Rapid, variable, and incomplete from the gastrointestinal tract1,11,141,143,144,145,146,147,148,155,156; 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 ingested155.

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

Distribution:

The volume of distribution (VolD) 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 VolD based on plasma concentration is much higher than the VolD based on whole blood concentrations, the difference reflecting the binding of tacrolimus to the red blood cells145,155. The mean VolDfor patients with liver allografts when measured in whole blood is 0.9 L/kg156.

Protein binding:

High to very high (75 to 99%), primarily to albumin and alpha1-acid glycoprotein1,145.

Biotransformation:

Hepatic, extensive, primarily by the cytochrome P450 3A enzymes1,157,158,283,284.

Half-life:

Distribution¾
0.9 hour147.

Elimination¾
Biphasic, variable: Terminal¾11.3 hours (range, 3.5 to 40.5 hours)141,148.

Time to peak concentration:

0.5 to 4 hours after oral administration141,148,155,156.

Note: The rate of absorption is reduced when tacrolimus is given with food145.

Peak serum concentration:

Plasma or blood¾Whole blood concentrations may be 12 to 67 times the
plasma concentrations1,155,156.

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
patients153,154.

In dialysis¾
Tacrolimus is not removed by dialysis141.

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 vehicle1.

Carcinogenicity

Tacrolimus is associated with an increased risk of malignancy, especially lymphomas and skin malignancies1. 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 regimens1,28,282.

Tumorigenicity

Studies in mice and rats did not show a relationship between the dose of tacrolimus and the incidence of tumors1.

Mutagenicity

Mutagenicity was not observed in bacterial or Chinese hamster cell in vitro testing, or in vivo tests performed in mice or rat hepatocytes1.

Pregnancy/Reproduction

Fertility¾Adequate and well-controlled studies have not been done in humans1.

Pregnancy¾Tacrolimus crosses the placenta1,162. 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 neonates1,160,161,162. One case of intrauterine growth retardation has been reported161. 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 transplantations162.

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 births1.

FDA Pregnancy Category C1.

Breast-feeding

Tacrolimus is distributed into breast milk1,162. Breast-feeding should be avoided during tacrolimus therapy1.

Pediatrics

Pediatric patients require higher doses of tacrolimus per kg of body weight to maintain trough concentrations similar to those of adult patients1,35,146,153,154. 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 age159,282.

Geriatrics

No information is available on the relationship of age to the effects of tacrolimus in geriatric patients1. Tacrolimus has been used in geriatric patients undergoing transplantation19; 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)¾not 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 vitroor in experimental animal models283.

The extent of induction or inhibition of cytochrome P450 enzymes may depend on the dose of the inducer or inhibitor285.

Aluminum hydroxide gel163¾(adsorbs tacrolimus; may lead to reduced blood concentrations of tacrolimus)

Bromocriptine164,165 or
Cimetidine167 or
Clarithromycin169 or
Clotrimazole170 or
>> Danazol167,171 or
Diltiazem167,175,177 or
Ethinyl estradiol165,177or
>> Erythromycin164,165,167,177,179,182,183,184 or
>> Fluconazole122,166,167,176,177,186 or
>> Itraconazole167,176,177 or
>> Ketoconazole164,167,165,176,177or
Nifedipine165,177 or
Omeprazole165 or
Verapamil164,165,167¾(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 used1,11)

Note: No interaction between fluconazole and tacrolimus was noted in one study in which the medications were administered intravenously to patients receiving bone marrow transplantation185. The mechanism of this interaction may be inhibition of metabolism of tacrolimus in the gut, leading to increased absorption185. This interaction may not occur to the same extent when tacrolimus is given intravenously as when it is given orally185.

Dexamethasone155,176,177,283 or
>> Rifampin155,153,189,190¾(may induce cytochrome P450 3A enzymes, leading to increased metabolism of tacrolimus and lower blood concentrations1,153,155)

>> Cyclosporine1,11¾(increased immunosuppression; tacrolimus may increase the bioavailability of cyclosporine194, or may inhibit the metabolism of cyclosporine165,195,196, leading to increased cyclosporine blood concentrations and toxicity; increased risk of nephrotoxicity with concurrent use)

Hyperkalemia-causing medications1 (see Appendix II), especially:
>> Diuretics, potassium-sparing¾¾(concurrent use with tacrolimus may result in hyperkalemia1)

Magnesium oxide163 or
Sodium bicarbonate155,163¾(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 bioavailability296)

Muromonab-CD3¾(increased incidence of post-transplant lymphoproliferative disorder [PTLD] with concurrent use12)

Nephrotoxic medications172 (see Appendix II), such as:
Aminoglycosides or
Amphotericin B or
Anti-inflammatory drugs, nonsteroidal or
Vancomycin¾¾(may be additive or synergistic impairment of renal function1,11,22,187)

Vaccines, killed virus¾(immune response to vaccines may be decreased1,191)

>> Vaccines, live virus¾(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 vaccine1,191)

Laboratory value alterations

The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)¾not necessarily inclusive (>> = major clinical significance):

With physiology/laboratory test values
Alanine aminotransferase (ALT [SGPT]) and
Alkaline phosphatase and
Aspartate aminotransferase (AST [SGOT])¾(values may be increased1; may indicate hepatotoxicity1)

Bilirubin, serum¾(concentrations may be increased1; may indicate hepatotoxicity1)

Blood urea nitrogen (BUN) and
>> Creatinine, serum1¾(concentrations may be increased1; may indicate nephrotoxicity1,27,28)

Calcium and
>> Magnesium, serum¾(concentrations may be decreased1)

Cholesterol, serum¾(values may be increased1,192,193)

>> Glucose, blood and
Triglycerides, serum¾(concentrations may be increased1,192,193)

Hematocrit value and
Hemoglobin concentration¾(may be decreased1)

Leukocytes (neutrophils [WBC])¾(blood counts may be increased or decreased1)

Platelets¾(blood counts may be decreased1)

Phosphate and
>> Potassium1¾(serum concentrations may be increased1,28)

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)¾not 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 oil¾(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 contraindicated1)

>> Allergy to tacrolimus, history of1¾

>> Malignancy, current¾(Tacrolimus use is associated with an increased susceptibility to malignancies1)

Risk-benefit should be considered when the following medical problems exist

>> Chickenpox, existing or recent (including recent exposure) or
>> Herpes zoster¾risk of severe generalized disease

Diabetes mellitus¾(risk of loss of glucose control)

Hepatic function impairment or
Hepatitis B or C infection, chronic or
>> Renal function impairment¾(dosage reduction may be required1,280,281; patients with post-transplant hepatic function impairment may have an increased risk of renal toxicity when taking tacrolimus197)

Hyperkalemia1¾(tacrolimus may exacerbate hyperkalemia)

>> Infection¾(immunosuppression may exacerbate infections1)

Neurologic function impairment¾(dosage reduction may be required1)

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, serum¾(recommended periodically to monitor hepatic function; more frequent monitoring required in the early post-transplant period)

Blood urea nitrogen (BUN) and
>> Creatinine, serum¾(recommended to monitor for nephrotoxicity; nephrotoxicity occurs most often in the early post-transplant period, especially if intravenous tacrolimus is administered)

>> Blood pressure measurements¾(frequent measurements recommended)

Calcium and
>> Magnesium and
Phosphate and
>> Potassium¾(frequent monitoring recommended in the early post-transplant period; periodic monitoring recommended thereafter)

Cholesterol, serum and
Triglycerides, serum¾(periodic monitoring recommended)

