Prograf (Tacrolimus)

PROGRAF®

Fujisawa

Tacrolimus

Immunosuppressant

Action And Clinical Pharmacology: Tacrolimus is a macrolide immunosuppressant produced by Streptomyces tsukubaensis.

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.

Tacrolimus has been demonstrated to suppress some humoral immunity and, to a greater extent, cell-mediated reactions such as allograft rejection, delayed type hypersensitivity, Freund’s adjuvant arthritis, experimental allergic encephalomyelitis and graft versus host disease in several animal species.

Tacrolimus inhibits T-lymphocyte activation, although the exact mechanism of action is not known. The minimum inhibitory tissue culture level of tacrolimus that prevents antigen stimulation of T-lymphocytes is 0.1 to 0.3 nM. 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 generation of nuclear factor of activated T-cells (NF-AT), a nuclear component thought to initiate the gene transcription for the formation of lymphokines (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. After oral administration, absorption of tacrolimus into the systemic circulation from the gastrointestinal tract is incomplete and can be variable. Elimination of tacrolimus is via hepatic metabolism with a mean terminal elimination half-life of 18.8 hours in kidney transplant patients, 11.7 hours in liver transplant patients and 34.2 hours in healthy volunteers following i.v. administration. Due to intersubject variability in tacrolimus pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy. Dosing individualization can be achieved by therapeutic drug monitoring of tacrolimus blood concentrations and evaluation of clinical status (see Dosage). 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 can be variable. Mean (±S.D.) pharmacokinetic parameters of tacrolimus in whole blood after oral administration to volunteers in 2 studies.

The two different dose strengths of tacrolimus capsules (1 and 5 mg) are bioequivalent.

In 26 kidney transplant patients, peak concentrations (Cmax) were achieved at approximately 1 to 3 hours. The absorption half-life of tacrolimus in 17 liver transplant patients averaged 0.6 hour (S.D. 1.0 hour) with peak concentrations (Cmax) in blood and plasma being achieved at approximately 1.5 to 3.5 hours. Mean (±S.D.) pharmacokinetic parameters of tacrolimus in whole blood after initial dose in adult kidney and liver transplant patients are presented in Table II.

The absolute bioavailability of tacrolimus is approximately 17% in kidney transplant patients, 22% in adult liver transplant patients, 34% in pediatric liver transplant patients, and 18% in healthy volunteers.

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

The effect was most pronounced with the high-fat meal: mean area under the curve (AUC0-96) and Cmax were decreased 37% and 77%, respectively; Tmax was lengthened 5-fold. The high-carbohydrate meal decreased AUC0-96 and Cmax by 28% and 65%, respectively.

The effect of food was also studied in 11 liver transplant patients. Tacrolimus was administered in the fasted state or 15 minutes after a breakfast of known fat content (34% of 400 total calories). The results indicate that the presence of food reduces the absorption of tacrolimus in these patients (decrease in AUC and Cmax and increase in Tmax). The relative oral bioavailability (whole blood) was reduced by 27.0 (±18.2%) compared to administration in the fasting state.

In healthy volunteers, the time of the meal also affected tacrolimus bioavailability. Relative to the fasted state, there was little effect on tacrolimus bioavailability when administered 1 hour prior to a high-fat breakfast, whereas bioavailability (both extent and rate of absorption) was greatly reduced when the drug was administered immediately or 1.5 hours after the meal. When given immediately following the meal, Cmax was reduced 71%, AUC0-96 was reduced by 39%, and Tmax was delayed 1.6 hours relative to the fasting condition. When administered 1.5 hours following the meal, Cmax was reduced 63%, AUC0-96 was reduced 39%, and Tmax was delayed 1.4 hours relative to the fasted condition.

Distribution: The apparent volume of distribution (based on whole blood concentrations) of tacrolimus is approximately 1.41, 1.91 and 0.85 L/kg in kidney transplant patients, healthy volunteers and adult liver transplant patients, respectively;

The plasma protein binding of tacrolimus is approximately 99% and is independent of concentration over a range of 5 to 50 ng/mL. Tacrolimus is bound to proteins, mainly albumin and a-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 ranged from 12 to 67 (mean 35).

In 18 kidney transplant patients, tacrolimus trough concentrations from 3 to 30 ng/mL measured at 10 to 12 hours post dose (Cmin) correlated well with the AUC 0-12 (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.

