Janssen Products

Tacrolimus

PROGRAF^TM

DESCRIPTION:
Tacrolimus (Prograf^TM) is available for oral administration as capsules containing the equivalent of 1 mg of anhydrous tacrolimus. Inactive ingredients include lactose, hydroxypropyl methylcellulose, croscarmellose sodium, and magnesium stearate. The capsule shell contains gelatin and titanium dioxide.

Tacrolimus, previously known as FK506, is the active ingredient in Prograf^TM. Tacrolimus is a macrolide immunosuppressant produced by Streptomyces tsukubaensis.

Tacrolimus appears as white crystals or crystalline powder. It is practically insoluble in water, freely soluble in ethanol, and very soluble in methanol and chloroform.

CLINICAL PHARMACOLOGY:
Mechanism of Action
Tacrolimus prolongs the survival of the host and transplanted graft in animal transplant models of liver, kidney, heart, bone marrow, small bowel and pancreas, lung and trachea, skin, cornea, and limb.

In animals, tacrolimus has been demonstrated to suppress some humoral immunity and, to a greater extent, cell-mediated reactions such as allograft rejection, delayed type hypersensitivity, collagen-induced arthritis, experimental allergic encephalomyelitis, and graft versus host disease.

Tacrolimus inhibits T-lymphocyte activation, although the exact mechanism of action is not known. Experimental evidence suggests that tacrolimus binds to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin is then formed and the phosphatase activity of calcineurin inhibited. This effect may prevent the dephosphorylation and translocation of nuclear factor of activated T-cells (NF-AT), a nuclear component thought to initiate gene transcription for the formation of lymphokines (such as interleukin-2, gamma interferon). The net result is the inhibition of T-lymphocyte activation (i.e., immunosuppression).

Pharmacokinetics
Tacrolimus activity is primarily due to the parent drug. The pharmacokinetic parameters (mean±S.D.) of tacrolimus have been determined following intravenous (IV) and oral (PO) administration in healthy volunteers, liver transplant and kidney transplant patients. (See table below.)

Due to intersubject variability in tacrolimus pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy. (See DOSAGE AND ADMINISTRATION). Pharmacokinetic data indicate that whole blood concentrations rather than plasma concentrations serve as the more appropriate sampling compartment to describe tacrolimus pharmacokinetics.

Absorption
Absorption of tacrolimus from the gastrointestinal tract after oral administration is incomplete and variable. The absolute bioavailability of tacrolimus was 17±10% in adult kidney transplant patients (N=26), 22±6% in adult liver transplant patients (N=17), and 18±5% in healthy volunteers (N=16).

A single dose study conducted in 32 healthy volunteers established the bioequivalence of the 1 mg and 5 mg capsules. Another single dose study in 32 healthy volunteers established the bioequivalence of the 0.5 mg and 1 mg capsules. Tacrolimus maximum blood concentrations (Cmax) and area under the curve (AUC) appeared to increase in a dose-proportional fashion in 18 fasted healthy volunteers receiving a single oral dose of 3, 7 and 10 mg.

In 18 kidney transplant patients, tacrolimus trough concentrations from 3 to 30 ng/mL measured at 10-12 hours post-dose (Cmin) correlated well with the AUC (correlation coefficient 0.93). In 24 liver transplant patients over a concentration range of 10 to 60 ng/mL, the correlation coefficient was 0.94.

Food Effects: The rate and extent of tacrolimus absorption were greatest under fasted conditions. The presence and composition of food decreased both the rate and extent of tacrolimus absorption when administered to 15 healthy volunteers.

The effect was most pronounced with a high-fat meal (848 kcal, 46% fat): mean AUC and Cmax were decreased 37% and 77%, respectively; Tmax was lengthened 5-fold. A high-carbohydrate meal (668 kcal, 85% carbohydrate) decreased mean AUC and mean Cmax by 28% and 65% respectively.

In healthy volunteers (N=16), the time of the meal also affected tacrolimus bioavailability. When given immediately following the meal, mean Cmax was reduced 71%, and mean AUC was reduced 39%, relative to the fasted condition. When administered 1.5 hours following the meal, mean Cmax was reduced 63%, and mean AUC was reduced 39%, relative to the fastes condition.

In 11 liver transplant patients, tacrolimus (Prograf^TM) administered 15 minutes after a high fat (400 kcal, 34% fat) breakfast, resulted in decreased AUC (27±18%) and Cmax (50±19%), as compared to a fasted state.

Distribution
The plasma protein binding of tacrolimus is approximately 99% and is independent of concentration over a range of 5-50 ng/mL. Tacrolimus is bound mainly to albumin and alpha-1-acid glycoprotein, and has a high level of association with erythrocytes. The distribution of tacrolimus between whole blood and plasma depends on several factors, such as hematocrit, temperature at the time of plasma separation, drug concentration, and plasma protein concentration. In a U.S. study, the ratio of whole blood concentration to plasma concentration averaged 35 (range 12 to 67).