Complete blood counts (CBCs)¾(monitoring of CBC recommended to detect tacrolimus-induced blood dyscrasias; changes in the neutrophil count may also indicate infection)

>> Glucose, blood¾(frequent monitoring recommended in the early post-transplant period; periodic monitoring recommended thereafter)

>> Tacrolimus concentrations, whole blood, trough¾(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 transplantation172; for the subsequent 2 months, lower blood concentrations [i.e., 5 to 15 mcg/mL (6.1 to 18.3 micromoles/L)] are often recommended172,198; 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] thereafter199; 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] thereafter61)
(trough blood concentrations should be measured frequently in the early post-transplant period172; 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 hospitalization172; concentrations should be measured after adjustment in the tacrolimus dose, and after the addition or removal of medications that may alter tacrolimus absorption or clearance172)
(high tacrolimus blood concentrations are correlated with toxicity198,200,201; low tacrolimus blood concentrations are not as well-correlated with episodes of rejection198,200,201; 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)¾not necessarily inclusive:

 

Those indicating need for medical attention

Incidence more frequent
Asthenia93 loss of energy or weakness); blood dyscrasias28,93,103,202,203,204 including red cell aplasia (fever and sore throat; pale skin; unusual bleeding or bruising; unusual tiredness or weakness); gastrointestinal disturbance28,33,50,55,67,70,78,79,85,93,101,214,217,218, including abdominal pain93,101diarrhea28,67,79,93,127loss of appetite28,79,93,217nausea28,67,79,93,101,113vomiting28,67,93,113; hyperglycemia16,19,27,28,29,36,38,70,73,78,81,82,87,93,101,109,110,113,192,193, 205,207,214,215,221,222,223,224,227,228 frequent urination); hyperkalemia28,38,93,101,113,205 (abdominal pain; nausea or vomiting; weakness); hypomagnesemia1 (muscle trembling or twitching); infection10,16,19,27,28,29,31,33,36,38,45,47,55,67,70,75,78,85,89,93,101,103,2152, 2,243,244,245,246,247 fever or chills); nephrotoxicity19,20,27,28,29,36,38,39,47,50,55,67,73,78,80,81,85,89,93,108,109,110, 112,113,187,197,205,207,214,215,216,229,230,231,232,233,234,235,236,237,238,239; neurotoxicity16,20,27,28,29,31,33,36,38,50,55,67,70,78,79,82,89,93,101,109,110,112, 113,205,206,207,210,211,212,214,215,216, including abnormal dreamsagitationanxietyconfusion211depression217dizziness79hallucinations (seeing or hearing things that are not there)headache28,79,93,101,109,110,113,211,215insomnia79,93,127,211,215 (trouble in sleeping)nervousnessseizures27,31,38,211tremor27,28,36,79,93,101,113 trembling and shaking of hands)paresthesia27,28,127,211,215 tingling); peripheral edema93 swelling of ankles, feet, or lower legs); pleural effusion shortness of breath78); pruritus28,79,93 itching); skin rash28,78

Incidence less frequent
Cardiovascular effects16,19,33,70,78, including cardiomyopathy250,253 shortness of breath)chest pain79hyperlipidemia192,257hypertension16,19,28,31,38,39,78,109,216,258; hyperesthesia79 (increased sensitivity to pain); muscle cramps79; neuropathy27 numbness or pain in legs); osteoporosis249; sweating79; tinnitus79 ringing in ears); visual disturbance79 (blurred vision)

Incidence rare
Anaphylaxis flushing of face or neck; shortness of breath; wheezing)¾with parenteral use; hepatotoxicity39,93,219 flu-like symptoms); PTLD9,10,16,38,39,55,75,78,101,103,259,260,261 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 age159.

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 tacrolimus1. The patients receiving the overdoses of tacrolimus experienced more new-onset diabetes, nephrotoxicity, and neurotoxicity as compared to patients receiving lower doses1.

There is limited literature on the effects of massive overdoses of tacrolimus in humans1. 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 overdose1,294.

In toxicity studies in rats, mortalities first occurred at intravenous doses 16 times the recommended human dose1.

Treatment of overdose

Treatment is symptomatic and supportive1. Clearance of tacrolimus cannot be enhanced by dialysis because tacrolimus is extensively bound to erythrocytes and plasma proteins1.

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

CarcinogenicityUse of tacrolimus is associated with an increased incidence of malignancy

Pregnancy¾Tacrolimus crosses the placenta; transplant patients should not conceive shortly after transplantation or while being treated for transplant-related complications

Breast-feeding¾Tacrolimus is distributed into breast milk; breast-feeding should be avoided

Dental¾Dental 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 dosingMissed 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 patient1,172. 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)1. 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 transplantation172. In some cases, it may be possible to wean the patient from other immunosuppressants and maintain the patient on tacrolimus monotherapy153,172.

When converting from cyclosporine to tacrolimus, it is recommended that cyclosporine be discontinued 24 hours before initiating tacrolimus therapy1,172. 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 initially172. Liver transplant patients with poor hepatic graft function have increased risk for developing renal function impairment1,281.

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 graft199.

Vaccination schedules should be continued, except for live vaccines191. 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 response191. 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 globulin159.

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 orally172. When receiving parenteral tacrolimus, patients should be monitored closely for anaphylaxis, especially during the first 30 minutes of the infusion1. Patients receiving tacrolimus parenterally should be switched to oral tacrolimus as soon as it can be tolerated1,172.

Diet/Nutrition

The rate of absorption of oral tacrolimus is decreased in the presence of food145, but the extent of absorption may or may not be affected, depending on the type of food ingested155. Tacrolimus should be given consistently with relation to food172,199.

Bioavailability of tacrolimus may be increased by ingestion of grapefruit or grapefruit juice, resulting in toxic blood concentrations of tacrolimus1.

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 dose1,172,188. If adverse effects do not respond to a reduction in dose, it may be advisable to convert the patient to a cyclosporine-based immunosuppressant regimen172,213,217.

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)* or
[Transplant rejection, solid organ, other (prophylaxis)]*or
[Transplant rejection, liver (treatment)] or
[Transplant rejection, solid organ, other (treatment)]*¾
Oral, 0.1 to 0.15 mg per kg of body weight per day, in two divided doses, initially153,172. The dose should be adjusted based on trough blood concentrations1.

[Graft-versus-host disease (prophylaxis)107,109]*¾
Oral, 0.12 mg per kg of body weight per day in two divided doses, starting when the patient can tolerate oral medications109. The dose should be adjusted based on trough blood concentrations109.

[Graft-versus-host disease (treatment)]*¾
Oral, 0.3 mg per kg of body weight per day in two divided doses, starting when the patient can tolerate oral medications113. The dose should be adjusted based on trough blood concentrations.

Tacrolimus is used as part of a regimen to treat graft-versus-host disease113. Other agents used to treat graft-versus-host disease may include methotrexate and/or corticosteroids113.

[Uveitis, severe, refractory (treatment)]*131,132,133,134¾
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)* or
[Transplant rejection, solid organ, other (prophylaxis)]*or
[Transplant rejection, liver (treatment)] or
[Transplant rejection, solid organ, other (treatment)]*¾
Oral, 0.1 to 0.3 mg per kg of body weight per day, in two divided doses, initially61,153,199. The dose should be adjusted based on trough blood concentrations1.

[Graft-versus-host disease (prophylaxis)]*¾
See Usual adult and adolescent dose. Pediatric patients may require higher doses to attain therapeutic blood trough concentrations.