Metabolism: Tacrolimus is extensively metabolized by the mixed-function oxidase system, primarily the cytochrome P450 enzyme system (CYPIIIA). 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; the 13-demethyl, 15-demethyl and 15- and 31-double-demethylated metabolites were shown to retain an activity of less than 10%.

Excretion: The clearance of tacrolimus is 0.040, 0.083 and 0.042 L/h/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.

Special Populations: Pediatric Patients: A study in liver transplantation has been conducted in 16 pediatric patients (age range: 0.7 to 13.2 years). A mean terminal elimination half-life of 11.5 hours was determined following an i.v. dose of 0.037 mg/kg/day in 12 patients; the volume of distribution was 2.6 L/kg, whereas clearance was 0.135 L/h/kg. In 9 patients receiving capsule formulation, a mean Cmax of 48.4 ng/mL was attained at a mean Tmax of 2.7 hours following an oral dose of 0.152 mg/kg as tacrolimus capsules. The AUC (0-72h) was 337 ng.h/mL. The absolute bioavailability was 31%.

Whole blood trough concentrations from 31 pediatric patients (less than 12 years old) showed that pediatric patients need higher doses than adults to achieve similar tacrolimus trough concentrations, suggesting that the pharmacokinetic characteristics of tacrolimus are different in pediatric patients compared to adults (see Dosage).

Renal Insufficiency: Tacrolimus pharmacokinetics following a single i.v. administration have been determined in 12 patients (7 not on dialysis and 5 on dialysis) prior to their kidney transplant.

The disposition of tacrolimus in patients with renal dysfunction was not different from that in normal volunteers (see previous tables). The clearance was similar whereas volume of distribution was smaller and the mean terminal elimination half-life shorter than that of normal volunteers.

Hepatic Insufficiency: Tacrolimus pharmacokinetics have been determined in 6 patients with mild hepatic dysfunction (mean Pugh score: 6.2) following single i.v. and oral administrations.

The disposition of tacrolimus in patients with mild hepatic dysfunction was not substantially different from that in normal volunteers (see previous tables). In general, tacrolimus elimination half-life was longer and volume of distribution larger in patients with mild hepatic dysfunction compared to normal volunteers. The clearance in both populations was similar and since tacrolimus is extensively metabolized at multiple sites, patients with mild hepatic dysfunction may not require lower maintenance doses of tacrolimus than patients with normal hepatic function.

Clinical Studies: Kidney Transplantation: The safety and efficacy of tacrolimus-based immunosuppression following kidney transplantation were assessed in 2 randomized, multicentre, nonblinded, prospective studies. The active control groups were treated with cyclosporine-based immunosuppression. These studies were designed to evaluate whether the 2 regimens were therapeutically equivalent for 1-year patient and graft survival. Based on the results from these 2 studies, the tacrolimus-based regimen was found to be therapeutically equivalent to the cyclosporine-based regimen.

In 1 trial, 412 kidney transplant patients were enrolled at 19 clinical sites in the U.S.; 205 patients were randomized to tacrolimus-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. Tacrolimus was initiated when renal function was stable as indicated by a serum creatinine £4 mg/dL (353.6 µmol/L). Tacrolimus was initiated a median of 4 days after transplantation. Patients less than 6 years of age were excluded.

In the second trial, 448 kidney transplant patients were enrolled at 15 clinical sites in Europe; 303 patients were randomized to tacrolimus-based immunosuppression and 145 patients were randomized to cyclosporine-based immunosuppression. Tacrolimus was initiated within 24 hours of transplantation and was administered with corticosteroids and azathioprine. Patients less than 18 years of age were excluded.

One-year patient and graft survival in the tacrolimus-based treatment groups were equivalent to those in the cyclosporine-based treatment groups. The overall 1-year patient survival (tacrolimus and cyclosporine combined) was 96.1% in the U.S. study and 94.2% in the European study. The overall 1-year graft survival was 89.6% in the U.S. study and 83.7% in the European study.

