusion, pruritus, skin rash, cardiomyopathy, chest pain, hyperlipidemia, hypertension, hyperesthesia, muscle cramps, neuropathy, osteoporosis, sweating, tinnitus, visual disturbance, anaphylaxis, hepatotoxicity, and post-transplant lymphoproliferative disorder


General Dosing Information
Dosage regimens for tacrolimus vary among transplant centers. Dosage of tacrolimus should be adjusted based on the clinical response of each patient {01} {172}. Whole blood trough concentrations can be used as a guide to appropriate dosing. High whole blood trough concentrations are associated with an increase in toxicity.

Tacrolimus usually is used in conjunction with other immunosuppressants (e.g., corticosteroids and azathioprine) {01}. Corticosteroids typically are tapered following transplantation to target doses of prednisone for adult patients of 2.5 to 5 mg per day six months after transplantation {172}. In some cases, it may be possible to wean the patient from other immunosuppressants and maintain the patient on tacrolimus monotherapy {153} {172}.

When converting from cyclosporine to tacrolimus, it is recommended that cyclosporine be discontinued 24 hours before initiating tacrolimus therapy {01} {172}. In some transplant centers, cyclosporine whole blood concentrations are measured, and tacrolimus therapy started if cyclosporine concentrations are less than 100 micrograms per liter (mcg/L) {172}.

Patients receiving lower-quality hepatic allografts or with poor early hepatic graft function should receive lower doses of tacrolimus initially {172}. Liver transplant patients with poor hepatic graft function have increased risk for developing renal function impairment {01} {281}.

Antiviral prophylaxis, i.e., with acyclovir, ganciclovir, and immune globulins, may be advisable for some patients receiving tacrolimus, especially cytomegalovirus (CMV) prophylaxis in patients who have not been exposed to CMV prior to transplantation who receive a CMV-positive graft {199}.

Vaccination schedules should be continued, except for live vaccines {191}. Vaccinations against hepatitis A and B are recommended. Inactivated poliovirus vaccine should be used instead of oral poliovirus vaccine for both the patient and for people living in the same household as the patient. Vaccines given to immunosuppressed patients may not result in a protective antibody response {191}. Protective antibody concentrations should be checked after the vaccine has been administered.

If a patient is exposed to measles, mumps, rubella, or varicella for the first time while receiving tacrolimus, the patient should receive prophylactic therapy with immune globulin, i.e., pooled human immune globulin or varicella immune globulin {159}.

For parenteral dosage forms only
Because parenteral tacrolimus is associated with the development of more adverse effects, including anaphylaxis and renal function impairment, than is oral tacrolimus, parenteral tacrolimus should be used only in patients unable to take tacrolimus orally {172}. When receiving parenteral tacrolimus, patients should be monitored closely for anaphylaxis, especially during the first 30 minutes of the infusion {01}. Patients receiving tacrolimus parenterally should be switched to oral tacrolimus as soon as it can be tolerated {01} {172}.

Diet/Nutrition
The rate of absorption of oral tacrolimus is decreased in the presence of food {145}, but the extent of absorption may or may not be affected, depending on the type of food ingested {155}. Tacrolimus should be given consistently with relation to food {172} {199}.

Bioavailability of tacrolimus may be increased by ingestion of grapefruit or grapefruit juice, resulting in toxic blood concentrations of tacrolimus {01}.

Raw oysters or other shellfish may contain bacteria that can cause serious illness, and possibly death. Even eating oysters from “clean” water or good restaurants does not guarantee that the oysters do not contain the bacteria. Symptoms of this infection include sudden chills, fever, nausea, vomiting, blood poisoning, and sometimes death. Eating raw shellfish is not a problem for most healthy people; however, patients with the following conditions may be at greater risk: cancer, immune disorders, immunosuppression following organ transplantation, long-term corticosteroid use (as for asthma, arthritis, or prevention of graft rejection in organ transplantation), liver disease (including viral hepatitis), excessive alcohol intake (two to three drinks or more per day), diabetes, stomach problems (including previous stomach surgery and low stomach acid), and hemochromatosis.

For treatment of adverse effects
Recommended treatment consists of the following:
   • Many adverse effects (e.g., cardiomyopathy, gastrointestinal toxicity, hyperglycemia, hyperkalemia, hypomagnesemia, nephrotoxicity, neurotoxicity, pruritus, rash) may respond to a reduction in dose {01} {172} {188}. If adverse effects do not respond to a reduction in dose, it may be advisable to convert the patient to a cyclosporine-based immunosuppressant regimen {172} {213} {217}.


Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

TACROLIMUS CAPSULES

Usual adult and adolescent dose
Transplant rejection, liver (prophylaxis) or
Transplant rejection, kidney (prophylaxis)1 or
[Transplant rejection, solid organ, other (prophylaxis)]1 or
[Transplant rejection, liver (treatment)] or
[Transplant rejection, solid organ, other (treatment)]1
Oral, 0.1 to 0.15 mg per kg of body weight per day, in two divided doses, initially {153} {172}. The dose should be adjusted based on trough blood concentrations {01}.

[Graft-versus-host disease (prophylaxis){107}{109}]1
Oral, 0.12 mg per kg of body weight per day in two divided doses, starting when the patient can tolerate oral medications {109}. The dose should be adjusted based on trough blood concentrations {109}.

[Graft-versus-host disease (treatment)]1
Oral, 0.3 mg per kg of body weight per day in two divided doses, starting when the patient can tolerate oral medications {113}. The dose should be adjusted based on trough blood concentrations.