[Graft-versus-host disease (treatment)]*¾
See Usual adult and adolescent dose. Pediatric patients may require higher doses to attain therapeutic blood trough concentrations112.

Usual geriatric dose

See Usual adult and adolescent dose.

Strength(s) usually available

U.S.¾
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)].

Canada¾
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 °C (59 and 86 °F).

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 suspension289.

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 orally172. Patients receiving tacrolimus parenterally should be switched to oral tacrolimus as soon as it can be tolerated1,172.

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 medications* or
[Transplant rejection, solid organ, other (prophylaxis), in patients unable to take oral medications]* 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]*¾
Continuous intravenous infusion, 0.01 to 0.05 mg per kg of body weight per day172, beginning no sooner than six hours after transplantation. The dose should be adjusted based on trough blood concentrations.

[Graft-versus-host disease (prophylaxis)]*¾
Intravenous infusion, 0.04 mg per kg of body weight per day as a continuous infusion started the day prior to bone marrow transplantation108. The dose should be adjusted based on trough blood concentrations108.

[Graft-versus-host disease (treatment)]*¾
Intravenous infusion, 0.1 mg per kg of body weight per day in two divided doses administered over four hours for each infusion113. The dose should be adjusted based on trough blood concentrations113.

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 medications* or
[Transplant rejection, solid organ, other (prophylaxis), in patients unable to take oral medications]* 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]*¾
See Usual adult and adolescent dose.

[Graft-versus-host disease (prophylaxis)]*¾
See Usual adult and adolescent dose. Pediatric patients may require higher doses to attain therapeutic blood trough concentrations.

[Graft-versus-host disease (treatment)]*¾
Intravenous infusion, 0.1 mg per kg of body weight per day as a continuous infusion112.

Usual geriatric dose

See Usual adult and adolescent dose.

Strength(s) usually available

U.S.¾
5 mg per mL (Rx)[Prograf (anhydrous) (alcohol 80% v/v) (polyoxyl 60 hydrogenated castor oil 200 mg per mL)].

Canada¾
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 °C (41 and 77 °F).

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)1.

Stability:

Diluted tacrolimus for injection should be used within 24 hours1. The prepared solution should be inspected for particulate matter and clarity before administration to the patient, and should be discarded if particulate matter is present1.

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 occur1,262.
====================================
References
===================================
1Prograf package insert (Fujisawa¾US), Rev 4/97, Rec 6/97.

2Prograf package insert (Fujisawa¾Canada), Rev 11/95, Rec 3/97.

3Todo S, Tzakis A, Reyes J, et al. Intestinal transplantation in humans under FK 506. Transplant Proc 1993; 25: 1198-9.

4Abu-Elmagd K, Tzakis A, Todo S, et al. Monitoring and treatment of intestinal allograft rejection in humans. Transplant Proc 1993; 25: 1202-3.

5Abu-Elmagd K, Todo S, Tzakis A, et al. Three years of clinical experience with intestinal transplantation. J Am Coll Surg 1994; 179: 385-400.

6Grant D. Current results of intestinal transplantation. Lancet 1996; 347: 1801-3.

7Todo S, Tzakis A, Reyes J, et al. Intestinal transplantation at the University of Pittsburgh. Transplant Proc 1994; 26: 1409-10.

8Calne R, Pollard S, Jamieson N, et al. Intestinal transplant for recurring mesenteric desmoid tumour. Lancet 1993; 342: 58-9.

9Todo S, Tzakis A, Reyes J, et al. Abdominal multivisceral transplantation. Transplantation 1995; 59: 234-40.

10Asfar S, Atkinson P, Ghent C, et al. Small bowel transplantation: a life-saving option for selected patients with intestinal failure. Dig Dis Sci 1996; 41: 875-83.

11Kelly P, Burckart G, Ventkataramanan R. Tacrolimus: a new immunosuppressive agent. Am J Health Syst Pharm 1995; 52: 1521-35.

12Transplant Immunology Advisory Panel Meeting, 11/20/96.

13Todo S, Tzakis A, Reyes J, et al. Small intestinal transplantation in humans with or without the colon. Transplantation 1994; 57: 840-8.

14Armitage J, Fricker F, Del Nido P, et al. The clinical trial of FK 506 as primary and rescue immunosuppression in pediatric cardiac transplantation. Transplant Proc 1991; 23: 3058-60.

15Armitage J, Fricker F, Del Nido P, et al. A decade (1982 to 1992) of pediatric cardiac transplantation and the impact of FK 506 immunosuppression. J Thorac Cardiovasc Surg 1993; 105: 464-73.

16Armitage J, Kormos R, Morita S, et al. Clinical trial of FK 506 immunosuppression in adult cardiac transplantation. Ann Thorac Surg 1992; 54: 205-11.

17Pham S, Kormos R, Kawai A, et al. Tacrolimus (FK 506) in clinical cardiac transplantation: a five-year experience. Transplant Proc 1996; 28: 1002-4.

18Pham S, Kormos R, Murali S, et al. Cardiac transplantation at the University of Pittsburgh: 1994 update. Clin Transpl 1994: 121-5.

19Pham S, Kormos R, Hattler B, et al. A prospective trial of tacrolimus (FK 506) in clinical heart transplantation: intermediate-term results. J Thorac Cardiovasc Surg 1996; 111: 764-72.

20Mueller A, Platz K, Blumhardt G, et al. The optimal immunosuppressant after liver transplantation according to diagnosis: cyclosporine A or FK506. Clin Transplant 1995; 9: 176-84.

21Hold.

22Neuhaus P. Optimized first-line FK506-based protocols in liver transplantation: experience from the University Hospital Rudolf Virchow, Berlin. Transplant Proc 1994; 26: 3264-6.

23Hold.

24Todo S, Fung J, Starzl T, et al. Single-center experience with primary orthotopic liver transplantation with FK 506 immunosuppression. Ann Surg 1994; 220: 297-300.

25Fung J, Todo S, Abu-Elmagd K, et al. Randomized trial in primary liver transplantation under immunosuppression with FK 506 or cyclosporine. Transplant Proc 1993; 25: 1130.

26Klintmalm G. Clinical use of FK 506 in liver transplantation. Transplant Proc 1996; 28: 974-6.

27European FK506 Multicentre Liver Study Group. Randomized trial comparing tacrolimus (FK506) and cyclosporin in prevention of liver allograft rejection. Lancet 1994; 344: 423-8.

28The US Multicenter FK506 Liver Study Group. A comparison of tacrolimus (FK 506) and cyclosporine for immunosuppression in liver transplantation. N Engl J Med 1994; 331: 1110-5.

29Neuhaus P, Blumhardt G, Bechstein W, et al. Comparison of FK506- and cyclosporine-based immunosuppression in primary orthotopic liver transplantation. Transplantation 1995; 59: 31-40.

30Bechstein W, Neuhaus P, McMaster P, et al. Tacrolimus (FK 506) therapy is associated with a significant reduction in immunosuppression treatment failures following primary liver transplantation. Transplant Proc 1996; 28: 1008-10.

31Sun C, Chen C, Kuo Y, et al. Intensive care after orthotopic liver transplantation. Transplant Proc 1994; 26: 2246-7.

32Abu-Elmagd K, Todo S, Fung J, et al. Hepatic transplantation at the University of Pittsburgh: new horizons and paradigms after 30 years of experience. Clin Transpl 1994: 133-56.

33Fung J, Eliasziw M, Todo S, et al. The Pittsburgh randomized trial of tacrolimus compared to cyclosporine for hepatic transplantation. J Am Coll Surg 1996; 183: 117-25.