The 2 large, randomized clinical trials demonstrated that significantly fewer tacrolimus-treated patients (approximately 16% fewer) experienced an episode of acute rejection during the one-year treatment period compared with cyclosporine-treated patients (p
Significantly fewer tacrolimus-treated patients crossed over to cyclosporine therapy due to adverse events and acute rejection episodes compared to cyclosporine-treated patients transferring to tacrolimus therapy (p=.007). The majority of patients who crossed over from the cyclosporine therapy to tacrolimus therapy were due to rejection (n=27). The majority of patients who crossed over from tacrolimus therapy to cyclosporine therapy were due to adverse reactions (n=13) and rarely for rejection (n=2). Of 27 cyclosporine-treated patients demonstrating acute rejection episodes and transferred to tacrolimus, 21 of these patient rejection episodes resolved (77.8%). Of the 2 tacrolimus patients transferred to cyclosporine due to acute rejection, 1 of the rejection episodes resolved.

An open-label, rescue study assessed the effect of tacrolimus on 73 kidney transplant patients with biopsy-proven, corticosteroid-resistant acute rejection. Responses to tacrolimus therapy included improvement in 78% of patients, stabilization in 11% and progressive deterioration in 11%. Patient and graft survival 1 year postconversion to tacrolimus was 93% and 75% respectively.

Liver Transplantation: The safety and efficacy of tacrolimus administered in combination with adrenal corticosteroids was compared with cyclosporine-based immunosuppressive regimens in 2 randomized, prospective, open-labeled, multicentre studies after orthotopic liver transplantation. In addition, the efficacy of tacrolimus as rescue therapy in patients with liver allograft rejection refractory to standard therapy was examined in an open-labeled, nonrandomized, multicentre, historically controlled trial.

In 1 controlled trial, 529 patients were randomized to receive immunosuppression with tacrolimus (N=263) or cyclosporine-based regimens (N=266). Patient survival was equivalent with Kaplan-Meier actuarial 1-year estimates of 88% for both tacrolimus and cyclosporine-based regimens. Actuarial 1-year graft survival estimates were 82% for the tacrolimus group and 79% for the cyclosporine-based group. The incidences of acute rejection (68% vs 76%), steroid-resistant rejection requiring treatment with OKT3 (19% vs 36%), and refractory rejection (3% vs 15%) were lower in recipients of the tacrolimus regimen compared with cyclosporine-based regimens (see Table VIII). Cumulative adrenal corticosteroid use was lower in the tacrolimus group; however, equivalent doses of corticosteroids were not mandated for induction or maintenance in the 2 arms of the study. Other measures of efficacy, such as liver function tests and Karnofsky scores, showed similar improvement over time in both groups.

In the second controlled study, 545 patients were randomized to receive tacrolimus combined with adrenal corticosteroids (N=270) as a treatment for prevention of rejection of primary liver allograft patients, compared with cyclosporine-based therapy (N=275).

The estimated 1-year Kaplan-Meier patient survival rates were 81% for the tacrolimus treatment group and 75% for the cyclosporine-based treatment group. One-year estimated Kaplan-Meier graft survival rates were 76% for the tacrolimus group and 70% for the cyclosporine-based group. The acute rejection rate was 42% for the tacrolimus group compared with 55% for the cyclosporine-based group. The incidence of refractory rejection was also less in the tacrolimus group (3%) compared with the cyclosporine-based group (10%) (see Table IX). The cumulative amount of adrenal corticosteroids administered to patients in the tacrolimus group was less than in the cyclosporine-based group.

In a nonrandomized historically controlled trial, 125 patients previously treated with cyclosporine-based regimens with refractory acute or chronic liver allograft rejection were treated with tacrolimus plus adrenal corticosteroids as rescue therapy. Actuarial Kaplan-Meier estimates of survival at 1 year post-conversion to tacrolimus were 71% for patient survival and 56% for graft survival. Other measures of efficacy such as clinical response scores, liver function tests, and Karnofsky performance status showed improvement over time after conversion to tacrolimus.

Indications And Clinical Uses: For the prophylaxis of organ rejection in patients receiving allogeneic liver or kidney transplants. Tacrolimus is also indicated for the treatment of refractory rejection in patients receiving allogeneic liver or kidney transplants. Tacrolimus is to be used concomitantly with adrenal corticosteroids. Because of the risk of anaphylaxis, tacrolimus injection should be reserved for patients unable to take tacrolimus capsules orally.

Contra-Indications: In patients with a hypersensitivity to tacrolimus. The injection is contraindicated in patients with a hypersensitivity to HCO-60 (polyoxyl 60 hydrogenated castor oil).

Manufacturers’ Warnings In Clinical States: Increased susceptibility to infection and the possible development of lymphoma may result from immunosuppression. Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should prescribe tacrolimus. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient.