Metabolism
Tacrolimus is extensively metabolized by the mixed-function oxidase system, primarily the cytochrome P-450 system (CYP3A). A metabolic pathway leading to the formation of 8 possible metabolites has been proposed. Demethylation and hydroxylation were identified as the primary mechanisms of biotransformation in vitro. The major metabolite identified in incubations with human liver microsomes is 13-demethyl tacrolimus. In in vitro studies, a 31-demethyl metabolite has been reported to have the same activity as tacrolimus.

Excretion
The mean clearance following IV administration of tacrolimus is 0.040, 0.083 and 0.053 L/hr/kg in healthy volunteers, adult kidney transplant patients and adult liver transplant patients, respectively. In man, less than 1% of the dose administered is excreted unchanged in urine.

In a mass balance study of IV administered radiolabeled tacrolimus to 6 healthy volunteers, the mean recovery of radiolabel was 77.8±12.7%. Fecal elimination accounted for 92.4±1.0% and the elimination half-life based on radioactivity was 48.1±15.9% hours whereas it was 43.5±11.6 hours based on tacrolimus concentrations. The mean clearance of radiolabel was 0.029±0.015 L/hr/kg and clearance of tacrolimus was 0.029±0.009 L/hr/kg. When administered PO, the mean recovery of the radiolabel was 94.9±30.7%. Fecal elimination accounted for 92.6±30.7%, urinary elimination accounted for 2.3±1.1% and the elimination half-life based on radioactivity was 31.9±10.5 hours whereas it was 48.4±12.3 hours based on tacrolimus concentrations. The mean clearance of radiolabel was 0.226±0.116 L/hr/kg and clearance of tacrolimus 0.172±0.088 L/hr/kg.

Special Populations
Pediatric
Pharmacokinetics of tacrolimus have been studied in liver transplantation patients, 0.7 to 13.2 years of age. Following IV administration of a 0.037 mg/kg/day dose to 12 pediatric patients, mean terminal half-life, volume of distribution and clearance were 11.5±3.8 hours, 2.6±2.1 L/kg and 0.138±0.071 L/hr/kg, respectively. Following oral administration to 9 patients, mean AUC and Cmax were 337±167 ng·hr/mL and 43.4±27.9 ng/mL, respectively. The absolute bioavailability was 31±21%.

Whole blood trough concentrations from 31 patients less than 12 years old showed that pediatric patients needed higher doses than adults to achieve similar tacrolimus trough concentrations. (See DOSAGE AND ADMINISTRATION).

Renal and Hepatic Insufficiency
The mean pharmacokinetic parameters for tacrolimus following single administrations to patients with renal and hepatic impairment are given in the following table.

Renal Insufficiency:
Tacrolimus pharmacokinetics following a single IV administration were determined in 12 patients (7 not on dialysis and 5 on dialysis, serum creatinine of 3.9±1.6 and 12.0±2.4 mg/dL, respectively) prior to their kidney transplant. The pharmacokinetic parameters obtained were similar for both groups.

The mean clearance of tacrolimus in patients with renal dysfunction was similar to that in normal volunteers (see previous table).

Hepatic Insufficiency:
Tacrolimus pharmacokinetics have been determined in six patients with mild hepatic dysfunction (mean Pugh score: 6.2) following single IV and oral administrations. The mean clearance of tacrolimus in patients with mild hepatic dysfunction was not substantially different from that in normal volunteers (see previous table).

Race
A formal study to evaluate the pharmacokinetic disposition of tacrolimus in Black transplant patients has not been conducted. However, a retrospective comparison of Black and Caucasian kidney transplant patients indicated that Black patients required higher tacrolimus doses to attain similar trough concentrations. (See DOSAGE AND ADMINISTRATION).

Gender
The effect of gender on tacrolimus pharmacokinetics has not been evaluated, however, there was no difference in dosing by gender in the kidney transplant trial.

Clinical Studies
Liver Transplantation
The safety and efficacy of tacrolimus (Prograf^TM)-based immunosuppression following orthotopic liver transplantation were assessed in two prospective, randomized, non-blinded multicenter studies. The active control groups were treated with a cyclosporine-based immunosuppressive regimen. Both studies used concomitant adrenal corticosteroids as part of the immunosuppressive regimens. These studies were designed to evaluate whether the two regimens were therapeutically equivalent, with patient and graft survival at 12 months following transplantation as the primary endpoints. The tacrolimus (Prograf^TM)-based immunosuppressive regimen was found to be equivalent to the cyclosporine-based immunosuppressive regimens.

In one trial, 529 patients were enrolled at 12 clinical sites in the United States; prior to surgery, 263 were randomized to the tacrolimus (Prograf^TM)-based immunosuppressive regimen and 266 to a cyclosporine-based immunosuppressive regimen (CBIR). In 10 of the 12 sites, the same CBIR protocol was used, while 2 sites used different control protocols. This trial excluded patients with renal dysfunction, fulminant hepatic failure with Stage IV encephalopathy, and cancers; pediatric patients (£ 12 years old) were allowed.