34Cacciarelli T, Esquivel C, Cox K, et al. Oral tacrolimus (FK506) induction therapy in pediatric orthotopic liver transplantation. Transplantation 1996; 61: 1188-92.

35Inomata Y, Tanaka K, Egawa H, et al. The evolution of immunosuppression with FK506 in pediatric living-related liver transplantation. Transplantation 1996; 61: 247-52.

36Bismuth H. Comparison of FK 506- and cyclosporine-based immunosuppression: FK 506 therapy significantly reduces the incidence of acute, steroid-resistant, refractory, and chronic rejection whilst possessing a comparable safety profile. Transplant Proc 1995; 27: 45-9.

37Klintmalm G, Gibbs J, McMillan R, et al. Rejection: FK 506 for rescue or maintenance. Transplant Proc 1993; 25: 1914-5.

38Jain A, Fung J, Todo S, et al. One thousand consecutive primary orthotopic liver transplants under FK 506: survival and adverse events. Transplant Proc 1995; 27: 1099-104.

39Colombani P, Cigarroa F, Schwarz K, et al. Liver transplantation in infants younger than 1 year of age. Ann Surg 1996; 223: 658-62.

40Harrison D, Stewart A, Koneru B, et al. Reduction in hospital stay after liver transplantation. Transplant Proc 1996; 28: 896.

41Andrews W, Sommerauer J, Conlin C, et al. Comparison of cyclosporine- vs tacrolimus-based immunosuppression in pediatric liver transplantation. Transplant Proc 1996; 28: 897-8.

42Knoop C, Antoine M, Vachiery J, et al. FK 506 rescue therapy for irreversible airway rejection in heart-lung transplant recipients: report on five cases. Transplant Proc 1994; 26: 3240-1.

43Bolman R. Advantage¾FK 506: reduced chronic rejection for lung transplant recipients. Ann Thorac Surg 1995; 60: 495-6.

44Griffith B, Bando K, Hardesty R, et al. A prospective randomized trial of FK506 versus cyclosporine after human pulmonary transplantation. Transplantation 1994; 57: 848-51.

45Keenan R, Konishi H, Kawai A, et al. Clinical trial of tacrolimus versus cyclosporine in lung transplantation. Ann Thorac Surg 1995; 60: 580-5.

46Hariharan S, Munda R, Demmy A, et al. Conversion from cyclosporine to tacrolimus after pancreas transplantation. Transplant Proc 1995; 27: 2981-2.

47Ketel B, Turton-Weeks S, Reed K, et al. Tacrolimus-based vs cyclosporine-based immunotherapy in combined kidney-pancreas transplantation. Transplant Proc 1996; 28: 899.

48Burke G, Alejandro R, Roth D, et al. Use of FK 506 in simultaneous pancreas/kidney transplantation: lack of impairment of glycemic or lipid metabolism. Transplant Proc 1995; 27: 3119-20.

49Burke G, Alejandro R, Ciancio G, et al. The use of FK506 in simultaneous pancreas/kidney transplantation: rescue, induction, and maintenance immunosuppression. Transplant Proc 1995; 27: 3123-4.

50Stratta R, Taylor R, Castaldo P, et al. FK 506 induction and rescue therapy in pancreas transplant recipients. Transplant Proc 1996; 28: 991-2.

51Tesi R, Byer-Ashe M, Jaspan J. Conversion of pancreas transplants to FK 506 from CsA. Transplant Proc 1995; 27: 3032-3.

52Swanson C, Rubin M, Colquhoun S, et al. FK 506-based immunosuppression in clinical pancreas transplantation. Transplant Proc 1995; 27: 3031.

53Stratta R, Taylor R, Castaldo P, et al. Preliminary experience with FK 506 in pancreas transplant recipients. Transplant Proc 1996; 28: 991-2.

54Henley S, Larsen J, Mack-Shipman L, et al. Lipids following pancreas transplantation in recipients receiving FK 506. Transplant Proc 1995; 27: 2997.

55Gruessner R, Burke G, Stratta R, et al. A multicenter analysis of the first experience with FK506 for induction and rescue therapy after pancreas transplantation. Transplantation 1996; 61: 261-73.

56Ciancio G, Rosen A, Lereto-Grand B, et al. Current advantage of FK 506 in cadaveric kidney transplantation. Transplant Proc 1996; 28: 1000-1.

57Shapiro R, Jordan M, Scantlebury V, et al. Renal transplantation at the University of Pittsburgh: the impact of FK506. Clin Transpl 1994: 229-36.

58Kitamura M, Hiraga S, Kobayashi D, et al. Clinical experience of FK 506 for renal allograft transplantation. Transplant Proc 1994; 26: 1924-6.

59Japanese FK 506 Study Group. Morphopathological findings of renal allografts under FK 506 therapy. Transplant Proc 1994; 26: 1933-6.

60Sugito K, Morozumi K, Oikawa T. A comparative study of clinicopathologic characteristics of renal allografts under cyclosporine and FK 506 immunosuppression. Transplant Proc 1996; 28: 1335-7.

61Shapiro R, Scantlebury V, Jordan M, et al. Tacrolimus in pediatric renal transplantation. Transplantation 1996; 62: 1752-8.

62Ota K. Living donor kidney transplantation in Japan. Transplant Proc 1994; 26: 2084-8.

63Shapiro R, Jordan M, Scantlebury V. Randomized trial of FK 506/prednisone vs FK 506/azathioprine/prednisone after renal transplantation: preliminary report. Transplant Proc 1993; 25: 669-72.

64Japanese FK 506 Study Group. Japanese study of FK 506 on kidney transplantation: results of late Phase II study. Transplant Proc 1993; 25: 649-54.

65McCauley J, Shapiro R, Jordan M, et al. FK 506 in the management of nephrotic syndrome after renal transplantation. Transplant Proc 1993; 25: 1351-54.

66Birk P, Cook M, Schmidt W, et al. Preliminary experience with FK 506 in pediatric renal transplant recipients: a single-center report. Transplant Proc 1996; 28: 993-4.

67US Multicenter FK506 Kidney Transplant Group. One year follow-up of an open-label trial of FK506 for primary kidney transplantation. Transplantation 1996; 61: 1576-81.

68Shapiro R, Jordan M, Scantlebury V, et al. Randomized trial of FK 506/prednisone vs FK 506/azathioprine/prednisone in renal transplant patients. Transplant Proc 1995; 27: 814-7.

69Shapiro R, Jordan M, Scantlebury V, et al. A prospective randomized trial of FK 506-based immunosuppression after renal transplantation. Transplantation 1995; 59: 485-90.

70Japanese FK 506 Study Group. FK 506: long-term study in kidney transplantation. Transplant Proc 1995; 27: 818-21.

71Japanese FK 506 Study Group. Phase III study of FK 506 in kidney transplantation. Transplant Proc 1995; 27: 829-33.

72Gjertson D, Cecka J, Terasaki P. The relative effects of FK506 and cyclosporine on short- and long-term kidney graft survival. Transplantation 1995; 60: 1384-8.

73Ochiai T, Ishbashi M, Fukao K, et al. Japanese Multicenter Studies of FK506 in renal transplantation. Transplant Proc 1995; 27: 50-3.

74Scantlebury V, Shapiro R, McCauley J, et al. Renal transplantation under cyclosporine and FK506 for hemolytic uremic syndrome. Transplant Proc 1995; 27: 842-3.