Tacrolimus is used as part of a regimen to treat graft-versus-host disease {113}. Other agents used to treat graft-versus-host disease may include methotrexate and/or corticosteroids {113}.

[Uveitis, severe, refractory (treatment)]1{131}{132}{133}{134}
Oral, 0.1 to 0.15 mg per kg of body weight per day in two divided doses.


Usual pediatric dose
Transplant rejection, liver (prophylaxis) or
Transplant rejection, kidney (prophylaxis)1 or
[Transplant rejection, solid organ, other (prophylaxis)]1 or
[Transplant rejection, liver (treatment)] or
[Transplant rejection, solid organ, other (treatment)]1
Oral, 0.1 to 0.3 mg per kg of body weight per day, in two divided doses, initially {61} {153} {199}. The dose should be adjusted based on trough blood concentrations {01}.

[Graft-versus-host disease (prophylaxis)]1
See Usual adult and adolescent dose . Pediatric patients may require higher doses to attain therapeutic blood trough concentrations.

[Graft-versus-host disease (treatment)]1
See Usual adult and adolescent dose . Pediatric patients may require higher doses to attain therapeutic blood trough concentrations {112}.


Usual geriatric dose
See Usual adult and adolescent dose .

Strength(s) usually available
U.S.—


1 mg (Rx) [Prograf (anhydrous) (croscarmellose sodium) (gelatin) (hydroxypropyl methylcellulose) (lactose) (magnesium stearate) (titanium dioxide)]


5 mg (Rx) [Prograf (anhydrous) (croscarmellose sodium) (ferric oxide) (gelatin) (hydroxypropyl methylcellulose) (lactose) (magnesium stearate) (titanium dioxide)]

Canada—


1 mg (Rx) [Prograf (anhydrous) (croscarmellose sodium) (gelatin) (hydroxypropyl methylcellulose) (lactose) (magnesium stearate) (titanium dioxide)]


5 mg (Rx) [Prograf (anhydrous) (croscarmellose sodium) (ferric oxide) (gelatin) (hydroxypropyl methylcellulose) (lactose) (magnesium stearate) (titanium dioxide)]

Packaging and storage:
Store between 15 and 30 ºC (59 and 86 ºF).

Note: Tacrolimus suspension has been extemporaneously compounded by mixing the contents of 5-mg capsules with equal amounts of Ora-Plus™, a suspending vehicle for oral extemporaneous preparations, and Simple Syrup NF, to a final concentration of 0.5 mg per mL (mg/mL) {289}. The extemporaneously prepared tacrolimus suspension was found to be stable for at least 56 days in glass and plastic amber bottles stored between 24 and 26 °C (75.2 and 78.8 °F) {289}. Bioavailability testing has not been performed using the extemporaneously compounded suspension {289}.




Parenteral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

TACROLIMUS FOR INJECTION

Note: Tacrolimus injection is intended for intravenous infusion only.
Parenteral tacrolimus should be used only in patients unable to take tacrolimus orally {172}. Patients receiving tacrolimus parenterally should be switched to oral tacrolimus as soon as it can be tolerated {01} {172}.


Usual adult and adolescent dose
Transplant rejection, liver (prophylaxis), in patients unable to take oral medications or
Transplant rejection, kidney (prophylaxis), in patients unable to take oral medications1 or
[Transplant rejection, solid organ, other (prophylaxis), in patients unable to take oral medications]1 or
[Transplant rejection, liver (treatment), in patients unable to take oral medications] or
[Transplant rejection, solid organ, other (treatment), in patients unable to take oral medications]1
Continuous intravenous infusion, 0.01 to 0.05 mg per kg of body weight per day {172}, beginning no sooner than six hours after transplantation. The dose should be adjusted based on trough blood concentrations.

[Graft-versus-host disease (prophylaxis)]1
Intravenous infusion, 0.04 mg per kg of body weight per day as a continuous infusion started the day prior to bone marrow transplantation {108}. The dose should be adjusted based on trough blood concentrations {108}.

[Graft-versus-host disease (treatment)]1
Intravenous infusion, 0.1 mg per kg of body weight per day in two divided doses administered over four hours for each infusion {113}. The dose should be adjusted based on trough blood concentrations {113}.


Usual pediatric dose
Transplant rejection, liver (prophylaxis), in patients unable to take oral medications or
Transplant rejection, kidney (prophylaxis), in patients unable to take oral medications1 or
[Transplant rejection, solid organ, other (prophylaxis), in patients unable to take oral medications]1 or
[Transplant rejection, liver (treatment), in patients unable to take oral medications] or
[Transplant rejection, solid organ, other (treatment), in patients unable to take oral medications]1
See Usual adult and adolescent dose .

[Graft-versus-host disease (prophylaxis)]1
See Usual adult and adolescent dose . Pediatric patients may require higher doses to attain therapeutic blood trough concentrations.

[Graft-versus-host disease (treatment)]1
Intravenous infusion, 0.1 mg per kg of body weight per day as a continuous infusion {112}.


Usual geriatric dose
See Usual adult and adolescent dose .

Strength(s) usually available
U.S.—


5 mg per mL (Rx) [Prograf (anhydrous) (alcohol 80% v/v) (polyoxyl 60 hydrogenated castor oil 200 mg per mL)]

Canada—


5 mg per mL (Rx) [Prograf (anhydrous) (alcohol 80% v/v) (polyoxyl 60 hydrogenated castor oil 200 mg per mL)]

Packaging and storage:
Store between 5 and 25 ºC (41 and 77 ºF).

Preparation of dosage form:
Tacrolimus should be diluted with 5% dextrose injection or 0.9% sodium chloride injection to a concentration between 0.004 and 0.02 mg per mL (mg/mL) {01}.