Tacrolimus may cause neurotoxicity and nephrotoxicity, and the likelihood increases with higher blood levels. Nephrotoxicity has been noted in approximately 52% and 57% of kidney transplantation patients and in 40% and 36% of liver transplantation patients receiving tacrolimus in the U.S. and European randomized trials, respectively (see Adverse Effects). More overt nephrotoxicity is seen early after transplantation, characterized by increasing serum creatinine and a decrease in urine output. Impaired renal function requires close monitoring and may necessitate tacrolimus dosage reduction. In patients with persistent elevations of serum creatinine who are unresponsive to dosage adjustments, consideration should be given to changing to other immunosuppressive therapy. Care should be taken in using tacrolimus with other nephrotoxic drugs. In particular, to avoid excess nephrotoxicity, when switching patients from a cyclosporine-based regimen to a tacrolimus-based regimen, cyclosporine should be discontinued at least 24 hours prior to initiating tacrolimus. Tacrolimus dosing may be further delayed in the presence of elevated cyclosporine levels (see Precautions). When switching from tacrolimus to cyclosporine, tacrolimus should be discontinued for at least 24 hours.

Mild to severe hyperkalemia was reported in 31% and 21% of kidney transplant patients and in 45% and 13% of liver transplant recipients treated with tacrolimus in the U.S. and European randomized trials, respectively (see Adverse Effects). Serum potassium levels should be monitored and potassium sparing diuretics should not be used during tacrolimus 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 2 randomized studies (see Adverse Effects). Tremor occurred more often in tacrolimus-treated kidney transplant patients in the U.S. and European studies (54 and 35%, respectively), compared to cyclosporine-treated patients. The incidence of other neurological events was similar in the 2 treatment groups in both kidney studies (see Adverse Effects). 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 (see Adverse Effects). Coma and delirium also have been associated with high plasma concentrations of tacrolimus.

As in patients receiving other immunosuppressants, patients receiving tacrolimus 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. 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 following long-term immunosuppression therapy. Experience on combining tacrolimus with immunosuppressive drugs other than adrenal corticosteroids is limited because of the potency of tacrolimus and the risk of over immunosuppression and such combinations are not recommended.

Tacrolimus has been studied in combination with azathioprine and steroids (triple therapy) in recipients of kidney transplants. In a Phase II European trial, tacrolimus triple therapy was administered to 31 adults receiving cadaveric kidney transplants. Within 6 weeks post-transplant there were no deaths or graft losses. Six patients (19.4%) experienced acute rejection, with 1 patient experiencing corticosteroid resistant rejection. Three patients (9.7%) developed transient hyperglycemia, but no patient required long-term therapy for diabetes. Other adverse events reported frequently included infections (51.6%), minor neurological disorders (54.8%), and hypertension (48.8%). The University of Pittsburgh has studied double therapy (tacrolimus and steroids) compared to triple therapy in 204 adult recipients of kidney transplants between August 1991 and October 1992. The 1 year actuarial patient and graft survival of double therapy were 95 and 90% versus 91 and 82% for triple therapy (p=NS). The incidence of rejection was significantly lower with triple therapy in cadaveric recipients (39% versus 58%) but not significantly different in recipients from living related donors. New onset diabetes was seen in 20.2% of double therapy patients versus 7.7% of triple therapy patients. A U.S. Phase II trial studied 92 adult recipients of cadaveric kidney transplants randomized to 3 target whole blood concentration ranges of tacrolimus. All patients received antilymphoblast globulin induction with azathioprine and steroids followed by tacrolimus triple therapy initiated within 2 weeks post-transplant. With follow-up to 6 weeks post-transplant there were no patient deaths, and 1 graft loss. The incidence of rejection was 14% combining all tacrolimus treatment groups. Adverse events requiring dose reduction were significantly associated with target tacrolimus blood concentrations (36 to 62%).

Data on the safety and efficacy of tacrolimus in combination with immunosuppressants other than steroids in liver transplant patients are more limited. In the European multicentre liver transplant study, many patients received azathioprine or ATG/ALG when tacrolimus therapy was withheld. Seven patients received azathioprine in combination with tacrolimus and steroids. Of these 7 patients, 1 died and 1 lost their graft in the first year post-transplant.

A few patients receiving tacrolimus 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 injection should be reserved for patients who are unable to take tacrolimus capsules.