75Shapiro R, Tzakis A, Scantlebury V, et al. Improving results of pediatric renal transplantation. J Am Coll Surg 1994; 179: 424-32.

76Woodle E, Perdrizet G, Jendrisak M, et al. FK 506 rescue therapy: early conversion improves efficacy. Transplant Proc 1993; 25: 1990-1.

77Woodle E, Perdrizet G, Jendrisak M, et al. Recurrent rejection following FK 506 rescue therapy for acute hepatic allograft rejection. Transplant Proc 1993; 25: 1988-9.

78Egawa H, Esquivel C, So S, et al. FK 506 conversion therapy in pediatric liver transplantation. Transplantation 1994; 57: 1169-73.

79Fung J, Todo S, Tzakis A, et al. Conversion of liver allograft recipients from cyclosporine to FK 506-based immunosuppression: benefits and pitfalls. Transplant Proc 1991; 23: 14-21.

80Reggiani P, Orsenigo R, Gatti S, et al. Conversion to rescue therapy with FK 506: data from eight liver transplant patients. Transplant Proc 1994; 26: 3597-8.

81Rucay P, Samual D, Farges O, et al. FK 506 as treatment of late acute rejection in liver transplant patients. Transplant Proc 1995; 27: 1105-6.

82Sher L, Cosenza C, Petrovic L, et al. Tacrolimus (FK 506) for rescue of chronic rejection following orthotopic liver transplantation. Transplant Proc 1996; 28: 1011-3.

83The US Multicenter FK 506 Liver Study Group. Use of FK 506 for the prevention of recurrent allograft rejection after successful conversion from cyclosporine for refractory rejection. Transplant Proc 1993; 25: 635-7.

84Gibbs J, Husberg B, Klintmalm G. Outcome analysis of FK 506 therapy for acute and chronic rejection. Transplant Proc 1993; 25: 622-3.

85Millis J, Bruce D, Newell K, et al. Treatment of steroid-resistant rejection with tacrolimus prior to OKT3 in liver transplant recipients. Transplant Proc 1996; 28: 1014.

86Millis J, Woodle E, Piper J, et al. Tacrolimus for primary treatment of steroid-resistant hepatic allograft rejection. Transplantation 1996; 61: 1365-9.

87Chen C, Eng H, Chen Y, et al. FK 506 used as rescue therapy for refractory liver allograft rejection. Transplant Proc 1994; 26: 1927-9.

88Platz K, Mueller A, Zytowski M, et al. OKT3 vs FK 506 rescue management of acute steroid-resistant and chronic rejection. Transplant Proc 1995; 27: 1111-3.

89Platz K, Mueller A, Jonas S, et al. Toxicity versus rejection¾or why conversions between cyclosporine A and FK506 were performed after liver transplantation. Clin Transplant 1995; 9: 146-54.

90Hashikura Y, Kawasaki S, Matsunami H, et al. Immunosuppressant switching between cyclosporine and tacrolimus after liver transplantation. Transplant Proc 1996; 28: 1034-5.

91The European FK506 Multicentre Study Group. Reduced incidence of acute, refractory acute, and chronic rejection after liver transplantation with FK506-based immunosuppression. Transplant Proc 1994; 26: 3260-3.

92The US Multicenter FK 506 Liver Study Group. Prognostic factors for successful conversion from cyclosporine to FK 506-based immunosuppressive therapy for refractory rejection after liver transplantation. Transplant Proc 1993; 25: 641-3.

93The US Multicenter FK 506 Liver Study Group. Use of Prograf (FK 506) as rescue therapy for refractory rejection after liver transplantation. Transplant Proc 1993; 25: 679-88.

94Alloway R, Russell W, Gaber L, et al. Conversion from cyclosporine to tacrolimus in kidney, kidney/pancreas, and pancreas alone transplant recipients: the Memphis experience. Transplant Proc 1996; 28: 995-7.

95Hariharan S, Munda R, Cavallo T, et al. Rescue therapy with tacrolimus after combined kidney/pancreas and isolated pancreas transplantation in patients with severe cyclosporine nephrotoxicity. Transplantation 1996; 61: 1161-5.

96Kaufman D, Kaplan B, Kanwar Y, et al. The successful use of tacrolimus (FK506) in a pancreas/kidney transplant recipient with recurrent cyclosporine-associated hemolytic uremic syndrome. Transplantation 1995; 59: 1737-9.

97Shaffer D, Simpson M, Conway P, et al. Normal pancreas allograft function following simultaneous pancreas kidney transplantation after rescue therapy with tacrolimus (FK506). Transplantation 1995; 59: 1063-6.

98Jordan M, Shapiro R, Vivas C. FK 506 salvage of renal allografts with ongoing rejection failing cyclosporine immunosuppresion. Transplant Proc 1993; 25: 638-40.

99Mathew A, Talbot D, Minford E, et al. Reversal of steroid-resistant rejection in renal allograft recipients using FK506. Transplantation 1995; 60: 1182-4.

100Felldin M, Backman L, Brattstrom C, et al. Rescue therapy with tacrolimus (FK506) in renal transplant recipients¾a multicenter analysis. Transplant Proc 1995; 27: 3425.

101The Tacrolimus Kidney Transplantation Rescue Study Group. A multicenter trial of FK506 (tacrolimus) therapy in refractory acute renal allograft rejection. Transplantation 1996; 62: 594-9.

102Washburn W, Shafer D, Simpson M, et al. Tacrolimus rescue therapy for renal allograft rejection refractory to cyclosporine-based immunosuppression. Transplant Proc 1996; 28: 1015-6.

103Jordan M, Shapiro R, Vivas C, et al. FK506 "rescue" for resistant rejection of renal allografts under primary cyclosporine immunosuppression. Transplantation 1994; 57: 860-5.

104Eberhard O, Kliem V, Oldhafer K, et al. How to best use tacrolimus (FK506) for treatment of steroid- and OKT3-resistant rejection after renal transplantation. Transplantation 1996; 61: 1345-9.

105Woodle E, Thistlewaite J, Gordon J. Tacrolimus therapy for refractory acute renal allograft rejection: a prospective multicenter trial. Transplant Proc 1996; 28: 3163-4.

106Jordan M, Naraghi R, Shapiro R, et al. Tacrolimus rescue therapy for renal allograft rejection¾five-year experience. Transplantation 1997; 63: 223-8.

107Schwinhammer T, Bloom E. Pharmacologic prophylaxis of acute graft-versus-host disease after allogeneic marrow transplantation. Clin Pharm 1993; 12: 736-61.

108Fay J, Nash R, Wingard J, et al. FK 506-based immunosuppression for prevention of graft versus host disease after unrelated donor marrow transplantation. Transplant Proc 1995; 27: 1374.

109Nash R, Etzioni R, Storb R, et al. Tacrolimus (FK506) alone or in combination with methotrexate or methylprednisolone for the prevention of acute graft-versus-host disease after marrow transplantation from HLA-matched siblings: a single-center study. Blood 1995; 85: 3746-53.

110Fay J, Wingard J, Antin J, et al. FK506 (tacrolimus) monotherapy for prevention of graft-versus-host disease after histocompatible sibling allogeneic bone marrow transplantation. Blood 1996; 87: 3514-9.

111Masaoka T. Problems of bone marrow transplantation in Japan. Transplant Proc 1994; 26: 2358.

112Koehler M, Howrie D, Mirro J, et al. FK506 (tacrolimus) in the treatment of steroid-resistant acute graft-versus-host disease in children undergoing bone marrow transplantation. Bone Marrow Transplant 1995; 15: 895-9.