Stability:
Diluted tacrolimus for injection should be used within 24 hours {01}. The prepared solution should be inspected for particulate matter and clarity before administration to the patient, and should be discarded if particulate matter is present {01}.

Incompatibilities:
Tacrolimus for injection should not be stored in polyvinyl chloride (PVC) containers because the solution may be adsorbed by PVC containers, and leaching of phthalates in the PVC container may occur {01} {262}.



Developed: 08/14/1997



References
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  1. Masaoka T. Problems of bone marrow transplantation in Japan. Transplant Proc 1994; 26: 2358.
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  1. Kanamaru A, Takemoto Y, Kakishita E, et al. FK506 treatment of graft-versus-host disease developing or exacerbating during prophylaxis and therapy with cyclosporine and/or other immunosuppressants. Bone Marrow Transplant 1995; 15: 885-9.
  1. Felldin M, Bäckman L, Brattström C, et al. Rescue therapy with tacrolimus (FK506) in renal transplant recipients. Transplantation 1995; 60: 1182-4.
  1. Nakagawa H, Etoh T, Ishibashi Y, et al. Tacrolimus ointment for atopic dermatitis. Lancet 1994; 344: 883.
  1. Nakagawa H, Etoh T, Yokota Y, et al. Tacrolimus has antifungal activities against malassezia furfur isolated from healthy adults and patients with atopic dermatitis. Clin Investig 1996; 12: 244-50.
  1. Stephens J, Goldstein R, Crippin J, et al. Effects of orthotopic liver transplantation and immunosuppression on inflammatory bowel disease in primary sclerosing cholangitis patients. Transplant Proc 1993; 25: 1122-3.
  1. Lemster B, Huang L, Irish W, et al. Influence of FK 506 (tacrolimus) on circulating CD4+ T cells expressing CD25 and CD45RA antigens in patients with chronic progressive multiple sclerosis participating in an open-label drug safety trial. Autoimmunity 1994; 19: 89-98.
  1. McCauley J, Shapiro R, Ellis D, et al. Pilot trial of FK 506 in the management of steroid-resistant nephrotic syndrome. Nephrol Dial Transplant 1993; 8: 1286-90.
  1. McCauley J, Shapiro R, Jordan M, et al. FK 506 in the management of nephrotic syndrome after renal transplantation. Transplant Proc 1993; 25: 1351-4.
  1. McCauley J, Shapiro R, Scantlebury V, et al. FK 506 in the management of transplant-related nephrotic syndrome and steroid-resistant nephrotic syndrome. Transplant Proc 1991; 23: 3354-6.
  1. Bousvaros A, Leichtner A, Book L, et al. Treatment of pediatric autoimmune enteropathy with tacrolimus (FK506). Gastroenterology 1996; 111: 237-43.
  1. Van Thiel D, Carroll P, Abu-Elmagd K, et al. Tacrolimus (FK 506): a treatment for primary sclerosing cholangitis: results of an open-label preliminary trial. Am J Gastroenterol 1995; 90: 455-9.
  1. Abu-Elmagd K, Van Thiel D, Jegasothy B, et al. FK 506: a new therapeutic agent for severe recalcitrant psoriasis. Transplant Proc 1991; 23: 3322-4.
  1. Jegasothy B, Ackerman C, Todo S, et al. Tacrolimus (FK 506)—a new therapeutic agent for severe recalcitrant psoriasis. Arch Dermatol 1992; 128: 781-5.
  1. Lemster B, Carroll P, Rilo H, et al. IL-8/IL-8 receptor expression in psoriasis and the response to systemic tacrolimus (FK506) therapy. Clin Exp Immunol 1995; 99: 148-54.
  1. The European FK 506 Muticentre Psoriasis Study Group. Systemic tacrolimus (FK 506) is effective for the treatment of psoriasis in a double-blind, placebo-controlled study. Arch Dermatol 1996; 132: 419-23.
  1. Ruzicka T. Psoriatic arthritis: new types, new treatments. Arch Dermatol 1996; 132: 215-9.
  1. Abu-Elmagd K, Ackerman C, Jegasothy B, et al. Efficiacy of FK 506 in the treatment of recalcitrant pyoderma gangrenosum. Transplant Proc 1991; 23: 3328-9.
  1. Abu-Elmagd K, Van Thiel D, Jegasothy B, et al. Resolution of severe pyoderma gangrenosum in a patient with streaking leukocyte factor disease after treatment with tacrolimus (FK 506). Ann Intern Med 1993; 119: 595-8.
  1. Mochizuki M, Masuda K, Sakane T, et al. A clinical trial of FK506 in refractory uveitis. Am J Ophthalmol 1993; 115: 763-9.
  1. Mochizuki M, Masuda K, Shirao M, et al. Preclinical and clinical study of FK506 in uveitis. Curr Eye Res 1992; 11 Suppl: 87-95.
  1. Mochizuki M, Masuda K, Sakane T, et al. A multicenter open trial of FK506 in refractory uveitis, including Behcet's disease. Japanese FK 506 Study Group on Refractory Uveitis. Transplant Proc 1991; 23: 3343-6.
  1. Iskioka M, Ohno S, Nakamura S, et al. FK506 treatment of noninfectious uveitis. Am J Ophthalmol 1994; 118: 723-9.
  1. Nikolaidis N, Abu-Elmagd K, Thomson A, et al. Metabolic effects of FK 506 in patients with severe psoriasis: short-term follow-up of seven cases. Transplant Proc 1991; 23: 3325-7.