Patients receiving tacrolimus 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 1:1 000 should be available at the bedside as well as a source of oxygen.

Precautions: General: Hypertension is a common side effect of tacrolimus therapy (see Adverse Effects). Mild or moderate hypertension is more frequently reported than severe hypertension. The incidence of hypertension decreases over time. 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-associated hypertension, care should be taken since interference with tacrolimus metabolism may require a dosage reduction (see Drug Interactions).

Insulin-dependent post-transplant diabetes mellitus (PTDM) was reported in 20% and 6% of tacrolimus-treated kidney transplant patients in the U.S. and European studies respectively. Since the development of PTDM is related to increased whole blood trough concentrations of tacrolimus and higher doses of corticosteroids, trough concentrations of tacrolimus and/or steroid doses may be decreased if the risk/benefit assessment permits. In the U.S. multicentre trial, Black and Hispanic kidney transplant patients were at an increased risk of development of PTDM, regardless of randomized treatment. Insulin-dependence was reversible in some patients without discontinuation of tacrolimus or steroids, and therefore, the need for insulin therapy should be reassessed periodically.

Hyperglycemia was associated with the use of tacrolimus in 47% and 33% of liver transplant recipients in the U.S. and European randomized studies, respectively, and may require treatment (see Adverse Effects). Insulin-dependent diabetes was associated with the use of tacrolimus. This may reverse with dose decrease; however, it may be irreversible after prolonged tacrolimus administration.

Myocardial Hypertrophy: Myocardial hypertrophy has been reported in association with the administration of tacrolimus, 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.

Pregnancy: Tacrolimus at oral doses of 0.32 and 1 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 0.33X and 1.0X (based on body surface area corrections) the recommended clinical dose (0.3 mg/kg). 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 and 3.2 mg/kg (equivalent to 0.5X and 1.5X), the recommended clinical dose based on body surface area corrections to pregnant rats after organogenesis and during lactation, was associated with reduced pup weights.

Tacrolimus, given orally at 1 mg/kg (0.5´ the recommended clinical dose 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 adverse effects on female reproduction and embryo lethality. Effects on female reproductive function (parturition) and embryo lethal 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 (1.5 ´ the recommended clinical dose 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. Toxicities to parental rats were indicated by tremors and circling, as well as reduced weight gains and food consumption in males; and reduced food consumption during gestation and lactation in females. Adverse effects on reproductive parameters included: 1) increased copulatory intervals, 2) increased pre- and postimplantation loss of fetuses (resulting in smaller litter sizes), and 3) decreased numbers of dams delivering. No reduction in male or female fertility was evident. Adverse effects seen in pups were markedly reduced viability and a slight increase in the incidence of malformation (3 pups from 3 dams).

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 should be used during pregnancy only if the potential benefit to the mother justifies potential risk to the fetus.

In experience reported by the University of Pittsburgh, 11 female transplant patients maintained on tacrolimus therapy throughout pregnancy delivered 12 babies, with 1 patient conceiving twice. These patients received tacrolimus from week 1 to 20 months prior to conception. Ten of the pregnancies were successful, 4 with C-sections. The neonates showed no growth retardation or congenital anomalies. Hyperkalemia was observed in the majority of babies, but resolved within 24 to 48 hours without adverse effects. Two babies (both premature 22 and 24 weeks) died shortly after birth. One pregnancy was complicated by diabetes, hypertension and proteinuria, the other by CMV infection requiring ganciclovir therapy. Additional information includes a report of 1 newborn who had temporary anuria associated with high cord blood tacrolimus concentration; however, renal function was normal within 1 week. Another reference reports on the successful pregnancy (normal healthy male) in a 28-year-old female with bolus steroids and increased doses of tacrolimus for liver graft rejection. In this case, the cord blood plasma concentration was approximately one half that noted in maternal plasma.

Lactation: Since tacrolimus is excreted in human milk, nursing should be avoided.

Children: Experience with tacrolimus in pediatric kidney transplant patients is limited. Successful liver transplants have been performed in pediatric patients (ages 4 months up to 16 years) using tacrolimus. The majority of these patients were under 5 years of age. The 2 randomized active-controlled trials of tacrolimus in primary liver transplantation included 56 pediatric patients. Thirty-one patients were randomized to tacrolimus and 25 to cyclosporine-based therapies. Additionally, a minimum of 120 pediatric patients (median age 22.5 months) who underwent 122 liver transplants were studied in an uncontrolled published trial of tacrolimus in living related donor liver transplantation. Pediatric patients generally required higher doses of tacrolimus to maintain blood trough concentrations of tacrolimus similar to adult patients (see Dosage). This is thought to be a result of age related differences in the oxidative capacity of the cytochrome P450 enzyme system (CYP3A) used to metabolize tacrolimus.