113Kanamaru 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.

114Felldin M, Backman L, Brattstrom C, et al. Rescue therapy with tacrolimus (FK506) in renal transplant recipients. Transplantation 1995; 60: 1182-4.

115Nakagawa H, Etoh T, Ishibashi Y, et al. Tacrolimus ointment for atopic dermatitis. Lancet 1994; 344: 883.

116Nakagawa 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.

117Stephens 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.

118Lemster 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.

119McCauley 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.

120McCauley J, Shapiro R, Jordan M, et al. FK 506 in the management of nephrotic syndrome after renal transplantation. Transplant Proc 1993; 25: 1351-4.

121McCauley 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.

122Bousvaros A, Leichtner A, Book L, et al. Treatment of pediatric autoimmune enteropathy with tacrolimus (FK506). Gastroenterology 1996; 111: 237-43.

123Van 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.

124Abu-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.

125Jegasothy B, Ackerman C, Todo S, et al. Tacrolimus (FK 506)¾a new therapeutic agent for severe recalcitrant psoriasis. Arch Dermatol 1992; 128: 781-5.

126Lemster 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.

127The 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.

128Ruzicka T. Psoriatic arthritis: new types, new treatments. Arch Dermatol 1996; 132: 215-9.

129Abu-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.

130Abu-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.

131Mochizuki M, Masuda K, Sakane T, et al. A clinical trial of FK506 in refractory uveitis. Am J Ophthalmol 1993; 115: 763-9.

132Mochizuki M, Masuda K, Shirao M, et al. Preclinical and clinical study of FK506 in uveitis. Curr Eye Res 1992; 11 Suppl: 87-95.

133Mochizuki 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.

134Iskioka M, Ohno S, Nakamura S, et al. FK506 treatment of noninfectious uveitis. Am J Ophthalmol 1994; 118: 723-9.

135Nikolaidis 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.

136Goto 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.

137 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.

138Morris R. Modes of action of FK506, cyclosporin A, and rapamycin. Transplant Proc 1994; 26: 3272-5.

139Thomson A, Bonham C, Zeevi A. Mode of action of tacrolimus (FK506): molecular and cellular mechanisms. Ther Drug Monit 1995; 17: 584-91.

140Nakata 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.

141Venkataramanan R, Jain A, Warty V, et al. Pharmacokinetics of FK 506 in transplant patients. Transplant Proc 1991; 23: 2736-40.

142Jain 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.

143Jain A, Venkataramanan R, Lever J, et al. FK 506 in small bowel transplant recipients: pharmacokinetics and dosing. Transplant Proc 1994; 26: 1609-10.

144Venkataramanan R, Jain A, Cadoff E, et al. Pharmacokinetics of FK 506: preclinical and clinical studies. Transplant Proc 1990; 22: 52-6.

145Sewing K. Pharmacokinetics, dosing principles, and blood level monitoring of FK506. Transplant Proc 1994; 26: 3267-9.

146Yasuhara 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.

147Gruber 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.

148Venkataramanan 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.

149Thomson 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.

150Hold.

151Hold.

152Hold.

153McDiarmid S, Colonna J, Shaked A, et al. Differences in oral FK506 requirements between adult and pediatric liver transplant patients. Transplantation 1993; 55: 1328-32.

154Jain 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.

155Venkataramanan R, Swaminathan A, Prasad T, et al. Clinical pharmacokinetics of tacrolimus. Clin Pharmacokinet 1995; 404-30.

156Jusko W, Piekoszewski W, Klintmalm G, et al. Pharmacokinetics of tacrolimus in liver transplant patients. Clin Pharmacol Ther 1995; 57: 281-90.

157Shiraga 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.

158Vincent 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.

159Panel comment, 2/97.

160Jain A, Venkataramanan R, Lever J, et al. FK506 and pregnancy in liver transplant patients. Transplantation 1993; 56: 751.

161Yoshimura 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.

162Jain A, Venkataramanan R, Fung J, et al. Pregnancy following liver transplantation under tacrolimus. Transplantation. In press 1997.

163Steeves M, Abdallah H, Venkataramanan R, et al. Interaction of a novel immunosuppressant, FK506, and antacids. J Pharm Pharmacol 1991; 43: 574-7.

164Christians U, Guenderich F, Schmidt G, et al. In vitro metabolism of FK506, cytochrome P450 and drug interactions. Ther Drug Monit 1993; 15: 145.

165Lampen 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.

166Assan R, Fredj G, Larger E, et al. FK 506 / fluconazole interaction enhances FK 506 nephrotoxicity. Diabete Metab 1994; 20: 49-52.

167Rui X, Flowers J, Warty V, et al. Drug interactions with FK 506 [abstract]. Pharm Res 1992; 9: S314.

168Lake K, Canafax D. Important interactions of drugs with immunosuppressive agents used in transplant recipients. J Antimicrob Chemother 1995; 36 Suppl B: 11-22.

169Wolter 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.

170Mieles L, Venkataramanan R, Yokoyama I, et al. Interaction between FK 506 and clotrimazole in a liver transplant recipient. Transplantation 1992; 52: 1086-7.

171Shapiro R, Venkataramanan R, Warty V, et al. FK 506 interaction with danazol. Lancet 1993; 341: 1344-5.

172 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.

173Hold.

174Hold.

175Regazzi M, Alessiani M, Spada M, et al. Interaction between FK 506 and diltiazem in an animal model. Transplant Proc 1996; 28: 1017-8.

176Prasad 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.

177Iwasaki 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.

178Hold.

179Jensen C, Jordan M, Shapiro R, et al. Interaction between tacrolimus and erythromycin. Lancet 1994; 344: 825.

180Hold.

181Hold.

182Shaeffer M, Collier D, Sorrell M. Interaction between FK506 and erthromycin. Ann Pharmacother 1994; 38: 280-1.

183Jensen C, Jordan M, Shapiro R, et al. Interaction between tacrolimus and erythromycin. Lancet 1994; 344: 825.

184Padhi I, Long P, Babha M, et al. Interaction between tacrolimus and erythromycin. Ther Drug Monit 1997; 19: 120-2.

185Osokski 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.

186Manez R, Martin M, Raman D, et al. Fluconazole therapy in transplant recipients receiving FK506. Transplantation 1994; 27: 1521-3.

187Sheiner 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.

188Golling M, Lehmann T, Senninger N, et al. Tacrolimus reduction improves glucose metabolism and insulin secretion after liver transplantation. Transplant Proc 1996; 28: 3180-2.

189Kiuchi 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.

190Furlan V, Perello L, Jacquemin E, et al. Interactions between FK506 and rifampicin or erythromycin in pediatric liver recipients. Transplantation 1995; 59: 1217-8.

191CDC: 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.

192Steinmuller T, Graf K, Schleicher J, et al. The effect of FK506 versus cyclosporine on glucose and lipid metabolism¾a randomized trial. Transplantation 1994; 58: 669-74.

193Loss 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.

194Wu Y, Venkataramanan R, Suzuki M, et al. Interaction between FK 506 and cyclosporine in dogs. Transplant Proc 1991; 23: 2797-9.

195Pichard 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.

196Omar G, Ali Shah I, Thomson A, et al. FK 506 inhibition of cyclosporine metabolism by human liver microsomes. Transplant Proc 1991; 23: 934-5.

197Porayko 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.

198McMaster P, Mirza D, Ismail T, et al. Therapeutic drug monitoring of tacrolimus in clinical transplantation. Ther Drug Monit 1995; 17: 602-5.