  1. Goto T, Kino K, Hatanaka H, et al. Discovery of FK506, a novel immunosuppressant isolated from Streptomyces tsukubaensis. Transplant Proc 1987; 19 Suppl 6: 4-8.
  1. Kino K, Hatanaka H, Hashimoto M, et al. FK506, a novel immunosuppressant isolated from streptomyces. Fermentation, isolation, and physicochemical and biological characteristics. J Antibiot 1987; 40: 1249-55.
  1. Morris R. Modes of action of FK506, cyclosporin A, and rapamycin. Transplant Proc 1994; 26: 3272-5.
  1. Thomson A, Bonham C, Zeevi A. Mode of action of tacrolimus (FK506): molecular and cellular mechanisms. Ther Drug Monit 1995; 17: 584-91.
  1. Nakata S, Shirakura R, Ito T, et al. Immunosuppressive mechanisms of deoxymethylspergualin and FK506 on in vitro cytotoxic T lymphocytes. Transplant Proc 1994; 26: 1930-2.
  1. Venkataramanan R, Jain A, Warty V, et al. Pharmacokinetics of FK 506 in transplant patients. Transplant Proc 1991; 23: 2736-40.
  1. Jain A, Abu-Elmagd K, Abdallah H, et al. Pharmacokinetics of FK506 in liver transplant recipients after continuous intravenous infusion. J Clin Pharmacol 1993; 33: 606-11.
  1. Jain A, Venkataramanan R, Lever J, et al. FK 506 in small bowel transplant recipients: pharmacokinetics and dosing. Transplant Proc 1994; 26: 1609-10.
  1. Venkataramanan R, Jain A, Cadoff E, et al. Pharmacokinetics of FK 506: preclinical and clinical studies. Transplant Proc 1990; 22: 52-6.
  1. Sewing K. Pharmacokinetics, dosing principles, and blood level monitoring of FK506. Transplant Proc 1994; 26: 3267-9.
  1. Yasuhara M, Hashida T, Toraguchi M, et al. Pharmacokinetics and pharmacodynamics of FK506 in pediatric patients receiving living-related donor liver transplantations. Transplant Proc 1995; 27: 1108-10.
  1. Gruber S, Hewitt J, Sorenson A, et al. Pharmacokinetics of FK506 after intravenous and oral administration in patients awaiting renal transplantation. J Clin Pharmacol 1994; 34: 859-64.
  1. Venkataramanan R, Jain A, Warty V, et al. Pharmacokinetics of FK 506 following oral administration: a comparison of FK 506 and cyclosporine. Transplant Proc 1991; 23: 931-3.
  1. Thomson A, Nalesnik M, Abu-Elmagd K, et al. Influence of FK 506 on T lymphocytes, Langerhans' cells, and the expression of cytokine receptors and adhesion molecules in psoriatic skin lesions: a preliminary study. Transplant Proc 1991; 23: 3330-1.
  1. Hold.
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  1. McDiarmid S, Colonna J, Shaked A, et al. Differences in oral FK506 requirements between adult and pediatric liver transplant patients. Transplantation 1993; 55: 1328-32.
  1. Jain A, Fung J, Venkataramanan R. Comparative study of cyclosporine and FK506 dosage requirement in adult and pediatric orthotopic liver transplantation. Transplant Proc 1991; 23: 2763-6.
  1. Venkataramanan R, Swaminathan A, Prasad T, et al. Clinical pharmacokinetics of tacrolimus. Clin Pharmacokinet 1995; 404-30.
  1. Jusko W, Piekoszewski W, Klintmalm G, et al. Pharmacokinetics of tacrolimus in liver transplant patients. Clin Pharmacol Ther 1995; 57: 281-90.
  1. Shiraga T, Matsuda H, Nagase K, et al. Metabolism of FK506, a potent immunosuppressive agent, by cytochrome P450 3A enzymes in rat, dog, and human liver microsomes. Biochem Pharmacol 1994; 47: 727-35.
  1. Vincent S, Karanam B, Painter S, et al. In vitro metabolism of FK-506 in rat, rabbit, and human liver microsomes: identification of a major metabolite and of cytochrome P450 3A as the major enzymes responsible for its metabolism. Arch Biochem Biophys 1992; 294: 454-60.
  1. Panel comment, 2/97.
  1. Jain A, Venkataramanan R, Lever J, et al. FK506 and pregnancy in liver transplant patients. Transplantation 1993; 56: 751.
  1. Yoshimura N, Oka T, Fujiwara Y, et al. A case report of pregnancy in a renal transplant recipient treated with FK506 (tacrolimus). Transplantation 1996; 61: 1552-3.
  1. Jain A, Venkataramanan R, Fung J, et al. Pregnancy following liver transplantation under tacrolimus. Transplantation. In press 1997.
  1. Steeves M, Abdallah H, Venkataramanan R, et al. Interaction of a novel immunosuppressant, FK506, and antacids. J Pharm Pharmacol 1991; 43: 574-7.
  1. Christians U, Guenderich F, Schmidt G, et al. In vitro metabolism of FK506, cytochrome P450 and drug interactions. Ther Drug Monit 1993; 15: 145.
  1. Lampen A, Christians U, Guengerich F, et al. Metabolism of the immunosuppressant tacrolimus in the small intestine: cytochrome P450, drug interactions, and interindividual variability. Drug Metab Dispos 1995; 23: 1315-24.
  1. Assan R, Fredj G, Larger E, et al. FK 506 / fluconazole interaction enhances FK 506 nephrotoxicity. Diabete Metab 1994; 20: 49-52.
  1. Rui X, Flowers J, Warty V, et al. Drug interactions with FK 506 [abstract]. Pharm Res 1992; 9: S314.