In the second trial, 545 patients were enrolled at 8 clinical sites in Europe; prior to surgery, 270 were randomized to the tacrolimus (Prograf^TM)-based immunosuppressive regimen and 275 to CBIR. In this study, each center used its local standard CBIR protocol in the active-control arm. This trial excluded pediatric patients, but did allow enrollment of subjects with renal dysfunction, fulminant hepatic failure in Stage IV encephalopathy, and cancers other than primary hepatic with metastases.

One-year patient survival and graft survival in the tacrolimus (Prograf^TM)-based treatment groups were equivalent to those in the CBIR treatment groups in both studies. The overall one-year patient survival (CBIR and Prograf^TM-based treatment groups combined) was 88% in the U.S. study and 78% in the European study. The overall one-year graft survival (CBIR and Prograf^TM-based treatment groups combined) was 81% in the U.S. study and 73% in the European study. In both studies, the median time to convert from IV to oral tacrolimus (Prograf^TM) dosing was 2 days.

Because of the nature of the study design, comparisons of differences in secondary endpoints, such as incidence of acute rejection, refractory rejection or use of OKT3 for steroid-resistant rejection, could not be reliably made.

Kidney Transplantation
Tacrolimus (Prograf^TM)-based immunosuppression following kidney transplantation was assessed in a randomized, multicenter, non-blinded, prospective study. There were 412 kidney transplant patients enrolled at 19 clinical sites in the United States. Study therapy was initiated when renal function was stable as indicated by a serum creatinine £4 mg/dL (median of 4 days after transplantation, range 1 to 14 days). Patients less than 6 years of age were excluded.

There were 205 patients randomized to tacrolimus (Prograf^TM)-based immunosuppression and 207 patients were randomized to cyclosporine-based immunosuppression. All patients received prophylactic induction therapy consisting of an antilymphocyte antibody preparation, corticosteroids and azathioprine. Overall one year patient and graft survival was 96.1% and 89.6%, respectively and was equivalent between treatment arms.

Because of the nature of the study design, comparisons of differences in secondary endpoints, such as incidence of acute rejection, refractory rejection or use of OKT3 for steroid-resistant rejection, could not be reliably made.

INDICATIONS AND USAGE
Tacrolimus (Prograf^TM) is indicated for the prophylaxis of organ rejection in patients receiving allogeneic liver or kidney transplants. It is recommended that tacrolimus (Prograf^TM) be used concomitantly with adrenal corticosteroids.

CONTRAINDICATIONS
Tacrolimus (Prograf^TM) is contraindicated in patients with a hypersensitivity to tacrolimus.

WARNINGS
(See boxed WARNING.)
Insulin-dependent post-transplant diabetes mellitus (PTDM) was reported in 20% of tacrolimus (Prograf^TM)-treated kidney transplant patients (See table). The median time to onset of PTDM was 68 days. Insulin dependence was reversible in 15% of these patients at one year and in 50% at two years post transplant. Black and Hispanic kidney transplant patients were at an increased risk of development of PTDM.

Insulin-dependent post-transplant diabetes mellitus was reported in 18% and 11% of tacrolimus (Prograf^TM)-treated liver transplant patients and was reversible in 45% and 31% of these patients at one year post transplant, in the U.S. and European randomized studies, respectively (See Table below). Hyperglycemia was associated with the use of tacrolimus (Prograf^TM) in 47% and 33% of liver transplant recipients in the U.S. and European randomized studies, respectively, and may require treatment (see ADVERSE REACTIONS).

Tacrolimus (Prograf^TM) can cause neurotoxicity and nephrotoxicity, particularly when used in high doses. Nephrotoxicity was reported in approximately 52% of kidney transplantation patients and in 40% and 36% of liver transplantation patients receiving tacrolimus (Prograf^TM) in the U.S. and European randomized trials, respectively (see ADVERSE REACTIONS). More overt nephrotoxicity is seen early after transplantation, characterized by increasing serum creatinine and a decrease in urine output. Patients with impaired renal function should be monitored closely as the dosage of tacrolimus (Prograf^TM) may need to be reduced. In patients with persistent elevations of serum creatinine who are unresponsive to dosage adjustments, consideration should be given to changing to another immunosuppressive therapy. Care should be taken in using tacrolimus with other nephrotoxic drugs. In particular, to avoid excess nephrotoxicity, tacrolimus (Prograf^TM) should not be used simultaneously with cyclosporine. Tacrolimus (Prograf^TM) or cyclosporine should be discontinued at least 24 hours prior to initiating the other. In the presence of elevated tacrolimus (Prograf^TM) or cyclosporine concentrations, dosing with the other drug usually should be further delayed.