Heart failure, cardiomegaly and increased thickness of the myocardium have been reported in patients taking tacrolimus. Patients at risk for these effects are primarily children younger than 5 years undergoing liver “rescue”, small bowel or multivisceral transplantation with trough whole blood tacrolimus levels exceeding 25 ng/mL. Also, these patients at risk often have experienced fluid overload, renal and/or hepatic dysfunction, hypertension and are receiving large doses of corticosteroids and other concomitant medications. Cardiovascular function for such patients should be carefully monitored. In addition, tacrolimus trough whole blood levels should be maintained below 25 ng/mL. If cardiac abnormalities develop, dose reduction or discontinuation of tacrolimus should be considered in cases where the perceived risk to the patient outweighs the benefit.

Patients with Renal or Hepatic Impairment: For patients with renal insufficiency some evidence suggests that the use of lower doses may be warranted (see Dosage).

The use of tacrolimus 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 dose adjustments should be considered. Some evidence suggests that the use of lower doses may be warranted in these patients (see Dosage).

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 with drugs that may be associated with renal dysfunction. These include, and are not limited to, aminoglycosides, amphotericin B, and cisplatin. Initial clinical experience with tacrolimus and cyclosporine resulted in additive/synergistic nephrotoxicity when both agents were co-administered. Patients switched from cyclosporine to tacrolimus should receive the first tacrolimus dose no sooner than 24 hours after the last cyclosporine dose. Dosing may be further delayed in the presence of elevated cyclosporine levels.

Since tacrolimus is metabolized mainly by the cytochrome P450 IIIA enzyme systems, substances known to inhibit these enzymes may decrease the metabolism of tacrolimus with resultant increases in whole blood or plasma levels. Drugs known to induce these enzyme systems may result in an increased metabolism of tacrolimus and decreased whole blood or plasma levels. Monitoring of blood levels and appropriate dosage adjustments are essential when such drugs are used concomitantly.

Drugs That May Increase Tacrolimus Blood Levels: calcium channel blockers: diltiazem, nicardipine, verapamil, nifedipine; antifungal agents: clotrimazole, fluconazole, itraconazole, ketoconazole; macrolide antibiotics: erythromycin, clarithromycin, troleandomycin; gastrointestinal prokinetic agents: metoclopramide, cisapride; other drugs: cyclosporine, methylprednisolone, cimetidine, danazole, bromocriptine.

Drugs That May Decrease Tacrolimus Blood Levels: anticonvulsants: carbamazepine, phenobarbital, phenytoin; antibiotics: rifampin, rifabutin.

Other Drug Interactions : Immunosuppressants may affect vaccination. Therefore, during treatment with tacrolimus, 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.

Grapefruit juice affects P450 IIIA-mediated metabolism and should be avoided.

There is no data available regarding the effect of antacids on tacrolimus absorption.

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

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 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. For the in vitro CHO/HGRPT assay of mutagenicity, or in vivo clastogenicity assays performed in mice, tacrolimus did not cause unscheduled DNA synthesis in rodent hepatocytes.

An 80-week study in mice administered tacrolimus at oral doses of 0.3, 1 and 3 mg/kg/day showed no evidence of tumorigenicity. The 104 week studies in rats administered tacrolimus at oral doses of 0.2, 0.5, 1.25, 2.5 and 5 mg/kg/day demonstrated no evidence of tumorigenicity.

No impairment of fertility was demonstrated in studies of male and female rats. In reproduction studies in rats and rabbits, adverse effects on the fetus were observed mainly at dose levels that were toxic to dams. However, in female rats dosed during organogenesis, embryo toxicity (expressed as reduced pup weights) was seen at a dose which was one-third of the maternally toxic dose. At this same dose, when administered prior to mating and during gestation, tacrolimus was associated with adverse effects on female reproductive parameters and embryolethality. This dose was equivalent to 0.5X the clinical dose (see Pregnancy).