  1. Lake K, Canafax D. Important interactions of drugs with immunosuppressive agents used in transplant recipients. J Antimicrob Chemother 1995; 36 Suppl B: 11-22.
  1. Wolter K, Wagner K, Philipp T, et al. Interaction between FK 506 and clarithromycin in a renal transplant patient. Eur J Clin Pharmacol 1994; 47: 207-8.
  1. Mieles L, Venkataramanan R, Yokoyama I, et al. Interaction between FK 506 and clotrimazole in a liver transplant recipient. Transplantation 1992; 52: 1086-7.
  1. Shapiro R, Venkataramanan R, Warty V, et al. FK 506 interaction with danazol. Lancet 1993; 341: 1344-5.
  1. Busuttil R, Klintmalm G, Lake J, et al. General guidelines for the use of tacrolimus in adult liver transplant patients. Transplantation 1996; 61: 845-7.
  1. Hold.
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  1. Regazzi M, Alessiani M, Spada M, et al. Interaction between FK 506 and diltiazem in an animal model. Transplant Proc 1996; 28: 1017-8.
  1. Prasad T, Stiff D, Subbotina N, et al. FK 506 (tacrolimus) metabolism by rat liver microsomes and its inhibition by other drugs. Res Commun Chem Pathol Pharmacol 1994; 84: 35-45.
  1. Iwasaki K, Matsuda H, Nagase H, et al. Effects of twenty-three drugs on the metabolism of FK506 by human liver microsomes. Res Commun Chem Pathol Pharmacol 1994; 82: 209-16.
  1. Hold.
  1. Jensen C, Jordan M, Shapiro R, et al. Interaction between tacrolimus and erythromycin. Lancet 1994; 344: 825.
  1. Hold.
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  1. Shaeffer M, Collier D, Sorrell M. Interaction between FK506 and erthromycin. Ann Pharmacother 1994; 38: 280-1.
  1. Jensen C, Jordan M, Shapiro R, et al. Interaction between tacrolimus and erythromycin. Lancet 1994; 344: 825.
  1. Padhi I, Long P, Babha M, et al. Interaction between tacrolimus and erythromycin. Ther Drug Monit 1997; 19: 120-2.
  1. Osokski C, Dix S, Lin L, et al. Evaluation of the drug interaction between intravenous high-dose fluconazole and cyclosporine or tacrolimus in bone marrow transplant patients. Transplantation 1996; 61: 1268-72.
  1. Mañez R, Martin M, Raman D, et al. Fluconazole therapy in transplant recipients receiving FK506. Transplantation 1994; 27: 1521-3.
  1. Sheiner P, Mor E, Chodoff L, et al. Acute renal failure associated with the use of ibuprofen in two liver transplant recipients on FK506. Transplantation 1994; 57: 1131.
  1. Golling M, Lehmann T, Senninger N, et al. Tacrolimus reduction improves glucose metabolism and insulin secretion after liver transplantation. Transplant Proc 1996; 28: 3180-2.
  1. Kiuchi T, Tanaka K, Inomata Y, et al. Experience of tacrolimus-based immunosuppression in living-related liver transplantation complicated with graft tuberculosis: interaction with rifampicin and side effects. Transplant Proc 1996; 28: 3171-2.
  1. Furlan V, Perello L, Jacquemin E, et al. Interactions between FK506 and rifampicin or erythromycin in pediatric liver recipients. Transplantation 1995; 59: 1217-8.
  1. CDC: Recommendations of the Advisory Committee on Immunization Practices: Use of vaccines and immune globulins in persons with altered immunocompetence. MMWR Morb Mortal Wkly Rep 1993; 42(RR-4): 1-18.
  1. Steinmüller T, Graf K, Schleicher J, et al. The effect of FK506 versus cyclosporine on glucose and lipid metabolism—a randomized trial. Transplantation 1994; 58: 669-74.
  1. Loss M, Winkler M, Schneider A, et al. Glucose and lipid metabolism in liver transplant patients under long-term tacrolimus (FK 506) monotherapy. Transplant Proc 1996; 28: 1006-7.
  1. Wu Y, Venkataramanan R, Suzuki M, et al. Interaction between FK 506 and cyclosporine in dogs. Transplant Proc 1991; 23: 2797-9.
  1. Pichard L, Fabre I, Domergue J, et al. Effect of FK 506 on human hepatic cytochrome P-450: interaction with CyA. Transplant Proc 1991; 23: 2791-3.
  1. Omar G, Ali Shah I, Thomson A, et al. FK 506 inhibition of cyclosporine metabolism by human liver microsomes. Transplant Proc 1991; 23: 934-5.
  1. Porayko M, Textor S, Krom R, et al. Nephrotoxicity of FK 506 and cyclosporine when used as primary immunosuppression in liver transplant recipients. Transplant Proc 1993; 25: 665-8.
  1. McMaster P, Mirza D, Ismail T, et al. Therapeutic drug monitoring of tacrolimus in clinical transplantation. Ther Drug Monit 1995; 17: 602-5.
  1. Esquivel C, So S, McDiarmid S, et al. Suggested guidelines for the use of tacrolimus in pediatric liver transplant patients. Transplantation 1996; 61: 847-9.
  1. Kershner R, Fitzsimmons. Relationship of FK506 whole blood concentrations and efficacy and toxicity after liver and kidney transplantation. Transplantation 1996; 62: 920-6.
  1. Jusko W, Thomson A, Fung J, et al. Consensus document: therapeutic monitoring of tacrolimus (FK-506). Ther Drug Monit 1995; 17: 606-14.