Mild to severe hyperkalemia was reported in 31% of kidney transplant recipients and in 45% and 13% of liver transplant recipients treated with tacrolimus (Prograf^TM) in the U.S. and European randomized trials, respectively, and may require treatment (see ADVERSE REACTIONS). Serum potassium levels should be monitored and potassium-sparing diuretics should not be used during tacrolimus (Prograf^TM) therapy (see PRECAUTIONS).

Neurotoxicity, including tremor, headache, and other changes in motor function, mental status, and sensory function were reported in approximately 55% of liver transplant recipients in the two randomized studies. Tremor occurred more often in tacrolimus (Prograf^TM)-treated kidney transplant patients (54%) compared to cyclosporine-treated patients. The incidence of other neurological events in kidney transplant patients was similar in the two treatment groups (see ADVERSE REACTIONS). Tremor and headache have been associated with high whole-blood concentrations of tacrolimus and may respond to dosage adjustment. Seizures have occurred in adult and pediatric patients receiving tacrolimus (Prograf^TM) (see ADVERSE REACTIONS). Coma and delirium also have been associated with high plasma concentrations of tacrolimus.

As in patients receiving other immunosuppressants, patients receiving tacrolimus (Prograf^TM) are at increased risk of developing lymphomas and other malignancies, particularly of the skin. The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent. A lymphoproliferative disorder (LPD) related to Epstein-Barr Virus (EBV) infection has been reported in immunosuppressed organ transplant recipients. The risk of LPD appears greatest in young children who are at risk for primary EBV infection while immunosuppressed or who are switched to tacrolimus (Prograf^TM) following long-term immunosuppression therapy. Because of the danger of oversuppression of the immune system which can increase susceptibility to infection, combination immunosuppressant therapy should be used with caution.

A few patients receiving tacrolimus (Prograf^TM) injection have experienced anaphylactic reactions. Although the exact cause of these reactions is not known, other drugs with castor oil derivatives in the formulation have been associated with anaphylaxis in a small percentage of patients. Because of this potential risk of anaphylaxis, tacrolimus (Prograf^TM) injection should be reserved for patients who are unable to take tacrolimus (Prograf^TM) capsules.

Patients receiving tacrolimus (Prograf^TM) injection should be under continuous observation for at least the first 30 minutes following the start of the infusion and at frequent intervals thereafter. If signs or symptoms of anaphylaxis occur, the infusion should be stopped. An aqueous solution of epinephrine should be available at the bedside as well as a source of oxygen.

PRECAUTIONS
General
Hypertension is a common adverse effect of tacrolimus (Prograf^TM) therapy (see ADVERSE REACTIONS). Mild or moderate hypertension is more frequently reported than severe hypertension. Antihypertensive therapy may be required; the control of blood pressure can be accomplished with any of the common antihypertensive agents. Since tacrolimus may cause hyperkalemia, potassium-sparing diuretics should be avoided. While calcium-channel blocking agents can be effective in treating tacrolimus (Prograf^TM)-associated hypertension, care should be taken since interference with tacrolimus metabolism may require a dosage reduction (see Drug Interactions).

Renally and Hepatically Impaired Patients
For patients with renal insufficiency some evidence suggests that lower doses should be used (see DOSAGE AND ADMINISTRATION).

The use of tacrolimus (Prograf^TM) in liver transplant recipients experiencing post-transplant hepatic impairment may be associated with increased risk of developing renal insufficiency related to high whole-blood levels of tacrolimus. These patients should be monitored closely and dosage adjustments should be considered. Some evidence suggests that lower doses should be used in these patients (see DOSAGE AND ADMINISTRATION).

Myocardial Hypertrophy
Myocardial hypertrophy has been reported in association with the administration of tacrolimus (Prograf^TM), and is generally manifested by echocardiographically demonstrated concentric increases in left ventricular posterior wall and interventricular septum thickness. Hypertrophy has been observed in infants, children and adults. This condition appears reversible in most cases following dose reduction or discontinuance of therapy. In a group of 20 patients with pre- and post-treatment echocardiograms who showed evidence of myocardial hypertrophy, mean tacrolimus whole blood concentrations during the period prior to diagnosis of myocardial hypertrophy ranged from 11 to 53 ng/mL in infants (N=10, age 0.4 to 2 years), 4 to 46 ng/mL in children (N=7, age 2 to 15 years) and 11 to 24 ng/mL in adults (N=3, age 37 to 53 years).

In patients who develop renal failure or clinical manifestations of ventricular dysfunction while receiving tacrolimus (Prograf^TM) therapy, echocardiographic evaluation should be considered. If myocardial hypertrophy is diagnosed, dosage reduction or discontinuation of tacrolimus (Prograf^TM) should be considered.

Information for Patients
Patients should be informed of the need for repeated appropriate laboratory tests while they are receiving tacrolimus (Prograf^TM). They should be given complete dosage instructions, advised of the potential risks during pregnancy, and informed of the increased risk of neoplasia. Patients should be informed that changes in dosage should not be undertaken without first consulting their physician.