Adverse Reactions: Kidney Transplantation: The most common adverse reactions reported were infection, tremor, hypertension, decreased renal function, constipation, diarrhea, headache, abdominal pain and insomnia. Many of these adverse reactions were mild and responded to a reduction in dosage.

Insulin-dependent post-transplant diabetes mellitus (PTDM) was related to increased whole blood trough concentrations of tacrolimus and higher doses of corticosteroids. The median time to onset of PTDM was 68 days.

The incidence of adverse events was determined in 2 randomized Phase 3 comparative kidney transplant studies involving 508 patients receiving tacrolimus and 352 patients receiving cyclosporine. Adverse events that occurred in >15% of tacrolimus-treated patients (combined study results) are presented in Table X for the two controlled trials in kidney transplantation.

Less frequently observed adverse reactions in both kidney transplantation patients and liver transplantation patients are described under the Liver Transplantation subsection.

Liver Transplantation: The principal adverse reactions of tacrolimus are tremor, headache, diarrhea, hypertension, nausea and renal dysfunction. These occur with oral and i.v. administration of tacrolimus 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 therapy. Hyperglycemia has been noted in many patients; some may require insulin therapy.

The incidence of adverse events reported in 2 randomized comparative liver transplant trials was determined in 514 patients receiving tacrolimus and steroids and 515 patients receiving a cyclosporine-based regimen (CBIR). The proportion of patients reporting more than 1 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 in Table XI. The 2 studies included different patient populations and patients were treated with immunosuppressive regimens of differing intensities. Adverse events reported in >15% in tacrolimus patients (combined study results) are presented in Table XI for the 2 controlled trials in liver transplantation.

The following adverse events, not mentioned in Table XI, were reported with greater than 3% incidence in tacrolimus-treated patients. Nervous System (see Precautions): abnormal dreams, agitation, amnesia, anxiety, confusion, convulsion, depression, dizziness, emotional lability, encephalopathy, hallucinations, hypertonia, incoordination, myoclonus, nervousness, neuropathy, paresthesia, psychosis, somnolence, thinking abnormal.

Special Senses: abnormal vision, amblyopia, otitis media, tinnitus.

Digestive System: anorexia, cholangitis, cholestatic jaundice, dyspepsia, dysphagia, esophagitis, flatulence, gastritis, gastrointestinal hemorrhage, GGT increase, gastrointestinal perforation, hepatitis, ileus, increased appetite, jaundice, liver function test abnormal, liver damage, oral moniliasis, stomatitis, rectal disorder.

Cardiovascular: angina pectoris, chest pain, abnormal ECG, hemorrhage, hypotension, postural hypotension, tachycardia, thrombosis, vasodilatation.

Urogenital System (see Precautions): albuminuria, dysuria, hematuria, hydronephrosis, kidney failure, kidney tubular necrosis, toxic nephropathy, oliguria, urinary tract infection, urinary frequency.

Metabolic/Nutritional: acidosis, alkaline phosphatase increased, alkalosis, AST increased, ALT increased, bilirubinemia, dehydration, edema, healing abnormal, hypercalcemia, hypercholesterolemia, hyperlipemia, hyperphosphatemia, hyperuricemia, hypocalcemia, hypervolemia, hypoglycemia, hypokalemia, hypophosphatemia, hyponatremia, hypoproteinemia, lactic dehydrogenase increase, weight gain.

Endocrine System (see Precautions): diabetes mellitus.

Hemic/Lymphatic: coagulation disorder, ecchymosis, hypochromic anemia, leukopenia, prothrombin decreased.

Body as a Whole: abdomen enlarged, abscess, back pain, chills, flu syndrome, generalized edema, hernia, peritonitis, photosensitivity reaction, sepsis.

Musculoskeletal: arthralgia, cramps, generalized spasm, leg cramps, myalgia, myasthenia, osteoporosis.

Respiratory: asthma, bronchitis, cough increased, lung disorder, pharyngitis, pneumothorax, pneumonia, pulmonary edema, respiratory disorder, rhinitis, sinusitis, voice alteration.

Skin and Appendages: acne, alopecia, fungal dermatitis, herpes simplex, hirsutism, pruritus, rash, skin disorder, sweating.

The following nervous system adverse events were also reported: acute brain syndrome (0.2%), coma (2.1%), delirium (1.2%), dysarthria (0.4%), dystonia (0.4%), encephalopathy (2.5%), flaccid paralysis (0.4%), hemiplegia (0.8%), nystagmus (0.8%), paralysis (0.4%) and stupor (0.2%).