  1. Suzuki S, Osaka Y, Nakai I, et al. Pure red cell aplasia induced by FK506. Transplantation 1996; 61: 831-2.
  1. Winkler M, Schulze F, Jost U, et al. Anaemia associated with FK 506 immunosuppression. Lancet 1993; 341: 1035-6.
  1. Mach-Pascual S, Samil K, Beris P. Microangiopathic hemolytic anemia complicating FK506 (tacrolimus) therapy. Am J Hematol 1996; 52: 310-2.
  1. Alessiani M, Cillo U, Fung J, et al. Adverse effects of FK 506 overdosage after liver transplantation. Transplant Proc 1993; 25: 628-34.
  1. Williams E, Oatridge A, Holdcroft A, et al. Posterior leucoencephalopathy syndrome. Lancet 1996; 347: 1556-7.
  1. Mueller A, Platz K, Bechstein W, et al. Neurotoxicity following orthotopic liver transplantation: a comparison between cyclosporine and FK506. Transplantation 1994; 58: 155-69.
  1. Hold.
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  1. Mueller A, Platz K, Christe W, et al. Severe neurotoxicity after liver transplantation: association between FK 506 therapy and hepatitis C virus disease. Transplant Proc 1994; 26: 3131-2.
  1. Christe W. Neurological disorders in liver and kidney transplant recipients. Transplant Proc 1994; 26: 3175-6.
  1. Frank B, Perdrizet G, White H, et al. Neurotoxicity of FK 506 in liver transplant recipients. Transplant Proc 1993; 25: 1887-8.
  1. Mor E, Sheiner P, Schwartz M, et al. Reversal of severe FK506 side effects by conversion to cyclosporine-based immunosuppression. Transplantation 1994; 58: 380-2.
  1. Guy S, Fisher A, Schwartz M, et al. Immunosuppressive conversion for relief of side effects. Transplant Proc 1994; 26: 3235-6.
  1. Laskow D, Vincenti F, Neylan J, et al. Phase II FK 506 multicenter concentration control study: one-year follow-up. Transplant Proc 1995; 27: 809-11.
  1. Shaw L, Kaplan B, Kaufman D. Toxic effects of immunosuppressive drugs: mechanisms and strategies for controlling them. Clin Chem 1996; 42: 1316-21.
  1. Mor E, Schwersenz A, Sheiner P, et al. Reversal of gastrointestinal toxicity associated with long-term FK506 immunosuppression by conversion to cyclosporine in liver transplant recipients. Transplantation 1994; 57: 1130-1.
  1. Fisher A, Schwartz M, Mor E, et al. Gastrointestinal toxicity associated with FK 506 in liver transplant recipients. Transplant Proc 1994; 26: 3106-7.
  1. Fisher A, Mor E, Hytiroglou P, et al. FK506 hepatotoxicity in liver allograft recipients. Transplantation 1995; 59: 1631-2.
  1. Johnson M, Washburn W, Freeman R, et al. Hepatitis C viral infection in liver transplantation. Arch Surg 1996; 131: 284-91.
  1. Jindal R, Popescu I, Schwartz, et al. Diabetogenicity of FK506 versus cyclosporine in liver transplant recipients. Transplantation 1994; 58: 360-2.
  1. Furth S, Neu A, Colombani P, et al. Diabetes as a complication of tacrolimus (FK506) in pediatric renal transplant patients. Pediatr Nephrol 1996; 10: 64-6.
  1. Tabasco-Minguillan J, Mieles L, Carroll P, et al. Long-term insulin requirements after liver transplantation with FK506 in American veterans. Transplant Proc 1993; 25: 677-8.
  1. Tanabe K, Koga S, Takahashi K, et al. Diabetes mellitus after renal transplantation under FK 506 (tacrolimus) as primary immunosuppression. Transplant Proc 1996; 28: 1304-5.
  1. Hold.
  1. Hold.
  1. Senninger N, Golling M, Gatsis K, et al. Glucose metabolism following liver transplantation and immunosuppression with cyclosporine A or FK 506. Transplant Proc 1995; 27: 1127-8.
  1. Loss M, Winkler M, Schneider A, et al. Influence of long-term cyclosporine or FK 506 therapy on glucose and lipid metabolism in stable liver graft recipients. Transplant Proc 1995; 27: 1136-9.
  1. O'Gorman M, Fivush B, Wise B, et al. Proximal renal tubular acidosis secondary to FK506 in pediatric liver transplant patients. Clin Transplant 1995; 9: 312-6.
  1. Platz K, Mueller A, Blumhardt G, et al. Nephrotoxicity following orthotopic liver transplantation: a comparison between cyclosporine and FK506. Transplantation 1994; 58: 170-8.
  1. Lemoine A, Azoulay D, Dennison A, et al. FK 506 renal toxicity and lack of detectable cytochrome P-450 3A in the liver graft of a patient undergoing liver transplantation. Hepatology 1994; 20: 1472-7.
  1. Morozumi K, Sugito K, Oda A, et al. A comparative study of morphological characteristics of renal injuries of tacrolimus (FK506) and cyclosporine (CyA) in renal allografts: are the morphologic characteristics of FK506 and CyA nephrotoxicity similar? Transplant Proc 1996; 28: 1076-8.
  1. Nielsen F, Leyssac P, Kemp E, et al. Nephrotoxicity of FK 506: a preliminary study on comparative aspects of FK 506 and cyclosporine nephrotoxicity. Transplant Proc 1994; 26: 3104-5.
  1. The US Multicenter FK 506 Liver Study Group. Comparing nephrotoxicity of FK 506 and cyclosporine regimens after liver transplantation: preliminary results from US Multicenter Trial. Transplant Proc 1995; 27: 1114-6.