Patients should be informed that tacrolimus (Prograf^TM) can cause diabetes mellitus and should be advised of the need to see their physician if they develop frequent urination, increased thirst or hunger.

Laboratory Tests
Serum creatinine, potassium, and fasting glucose should be assessed regularly. Routine monitoring of metabolic and hematologic systems should be performed as clinically warranted.

Drug Interactions
Drug interaction studies with tacrolimus have not been conducted. Due to the potential for additive or synergistic impairment of renal function, care should be taken when administering tacrolimus (Prograf^TM) with drugs that may be associated with renal dysfunction. These include, but are not limited to, aminoglycosides, amphotericin B, and cisplatin. Initial clinical experience with co-administration of tacrolimus (Prograf^TM) and cyclosporine resulted in additive/synergistic nephrotoxicity. Patients switched from cyclosporine to tacrolimus (Prograf^TM) should receive the first tacrolimus (Prograf^TM) dose no sooner than 24 hours after the last cyclosporine dose. Dosing may be further delayed in the presence of elevated cyclosporine levels.

Drugs that May Alter Tacrolimus Concentrations
Since tacrolimus is metabolized mainly by the CYP3A enzyme systems, substances known to inhibit these enzymes may decrease the metabolism of tacrolimus with resultant increases in whole blood or plasma concentrations. Drugs known to induce these enzyme systems may result in an increased metabolism of tacrolimus and decreased whole blood or plasma concentrations. Monitoring of blood concentrations and appropriate dosage adjustments are essential when such drugs are used concomitantly.

*Drugs That May Increase Tacrolimus Blood Concentrations:

*Drugs That May Decrease Tacrolimus Blood Concentrations:

Anticonvulsants	Antibiotics
carbamazepine	rifabutin
phenobarbital	rifampin
phenytoin
*This table is not all inclusive.

Interaction studies with drugs used in HIV therapy have not been conducted. However, care should be exercised when drugs that are nephrotoxic (e.g., ganciclovir) or that are metabolized by CYP3A (e.g., ritonavir) are administered concomitantly with tacrolimus. Grapefruit juice affects CYP3A-mediated metabolism and should be avoided (See DOSAGE AND ADMINISTRATION).

Other Drug Interactions
Immunosuppressants may affect vaccination. Therefore, during treatment with tacrolimus (Prograf^TM), vaccination may be less effective. The use of live vaccines should be avoided; live vaccines may include, but are not limited to measles, mumps, rubella, oral polio, BCG, yellow fever, and TY 21a typhoid.¹

Carcinogenesis, Mutagenesis and Impairment of Fertility
An increased incidence of malignancy is a recognized complication of immunosuppression in recipients of organ transplants. The most common forms of neoplasms are non-Hodgkin's lymphomas and carcinomas of the skin. As with other immunosuppressive therapies, the risk of malignancies in tacrolimus (Prograf^TM) recipients may be higher than in the normal, healthy population. Lymphoproliferative disorders associated with Epstein-Barr Virus infection have been seen. It has been reported that reduction or discontinuation of immunosuppression may cause the lesions to regress.

No evidence of genotoxicity was seen in bacterial (Salmonella and E. Coli) or mammalian (Chinese hamster lung-derived cells) in vitro assays of mutagenicity, the in vitro CHO/HGPRT assay of mutagenicity, or in vivo clastogenicity assays performed in mice; tacrolimus did not cause unscheduled DNA synthesis in rodent hepatocytes.

Carcinogenicity studies were carried out in male and female rats and mice. In the 80-week mouse study and in the 104-week rat study no relationship of tumor incidence to tacrolimus dosage was found. The highest doses used in the mouse and rat studies were 0.8-2.5 times (mice) and 3.5-7.1 times (rats) the recommended clinical dose range of 0.1-0.2 mg/kg/day when corrected for body surafce area.

No impairment of fertility was demonstrated in studies of male and female rats. Tacrolimus, given orally at 1.0 mg/kg (0.7 - 1.4X the recommended clinical dose range of 0.1 - 0.2 mg/kg/day based on body surface area corrections) to male and female rats, prior to and during mating, as well as to dams during gestation and lactation, was associated with embryolethality and with adverse effects on female reproduction. Effects on female reproductive function (parturition) and embryolethal effects were indicated by a higher rate of pre-implantation loss and increased numbers of undelivered and nonviable pups. When given at 3.2 mg/kg (2.3 - 4.6X the recommended clinical dose range based on body surface area correction), tacrolimus was associated with maternal and paternal toxicity as well as reproductive toxicity including marked adverse effects on estrus cycles, parturition, pup viability, and pup malformations.