199Esquivel C, So S, McDiarmid S, et al. Suggested guidelines for the use of tacrolimus in pediatric liver transplant patients. Transplantation 1996; 61: 847-9.

200Kershner R, Fitzsimmons. Relationship of FK506 whole blood concentrations and efficacy and toxicity after liver and kidney transplantation. Transplantation 1996; 62: 920-6.

201Jusko W, Thomson A, Fung J, et al. Consensus document: therapeutic monitoring of tacrolimus (FK-506). Ther Drug Monit 1995; 17: 606-14.

202Suzuki S, Osaka Y, Nakai I, et al. Pure red cell aplasia induced by FK506. Transplantation 1996; 61: 831-2.

203Winkler M, Schulze F, Jost U, et al. Anaemia associated with FK 506 immunosuppression. Lancet 1993; 341: 1035-6.

204Mach-Pascual S, Samil K, Beris P. Microangiopathic hemolytic anemia complicating FK506 (tacrolimus) therapy. Am J Hematol 1996; 52: 310-2.

205Alessiani M, Cillo U, Fung J, et al. Adverse effects of FK 506 overdosage after liver transplantation. Transplant Proc 1993; 25: 628-34.

206Williams E, Oatridge A, Holdcroft A, et al. Posterior leucoencephalopathy syndrome. Lancet 1996; 347: 1556-7.

207Mueller A, Platz K, Bechstein W, et al. Neurotoxicity following orthotopic liver transplantation: a comparison between cyclosporine and FK506. Transplantation 1994; 58: 155-69.

208Hold.

209Hold.

210Mueller 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.

211Christe W. Neurological disorders in liver and kidney transplant recipients. Transplant Proc 1994; 26: 3175-6.

212Frank B, Perdrizet G, White H, et al. Neurotoxicity of FK 506 in liver transplant recipients. Transplant Proc 1993; 25: 1887-8.

213Mor E, Sheiner P, Schwartz M, et al. Reversal of severe FK506 side effects by conversion to cyclosporine-based immunosuppression. Transplantation 1994; 58: 380-2.

214Guy S, Fisher A, Schwartz M, et al. Immunosuppressive conversion for relief of side effects. Transplant Proc 1994; 26: 3235-6.

215Laskow 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.

216Shaw L, Kaplan B, Kaufman D. Toxic effects of immunosuppressive drugs: mechanisms and strategies for controlling them. Clin Chem 1996; 42: 1316-21.

217Mor 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.

218Fisher A, Schwartz M, Mor E, et al. Gastrointestinal toxicity associated with FK 506 in liver transplant recipients. Transplant Proc 1994; 26: 3106-7.

219Fisher A, Mor E, Hytiroglou P, et al. FK506 hepatotoxicity in liver allograft recipients. Transplantation 1995; 59: 1631-2.

220Johnson M, Washburn W, Freeman R, et al. Hepatitis C viral infection in liver transplantation. Arch Surg 1996; 131: 284-91.

221Jindal R, Popescu I, Schwartz, et al. Diabetogenicity of FK506 versus cyclosporine in liver transplant recipients. Transplantation 1994; 58: 360-2.

222Furth 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.

223Tabasco-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.

224Tanabe 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.

225Hold.

226Hold.

227Senninger 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.

228Loss 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.

229O'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.

230Platz K, Mueller A, Blumhardt G, et al. Nephrotoxicity following orthotopic liver transplantation: a comparison between cyclosporine and FK506. Transplantation 1994; 58: 170-8.

231Lemoine 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.

232Morozumi 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.

233Nielsen 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.

234The 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.

235Sakamoto 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.

236Backman L, Nicar M, Levy M, et al. Chronic nephrotoxicity of FK 506 after liver transplantation. Transplant Proc 1994; 26: 1803.

237Frei U, Wagner K. Renal function in liver transplant patients receiving FK506 or cyclosporin A immunosuppressive therapy. Transplant Proc 1994; 26: 3270-1.

238Stock 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.

239Japanese 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.

240Hold.

241Hold.

242Singh N, Gayowski T, Wagener M, et al. Increased infections in liver transplant recipients with recurrent hepatitis C virus hepatitis. Transplantation 1996; 61: 402-6.

243Roth D, Zucker K, Cirocco R, et al. A prospective study of hepatitis C virus infection in renal allograft recipients. Transplantation 1996; 61: 886-9.

244Singh 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.

245Kusne S, Manez R, Bonet H, et al. Infectious complications after small bowel transplantation in adults. Transplant Proc 1994; 26: 1682-3.

246Barkholt L, Ehrnst A, Veress B, et al. New criteria for diagnosing cytomegalovirus hepatitis in liver transplant patients. Transplant Proc 1995; 27: 1224-5.

247Singh N, Gayowski T, Wagener M, et al. Infectious complications in liver transplant recipients on tacrolimus. Transplantation 1994; 58: 774-8.

248Singh 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.

249Park K, Hay J, Lee S, et al. Bone loss after orthotopic liver transplantation: FK 506 versus cyclosporine. Transplant Proc 1996; 28: 1738-40.

250Dollinger M, Plevris J, Chauhan A, et al. Tacrolimus and cardiotoxicity in adult liver transplant recipients. Lancet 1995; 346: 507.

251Hold.

252Hold.

253Atkinson P, Joubert G, Barron A, et al. Hypertrophic cardiomyopathy associated with tacrolimus in paediatric transplant patients. Lancet 1995; 345: 894-6.

254Hanafusa 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.

255Manez R, Demetrius A, Starzl T. Rejection and hepatitis in liver transplants. Transplantation 1995; 57: 1824-5.

256Hold.

257Abouljoud 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.

258KoKado 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.

259Deschler 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.

260Reyes J, Tzakis A, Bonet H, et al. Lymphoproliferative disease after intestinal transplantation under primary FK 506 immunosuppression. Transplant Proc 1994; 26: 1426-7.

261Martinez 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.

262Taormino 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.

263Hold.

264Reynolds J, Trellis D, Abu-Elmagd K, et al. The rationale for FK 506 in inflammatory bowel disease. Can J Gastroenterol 1993; 7: 208-10.

265Todo S, Tzakis A, Abu-Elmagd K, et al. Intestinal transplantation in composite visceral grafts or alone. Ann Surg 1992; 216: 223-34.

266Todo S, Tzakis A, Abu-Elmagd K, et al. Cadaveric small bowel and small bowel-liver transplantation in humans. Transplantation 1992; 53: 369-76.

267Armitage 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.

268Starzl T, Donner A, Eliasziw M, et al. Randomized trialomania? The multicenter liver transplant trials of tacrolimus. Lancet 1995; 346: 1346-50.

269Todo 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.

270Todo S, Fung J, Demetrius A, et al. Early trials with FK 506 as primary treatment in liver transplantation. Transplant Proc 1990; 22: 13-6.

271Fung 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.

272Fung 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.

273Starzl T, Todo S, Fung J, et al. FK 506 for human liver, kidney, and pancreas transplantation. Lancet 1989; 2: 1000-4.

274Todo S, Fung J, Starzl T, et al. Liver, kidney, and thoracic organ transplantation under FK 506. Ann Surg 1990; 212: 295-305.

275Armitage 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.

276Armitage J, Kormos R, Fung J, et al. Preliminary experience with FK 506 in thoracic transplantation. Transplantation 1991; 52: 154-67.

277Starzl T, Fung J, Jordan M, et al. Kidney transplantation under FK 506. JAMA 1990; 264: 63-7.