  1. Sakamoto K, Yamada K, Arita S, et al. Sodium-losing nephropathy and distal tubular damage of transplant kidneys with FK506 administration. Transplant Proc 1995; 27: 826-8.
  1. Bäckman L, Nicar M, Levy M, et al. Chronic nephrotoxicity of FK 506 after liver transplantation. Transplant Proc 1994; 26: 1803.
  1. Frei U, Wagner K. Renal function in liver transplant patients receiving FK506 or cyclosporin A immunosuppressive therapy. Transplant Proc 1994; 26: 3270-1.
  1. Stock P, Ascher N, Osorio R, et al. Standard sequential immunosuppression with Minnesota antilymphoblast globulin and cyclosporine vs FK 506: a comparison of early nephrotoxicity. Transplant Proc 1993; 25: 675-6.
  1. Japanese FK 506 Study Group. Morphological characteristics of renal allografts showing renal dysfunction under FK 506 therapy: is graft biopsy available to reveal the morphological findings corresponding with FK 506 nephrotoxicity? Transplant Proc 1993; 25: 624-7.
  1. Hold.
  1. Hold.
  1. Singh N, Gayowski T, Wagener M, et al. Increased infections in liver transplant recipients with recurrent hepatitis C virus hepatitis. Transplantation 1996; 61: 402-6.
  1. Roth D, Zucker K, Cirocco R, et al. A prospective study of hepatitis C virus infection in renal allograft recipients. Transplantation 1996; 61: 886-9.
  1. Singh N, Gayowski T, Wagener M, et al. Pulmonary infections in liver transplant recipients receiving tacrolimus; changing patterns of microbial etiologies. Transplantation 1996; 61: 396-401.
  1. Kusne S, Manez R, Bonet H, et al. Infectious complications after small bowel transplantation in adults. Transplant Proc 1994; 26: 1682-3.
  1. Barkholt L, Ehrnst A, Veress B, et al. New criteria for diagnosing cytomegalovirus hepatitis in liver transplant patients. Transplant Proc 1995; 27: 1224-5.
  1. Singh N, Gayowski T, Wagener M, et al. Infectious complications in liver transplant recipients on tacrolimus. Transplantation 1994; 58: 774-8.
  1. Singh N, Gayowski T, Ndimbie O, et al. Recurrent hepatitis C virus hepatitis in liver transplant recipients receiving tacrolimus: association with rejection and increased immunosuppression after transplantation. Surgery 1996; 119: 452-6.
  1. Park K, Hay J, Lee S, et al. Bone loss after orthotopic liver transplantation: FK 506 versus cyclosporine. Transplant Proc 1996; 28: 1738-40.
  1. Dollinger M, Plevris J, Chauhan A, et al. Tacrolimus and cardiotoxicity in adult liver transplant recipients. Lancet 1995; 346: 507.
  1. Hold.
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  1. Atkinson P, Joubert G, Barron A, et al. Hypertrophic cardiomyopathy associated with tacrolimus in paediatric transplant patients. Lancet 1995; 345: 894-6.
  1. Hanafusa T, Ichikawa Y, Kyo M, et al. Long-term impact of hepatitis virus infection on kidney transplant recipients and a pilot study of the effects of interferon alpha on chronic hepatitis C. Transplant Proc 1995; 27: 956-7.
  1. Mañez R, Demetrius A, Starzl T. Rejection and hepatitis in liver transplants. Transplantation 1995; 57: 1824-5.
  1. Hold.
  1. Abouljoud M, Levy M. Klintmalm G, et al. Hyperlipidemia after liver transplantation: long-term results of the FK506/cyclosporine A US Multicenter Trial. Transplant Proc 1995; 27: 1121-3.
  1. KoKado Y, Takahara S, Kameoka H, et al. Hypertension in renal transplant recipients and its effect on long-term renal allograft survival. Transplant Proc 1996; 28: 1600-2.
  1. Deschler D, Osorio R, Ascher N, et al. Posttransplantation lymphoproliferative disorder in patients under primary tacrolimus (FK 506) immunosuppression. Arch Otolaryngol Head Neck Surg 1995; 121: 1037-41.
  1. Reyes J, Tzakis A, Bonet H, et al. Lymphoproliferative disease after intestinal transplantation under primary FK 506 immunosuppression. Transplant Proc 1994; 26: 1426-7.
  1. Martinez O, Villanueva J, Lawrence-Miyasaki L, et al. Molecular markers of Epstein-Barr virus infection in the circulation of transplant recipients. Transplant Proc 1995; 27: 1211-2.
  1. Taormino D, Abdallah H, Venkataramanan R, et al. Stability and sorption of FK 506 in 5% dextrose injection and 0.9% sodium chloride injection in glass, polyvinyl chloride, amd polyolefin containers. Am J Hosp Pharm 1992; 49: 119-22.
  1. Hold.
  1. Reynolds J, Trellis D, Abu-Elmagd K, et al. The rationale for FK 506 in inflammatory bowel disease. Can J Gastroenterol 1993; 7: 208-10.
  1. Todo S, Tzakis A, Abu-Elmagd K, et al. Intestinal transplantation in composite visceral grafts or alone. Ann Surg 1992; 216: 223-34.
  1. Todo S, Tzakis A, Abu-Elmagd K, et al. Cadaveric small bowel and small bowel-liver transplantation in humans. Transplantation 1992; 53: 369-76.