Pregnancy: Category C
In reproduction studies in rats and rabbits, adverse effects on the fetus were observed mainly at dose levels that were toxic to dams. Tacrolimus at oral doses of 0.32 and 1.0 mg/kg during organogenesis in rabbits was associated with maternal toxicity as well as an increase in incidence of abortions; these doses are equivalent to 0.5 - 1X and 1.6 - 3.3X the recommended clinical dose range (0.1 - 0.2 mg/kg) based on body surface area corrections. At the higher dose only, an increased incidence of malformations and developmental variations was also seen. Tacrolimus, at oral doses of 3.2 mg/kg during organogenesis in rats, was associated with maternal toxicity and caused an increase in late resorptions, decreased numbers of live births, and decreased pup weight and viability. Tacrolimus, given orally at 1.0 and 3.2 mg/kg (equivalent to 0.7 - 1.4X and 2.3 - 4.6X the recommended clinical dose range based on body surface area corrections) to pregnant rats after organogenesis and during lactation, was associated with reduced pup weights.

No reduction in male or female fertility was evident.

There are no adequate and well-controlled studies in pregnant women. Tacrolimus is transferred across the placenta. The use of tacrolimus during pregnancy has been associated with neonatal hyperkalemia and renal dysfunction. Tacrolimus (Prograf^TM) should be used during pregnancy only if the potential benefit to the mother justifies potential risk to the fetus.

Nursing Mothers
Since tacrolimus is excreted in human milk, nursing should be avoided.

Pediatric Patients
Experience with tacrolimus (Prograf^TM) in pediatric kidney transplant patients is limited. Successful liver transplants have been performed in pediatric patients (ages up to 16 years) using tacrolimus (Prograf^TM). The two randomized active-controlled trials of tacrolimus (Prograf^TM) in primary liver transplantation included 56 pediatric patients. Thirty-one patients were randomized to tacrolimus (Prograf^TM)-based and 25 to cyclosporine-based therapies. Additionally, a minimum of 122 pediatric patients were studied in an uncontrolled trial of tacrolimus in living related donor liver transplantation. Pediatric patients generally required higher doses of tacrolimus (Prograf^TM) to maintain blood trough concentrations of tacrolimus similar to adult patients (see DOSAGE AND ADMINISTRATION).

ADVERSE REACTIONS
Liver Transplantation
The principal adverse reactions of tacrolimus (Prograf^TM) are tremor, headache, diarrhea, hypertension, nausea, and renal dysfunction. These occur with oral and IV administration of tacrolimus (Prograf^TM) and may respond to a reduction in dosing. Diarrhea was sometimes associated with other gastrointestinal complaints such as nausea and vomiting.

Hyperkalemia and hypomagnesemia have occurred in patients receiving tacrolimus (Prograf^TM) therapy. Hyperglycemia has been noted in many patients; some may require insulin therapy (see WARNINGS).

The incidence of adverse events was determined in two randomized comparative liver transplant trials among 514 patients receiving tacrolimus and steroids and 515 patients receiving a cyclosporine-based regimen (CBIR). The proportion of patients reporting more than one adverse event was 99.8% in the tacrolimus group and 99.6% in the CBIR group. Precautions must be taken when comparing the incidence of adverse events in the U.S. study to that in the European study. The 12-month post-transplant information from the U.S. study and from the European study is presented below. The two studies also included different patient populations and patients were treated with immunosuppressive regimens of differing intensities. Adverse events reported in ³ 15% in tacrolimus patients (combined study results) are presented below for the two controlled trials in liver transplantation.

LIVER TRANSPLANTATION: ADVERSE EVENTS OCCURRING IN ³15% OF PROGRAF^TM-TREATED PATIENTS

Less frequently observed adverse reactions in both liver transplantation and kidney transplantation patient are described under the subsection Less Frequently Reported Adverse Reactions below.

Kidney Transplantation
The most common adverse reactions reported were infection, tremor, hypertension, decreased renal function, constipation, diarrhea, headache, abdominal pain and insomnia.
Adverse events that occurred in ³15% of tacrolimus (Prograf^TM)-treated kidney transplant patients are presented below:

KIDNEY TRANSPLANTATION: ADVERSE EVENTS OCCURRING IN ³15% OF PROGRAF^TM-TREATED PATIENTS

Less frequently observed adverse reactions in both liver transplantation and kidney transplantation patients are described under the subsection Less Frequently Reported Adverse Reactions shown below.

Less Frequently Reported Adverse Reactions
The following adverse events were reported in the range of 3% to less than 15% incidence in either liver or kidney transplant recipients who were treated with tacrolimus in the Phase 3 comparative trials.