278Shapiro R, Jordan M, Fung J, et al. Kidney transplantation under FK 506 immunosuppression. Transplant Proc 1991; 23: 920-3.

279Corry R, Egidi M, Shapiro R, et al. Pancreas transplantation with enteric drainage under tacrolimus induction therapy. Transplant Proc 1997; 29: 642.

280Starzl 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.

281Abu-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.

282Nalesnik 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.

283Stiff D, Venkataramanan R, Prasad T. Metabolism of FK 506 in differentially induced rat liver microsomes. Res Commun Chem Pathol Pharmacol 1992; 78: 121-4.

284Sattler 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.

285Hold.

286Peters D, Fitton A, Plosker G. Tacrolimus. A review of its pharmacology and therapeutic potential in hepatic and renal transplantation. Drugs 1993; 46: 746-94

287Todo S, Fung J, Starzl T, et al. Liver, kidney, and thoracic organ transplantation under FK 506. Ann Surg 1990; 212: 295-305.

288Starzl T, Todo S, Fung J, et al. FK 506 for liver, kidney, and pancreas transplantation. Lancet 1989; 2: 1000-4.

289Jacobson 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.

290Rodriguez 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.

291Van 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.

292 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.

293Panel comment, 7/97.

294Mrvos R, Hodgman M, Krenzelok E. Tacrolimus (FK 506) overdose: a report of five cases. Clin Toxicol 1997; 35: 395-9.

295Fleeger CA, editor. USP dictionary of USAN and international drug names 1997. Rockville, MD: The United States Pharmacopeial Convention, Inc; 1996. p. 687.

296Dressler 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.

TACROLIMUS (USO TOPICO)
------------------------

297 Tacrolimus (FK506) ointment for atopic dermatitis:

A phase I study in adults and children

Samer Alaiti, MD,a Sewon Kang, MD,b Virginia C. Fiedler, MD,a Charles N. Ellis, MD,b David V. Spurlin, MD,b Darrell Fader, MD,b Grigoriy Ulyanov, MD,a Shrikant D. Gadgil,MD,c Atsushi Tanase, PharmD,c Ira Lawrence, MD,c Patricia Scotellaro, PhD,c Kathleen Raye, BS,c and Ihor Bekersky, PhDc Chicago and Deerfield, Illinois, and Ann Arbor,MichiganBackground:

Tacrolimus is a potent immunosuppressant used in organ transplant recipients; an ointment formulation is being developed as a therapeutic agent for atopic dermatitis. Objective: Our purpose was to define the pharmacokinetics and evaluate tacrolimus 0.3% ointment as therapy for moderate to severe atopic dermatitis.

 Methods: Thirty-nine patients, 5 to 75 years of age, received 14 applications over 8 days. Serial blood samples were collected on days 1 and 8, with predose samples collected on days 2 through 7.

Overall response and signs/symptoms were rated dailyon days 1 through 11. Incidence of adverse events and laboratory profile were determined. Results: Mean area under the curve (0.9 to 42.5 ng¹hr/ml) was highly variable and appeared to be related to size of application area. No systemic accumulation of tacrolimus was observed.

Comparison to historical intravenous data indicates thatabsolute bioavailability of topical tacrolimus was less than 0.5%.

Ninety-five percent of patients showed at least good improvement.

All adverse events were transient. Burningwas the most common application site adverse event and vasodilatation ("flushing/warmth") was the most common nonapplication site adverse event. No drug-related changes in laboratory profile were observed. 

Conclusion: The results of this study suggest that tacrolimus 0.3% ointment may be a safe and effective therapy for atopic dermatitis. (J Am Acad Dermatol1998;38:69-76.)
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298 A short-term trial of tacrolimus ointment for atopic dermatitis. 

European Tacrolimus Multicenter Atopic Dermatitis Study Group.
RRuzicka T; Bieber T; Schopf E; Rubins A; Dobozy A; Bos JD; Jablonska S; Ahmed I; Thestrup-Pedersen K; Daniel F; Finzi A; Reitamo S
Department of Dermatology at Heinrich Heine University, Dusseldorf, Germany. N Engl J Med (UNITED STATES) Sep 18 1997 337 (12) p816-21 

BACKGROUND: Tacrolimus (FK 506) is an effective immunosuppressant drug for the prevention of rejection after organ transplantation, and preliminary studies suggest that topical application of tacrolimus is effective in the treatment of atopic dermatitis. METHODS: We conducted a randomized, doubleblind, multicenter study that compared 0.03 percent, 0.1 percent, and 0.3 percent tacrolimus ointment with vehicle  alone in patients with moderate to severe atopic dermatitis. The ointment was applied twice daily to a defined, symptomatic area of 200 to 1000 cm2 of skin for three weeks. The primary end point was the change in the summary score for erythema,  edema, and pruritus between the first and last days of treatment. RESULTS: After three weeks of treatment, the median percentage decrease in the summary score for  dermatitis on the trunk and extremities was 66.7 percent for the 54 patients receiving 0.03 percent tacrolimus, 83.3 percent for the 54 patients receiving 0.1  percent tacrolimus, 75.0 percent for the 51 patients receiving 0.3 percent tacrolimus, and 22.5 percent for the 54 patients receiving vehicle alone (P<0.001). The results for the face and neck were similar. The differences among the three tacrolimus groups were not statistically significant. A sensation of burning at the  site of application was the only adverse event that was significantly more frequent with tacrolimus than with vehicle alone (P<0.001). Throughout the study, most  patients in all three tacrolimus groups had blood concentrations of tacrolimus below 0.25 ng per milliliter. The highest concentration was 4.9 ng per milliliter, which  was reported in the group receiving 0.3 percent tacrolimus

CONCLUSIONS: The short-term application of tacrolimus ointment is effective in the treatment of atopic dermatitis, with the sensation of burning being the main side effect.
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 299.) Archives ofDermatology Abstracts - September 1998 Topical Tacrolimus Is Not Effective in Chronic PlaquePsoriasis A Pilot Study Ingrid M. Zonneveld, MD; Andris Rubins, MD; Stephanie Jablonska,MD; Attila Dobozy, MD; Theo Ruzicka, MD; Peter Kind, MD; LouisDubertret, MD; Jan D. Bos, MD Background: Cyclosporine for the treatment of psoriasis constitutes a newpproach. Alternative systemic cyclosporine derivatives have been studiedto find an immunosuppressive drug with fewer adverse effects. Tacrolimus isone of these new immunosuppressive drugs. Systemically, it has been proveneffective in treating psoriasis. A topical formulation of tacrolimus is attractivebecause it has fewer adverse effects and is useful for a large group ofpatients. We report for the first time on the efficacy of nonocclusive topicaltacrolimus in the treatment of psoriasis. Observations: After a washout phase of 2 weeks, patients wererandomized to receive 0.005% calcipotriol ointment twice daily, placeboointment once daily, or 0.3% tacrolimus ointment once daily. One psoriaticplaque was treated with a surface area of 40 to 200 cm2. Efficacy wasestimated using the local psoriasis severity index. The reduction in the localpsoriasis severity index score after 6 weeks was 62.5% in the calcipotriolgroup, 33.3% in the tacrolimus group, and 42.9% in the placebo group. Conclusions: There was no statistically significant difference between theefficacy of tacrolimus and placebo ointment (P=.77). Calcipotriol ointment,applied twice daily, had a better effect than tacrolimus ointment and placeboointment once daily. Ach Dermatol. 1998;134:1101-1102 

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