  1. Armitage J, Kormos R, Griffith B, et al. The clinical trial of FK 506 as primary and rescue immunosuppression in cardiac transplantation. Transplant Proc 1991; 23: 1149-52.
  1. Starzl T, Donner A, Eliasziw M, et al. Randomized trialomania? The multicenter liver transplant trials of tacrolimus. Lancet 1995; 346: 1346-50.
  1. Todo S, Fung J, Tzakis A, et al. One hundred ten consecutive primary orthotopic liver transplants under FK 506 in adults. Transplant Proc 1991; 23: 1397-402.
  1. Todo S, Fung J, Demetrius A, et al. Early trials with FK 506 as primary treatment in liver transplantation. Transplant Proc 1990; 22: 13-6.
  1. Fung J, Abu-Elmagd K, Jain A, et al. A randomized trial of primary liver transplantation under immunosuppression with FK 506 versus cyclosporine. Transplant Proc 1991; 23: 2977-83.
  1. Fung J, Todo S, Jain A, et al. Conversion of liver allograft recipients with cyclosporine related complications from cyclosporine to FK 506. Transplant Proc 1990; 22: 6-12.
  1. Starzl T, Todo S, Fung J, et al. FK 506 for human liver, kidney, and pancreas transplantation. Lancet 1989; 2: 1000-4.
  1. Todo S, Fung J, Starzl T, et al. Liver, kidney, and thoracic organ transplantation under FK 506. Ann Surg 1990; 212: 295-305.
  1. Armitage J, Fricker F, Kurland G, et al. Pediatric lung transplantation: the years 1985 to 1992 and the clinical trial of FK 506. J Thorac Cardiovasc Surg 1993; 105: 337-46.
  1. Armitage J, Kormos R, Fung J, et al. Preliminary experience with FK 506 in thoracic transplantation. Transplantation 1991; 52: 154-67.
  1. Starzl T, Fung J, Jordan M, et al. Kidney transplantation under FK 506. JAMA 1990; 264: 63-7.
  1. Shapiro R, Jordan M, Fung J, et al. Kidney transplantation under FK 506 immunosuppression. Transplant Proc 1991; 23: 920-3.
  1. Corry R, Egidi M, Shapiro R, et al. Pancreas transplantation with enteric drainage under tacrolimus induction therapy. Transplant Proc 1997; 29: 642.
  1. Starzl T, Abu-Elmagd K, Tzakis A, et al. Selected topics on FK 506, with special references to rescue of extrahepatic whole organ grafts, transplantation of “forbidden organs,” side effects, mechanisms, and practical pharmacokinetics. Tranplant Proc 1991; 23: 914-9.
  1. Abu-Elmagd K, Fung J, Alessiani M, et al. The effect of graft function on FK 506 plasma levels, dosages, and renal function, with particular reference to the liver. Transplantation 1991; 52: 71-7.
  1. Nalesnik M, Demetris A, Fung J, et al. Lymphoproliferative disorders arising under immunosuppression with FK 506: initial observations in a large transplant population. Transplant Proc 1991; 23: 1108-10.
  1. Stiff D, Venkataramanan R, Prasad T. Metabolism of FK 506 in differentially induced rat liver microsomes. Res Commun Chem Pathol Pharmacol 1992; 78: 121-4.
  1. Sattler M, Guengerich F, Yun C, et al. Cytochrome P450 3A enzymes are responsible for biotransformation of FK 506 and rapamycin in man and rats. Metabolism 1992; 20: 753-61.
  1. Hold.
  1. Peters D, Fitton A, Plosker G. Tacrolimus. A review of its pharmacology and therapeutic potential in hepatic and renal transplantation. Drugs 1993; 46: 746-94
  1. Todo S, Fung J, Starzl T, et al. Liver, kidney, and thoracic organ transplantation under FK 506. Ann Surg 1990; 212: 295-305.
  1. Starzl T, Todo S, Fung J, et al. FK 506 for liver, kidney, and pancreas transplantation. Lancet 1989; 2: 1000-4.
  1. Jacobson P, Johnson C, West N, et al. Stability of tacrolimus in an extemporaneously compounded oral liquid. Am J Health Syst Pharm 1997; 54: 178-80.
  1. Rodriguez Rilo H, Subbotin V, Selby R, et al. Rapid hair regrowth in refractory alopecia universalis associated with autoimmune disease following liver transplantation and tacrolimus (FK506) therapy. Transplantation 1995; 59: 1350-3.
  1. Van Thiel D, Wright H, Carroll P, et al. Tacrolimus: a potential new treatment for autoimmune chronic active hepatitis: results of an open-label preliminary trial. Am J Gastroenterol 1995; 90: 771-6.
  1. Thomson A, Carroll P, McCauley J, et al. FK 506: a novel immunosuppressant for treatment of autoimmune disease. Rationale and preliminary clinical experience at the University of Pittsburgh. Springer Semin Immunopathol 1993; 14: 323-44.
  1. Panel comment, 7/97.
  1. Mrvos R, Hodgman M, Krenzelok E. Tacrolimus (FK 506) overdose: a report of five cases. Clin Toxicol 1997; 35: 395-9.
  1. Fleeger CA, editor. USP dictionary of USAN and international drug names 1997. Rockville, MD: The United States Pharmacopeial Convention, Inc; 1996. p. 687.
  1. Dressler D, Boswell G, Tracewell W, et al. Concomitant administration of antacids and tacrolimus did not alter tacrolimus absorption in normal volunteers. ASTP 16th annual meeting; 1997 May 10-14; Chicago abstract p. 131.
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