NERVOUS SYSTEM: (see WARNINGS) abnormal dreams, agitation, amnesia, anxiety, confusion, convulsion, depression, dizziness, emotional lability, encephalopathy, hallucinations, hypertonia, incoordination, myoclonus nervousness, neuropathy, psychosis, somnolence, thinking abnormal; SPECIAL SENSES: abnormal vision, amblyopia, ear pain, otitis media, tinnitus; GASTROINTESTINAL: anorexia, cholangitis, cholestatic jaundice, dyspepsia, dysphagia, esophagitis, flatulence, gastritis, gastrointestinal hemorrhage, GGT increase, GI perforation, hepatitis, ileus, increased appetite, jaundice, liver damage, liver function test abnormal, oral moniliasis, rectal disorder, stomatitis; CARDIOVASCULAR: angina pectoris, chest pain, deep thrombophlebitis, abnormal ECG, hemorrhage, hypotension, postural hypotension, peripheral vascular disorder, phlebitis, tachycardia, thrombosis, vasodilatation; UROGENITAL: (see WARNINGS) albuminuria, cystitis, dysuria, hematuria, hydronephrosis, kidney failure, kidney tubular necrosis, nocturia, pyuria, toxic nephropathy, oliguria, urinary frequency, urinary incontinence, vaginitis; METABOLIC/NUTRITIONAL: acidosis, alkaline phosphatase increased, alkalosis, ALT (SGPT) increased, AST (SGOT) increased, bicarbonate decreased, bilirubinemia, BUN increased, dehydration, GGT increased, healing abnormal, hypercalcemia, hypercholesterolemia, hyperlipemia, hyperphosphatemia, hyperuricemia, hypervolemia, hypocalcemia, hypoglycemia, hyponatremia, hypophosphatemia, hypoproteinemia, lactic dehydrogenase increase, weight gain; ENDOCRINE: (see PRECAUTIONS) Cushing's syndrome, diabetes mellitus; HEMIC/LYMPHATIC: coagulation disorder, ecchymosis, hypochromic anemia, leukocytosis, leukopenia, polycythemia, prothrombin decreased, serum iron decreased, thrombocytopenia; MISCELLANEOUS: abdomen enlarged, abscess, accidental injury, allergic reaction, cellulitis, chills, flu syndrome, generalized edema, hernia, peritonitis, photosensitivity reaction, sepsis; MUSCULOSKELETAL: arthralgia, cramps, generalized spasm, joint disorder, leg cramps, myalgia, myasthenia, osteoporosis; RESPIRATORY: asthma, bronchitis, cough increased, lung disorder, pneumothorax, pulmonary edema, pharyngitis, pneumonia, respiratory disorder, rhinitis, sinusitis, voice alteration; SKIN: acne, alopecia, exfoliative dermatitis, fungal dermatitis, herpes simplex, hirsutism, skin discoloration, skin disorder, skin ulcer, sweating.

There have been rare spontaneous reports of myocardial hypertrophy associated with clinically manifested ventricular dysfunction in patients receiving tacrolimus (Prograf^TM) therapy (see PRECAUTIONS - Myocardial Hypertrophy).

OVERDOSAGE
Limited overdosage experience is available. Acute overdosages of up to 30 times the intended dose have been reported. Almost all cases have been asymptomatic and all patients recovered with no sequelae. Occasionally, acute overdosage has been followed by adverse reactions consistent with those listed in the ADVERSE REACTIONS section except in one case where transient urticaria and lethargy were observed. Based on the poor aqueous solubility and extensive erythrocyte and plasma protein binding, it is anticipated that tacrolimus is not dialyzable to any significant extent; there is no experience with charcoal hemoperfusion. The oral use of activated charcoal has been reported in treating acute overdoses, but experience has not been sufficient to warrant recommending its use. General supportive measures and treatment of specific symptoms should be followed in all cases of overdosage.

In acute oral and IV toxicity studies, mortalities were seen at or above the following doses: in adult rats, 52X the recommended human oral dose; in immature rats, 16X the recommended oral dose; and in adult rats, 16X the recommended human IV dose (all based on body surface area corrections).

DOSAGE AND ADMINISTRATION

Liver Transplantation
It is recommended that patients initiate oral therapy with tacrolimus (Prograf^TM) capsules if possible. The initial dose of tacrolimus (Prograf^TM) should be administered no sooner than 6 hours after transplantation. The recommended starting oral dose of tacrolimus (Prograf^TM) capsules is 0.10-0.15 mg/kg/day administered in two divided daily doses every 12 hours. Co-administered grapefruit juice has been reported to increase tacrolimus blood trough concentrations in liver transplant patients. (See Drugs that May Alter Tacrolimus Concentrations.)

Dosing should be titrated based on clinical assessments of rejection and tolerability. Lower tacrolimus (Prograf^TM) dosages may be sufficient as maintenance therapy. Adjunct therapy with adrenal corticosteroids is recommended early post transplant.

Dosage and typical tacrolimus whole blood trough concentrations are shown in the table above; blood concentration details are described in Blood Concentration Monitoring: Liver Transplantation below.

Kidney Transplantation
The recommended starting oral dose of tacrolimus (Prograf^TM) is 0.2 mg/kg/day administered every 12 hours in two divided doses. The initial dose of tacrolimus (Prograf^TM) may be administered within 24 hours of transplantation, but should be delayed until renal function has recovered (as indicated for example by a serum creatinine £4 mg/dL). Black patients may require higher doses to achieve comparable blood concentrations. Dosage and typical tacrolimus whole blood trough concentrations are shown in the table above; blood concentration details are described in Blood Concentration Monitoring: Kidney Transplantation below.

Pediatric Patients
Pediatric liver transplantation patients without pre-existing renal or hepatic dysfunction have required and tolerated higher doses than adults to achieve similar blood concentrations. Therefore, it is recommended that therapy be initiated in pediatric patients at a starting oral dose of 0.15-0.20 mg/kg/day. Dose adjustments may be required. Experience in pediatric kidney transplantation patients is limited.

Patients with Hepatic or Renal Dysfunction
Due to the potential for nephrotoxicity, patients with renal or hepatic impairment should receive doses at the lowest value of the recommended oral dosing ranges. Further reductions in dose below these ranges may be required. Tacrolimus (Prograf^TM) therapy usually should be delayed up to 48 hours or longer in patients with post-operative oliguria.

Conversion from One Immunosuppressive Regimen to Another
Tacrolimus (Prograf^TM) should not be used simultaneously with cyclosporine. Tacrolimus (Prograf^TM) or cyclosporine should be discontinued at least 24 hours before initiating the other. In the presence of elevated tacrolimus (Prograf^TM) or cyclosporine concentrations, dosing with the other drug usually should be further delayed.

Blood Concentration Monitoring
Monitoring of tacrolimus blood concentrations in conjunction with other laboratory and clinical parameters is considered an essential aid to patient management for the evaluation of rejection, toxicity, dose adjustments and compliance. Factors influencing frequency of monitoring include but are not limited to hepatic or renal dysfunction, the addition or discontinuation of potentially interacting drugs and the posttransplant time. Blood concentration monitoring is not a replacement for renal and liver function monitoring and tissue biopsies.

Two methods have been used for the assay of tacrolimus, a microparticle enzyme immunoassay (MEIA) and an ELISA. Both methods have the same monoclonal antibody for tacrolimus. Comparison of the concentrations in published literature to patient concentrations using the current assays must be made with detailed knowledge of the assay methods and biological matrices employed. Whole blood is the matrix of choice and specimens should be collected into tubes containing ethylene diamine tetraacetic acid (EDTA) anti-coagulant. Heparin anti-coagulation is not recommended because of the tendency to form clots on storage. Samples which are not analyzed immediately should be stored at room temperature or in a refrigerator and assayed within 7 days; if samples are to be kept longer they should be deep frozen at -20°C for up to 12 months.

Liver Transplantation
Although there is lack of direct correlation between tacrolimus concentrations and drug efficacy, data from Phase II and III studies of liver transplant patients have shown an increasing incidence of adverse events with increasing trough blood concentrations. Most patients are stable when trough whole blood concentrations are maintained between 5 to 20 ng/mL. Long term posttransplant patients often are maintained at the low end of this target range.

Data from the U.S. clinical trial show that tacrolimus whole blood concentrations, as measured by ELISA, were most variable during the first week post-transplantation. After this early period, the median trough blood concentrations, measured at intervals from the second week to one year post-transplantation, ranged from 9.8 ng/mL to 19.4 ng/mL.

Therapeutic Drug Monitoring, 1995, Volume 17, Number 6 contains a consensus document and several position papers regarding the therapeutic monitoring of tacrolimus from the 1995 International Consensus Conference on Immunosuppressive Drugs. Refer to these manuscripts for further discussions of tacrolimus monitoring.

Kidney Transplantation
Data from the U.S. study indicates that trough concentrations of tacrolimus in whole blood, as measured by IMxÒ, were most variable during the first week of dosing. During the first three months, 80% of the patients maintained trough concentrations between 7-20 ng/mL, and then between 5-15 ng/mL, through one-year.

The relative risk of toxicity is increased with higher trough concentrations. Therefore, monitoring of whole blood trough concentrations is recommended to assist in the clinical evaluation of toxicity.

HOW SUPPLIED
Oblong, white, branded with red "1 mg" on the capsule cap and "†617" on the capsule body, supplied in 5 blister cards of 10 capsules, containing the equivalent of 1 mg anhydrous tacrolimus.

Storage conditions
Store between 15°C - 30°C in a dry place.
Keep out of reach of children.

CAUTION: Food, Drugs, Devices and Cosmetics Act prohibits dispensing without prescription.

REFERENCE:

1. CDC: Recommendations of the Advisory Committee on Immunization Practices: Use of vaccines and immune globulins in persons with altered immunocompetence. MMWR 1993; 42(RR-4);1-18.

Manufactured by:
Fujisawa Ireland, Ltd.
Killorglin, Co. Kerry Ireland
Packed by:
Interphil Laboratories, Inc.
Canlubang Industrial Estate
Bo. Pittland, Cabuyao, Laguna
for: Johnson & Johnson (Philippines), Inc.
Edison Road, Bo. Ibayo
Parañaque, Metro Manila
Exclusively distributed by:
Zuellig Pharma Corporation
Sen. Gil Puyat Avenue Extension
Makati City