There have been rare spontaneous reports of myocardial hypertrophy associated with clinically manifested ventricular dysfunction in patients receiving tacrolimus therapy (see Precautions, Myocardial Hypertrophy).

There has been a report of pure red cell aplasia in a renal transplant recipient who was receiving tacrolimus. This condition was reversed upon termination of the administration of tacrolimus.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Limited overdosage experience is available. Acute overdosages of up to 30 times the intended dose have been reported. All patients recovered with no sequelae. Acute overdosage has been followed by adverse reactions consistent with those listed in the Adverse Effects section, including mild elevations of renal function markers (creatinine), nausea, headache, hyperreflexia, oliguria, hypotension, tremor and elevations in liver enzymes. In one case transient urticaria and lethargy were observed and in another case acute anuric renal insufficiency developed. 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 i.v. toxicity studies, mortalities were seen at or above the following doses: in adult rats, 52 ´ the recommended human oral dose: in immature rats, 16 ´ the recommended oral dose and in adult rats, 16´ the recommended human i.v. dose (all based on body surface area corrections).

Dosage And Administration: Injection: For i.v. infusion only.

Note: Anaphylactic reactions have occurred with injectables containing castor oil derivatives (see Warnings).

In patients unable to take oral capsules, therapy may be initiated with the injection. The initial dose of tacrolimus should be administered no sooner than 6 hours after transplantation. The recommended starting dose of injection is 0.05 to 0.10 mg/kg/day as a continuous i.v. infusion. Adult patients should receive doses at the lower end of the dosing range. Concomitant adrenal corticosteroid therapy is recommended early post transplantation. Continuous i.v. infusion of tacrolimus injection should be continued until the patient can tolerate oral administration of tacrolimus capsules.

Preparation for Administration and Stability: The injection must be diluted with 0.9% Sodium Chloride Injection or 5% Dextrose Injection to a concentration between 0.004 mg/mL and 0.02 mg/mL prior to use. Diluted infusion solution should be stored in glass or polyethylene containers and should be discarded after 24 hours. The diluted infusion solution should not be stored in a PVC container due to poor stability and the potential for extraction of phthalates. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Capsules: Kidney Transplantation: The recommended starting oral dose is 0.2 to 0.3 mg/kg/day administered every 12 hours in 2 divided doses. The initial dose may be administered within 24 hours of transplantation. Black patients may require higher doses to achieve comparable blood levels. Dosage and typical tacrolimus whole blood trough concentrations are shown in Table XII; blood concentration details are described in Blood Level Monitoring: Kidney Transplantation below.

Liver Transplantation: It is recommended that patients be converted from i.v. to oral tacrolimus capsules as soon as oral therapy can be tolerated. This usually occurs within 2 to 3 days. The first dose of oral therapy should be given 8 to 12 hours after discontinuing the i.v. infusion. The recommended starting oral dose is 0.15 to 0.30 mg/kg/day administered in 2 divided daily doses every 12 hours. The initial dose should be administered no sooner than 6 hours after transplantation. Adult patients should receive doses at the lower end of the dosing range.

Some centres use lower tacrolimus doses during maintenance therapy post transplantation. Dosing should be titrated based on clinical assessment of rejection and tolerability. Adjunct therapy with adrenal corticosteroids is recommended early post transplant.

Children: 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 the high end of the recommended i.v. and oral dosing ranges (0.1 mg/kg/day i.v. and 0.3 mg/kg/day oral). Dose adjustments may be required. Although experience in pediatric transplantation patients is limited, the dosing guidelines listed above should be followed.

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 i.v. and oral dosing ranges. Further reductions in dose below these ranges may be required. Patients with postoperative oliguria may have the initiation of tacrolimus therapy delayed up to 48 hours or longer as circumstances warrant.

Conversion to Tacrolimus from Cyclosporine: Patients converted from cyclosporine to tacrolimus should receive the first tacrolimus dose no sooner than 24 hours after the last cyclosporine dose. Dosing may be further delayed in the presence of elevated cyclosporine levels. Patients converted from tacrolimus to cyclosporine should receive the first cyclosporine dose no sooner than 24 hours after the last tacrolimus dose. Dosing may be further delayed in the presence of elevated tacrolimus levels.

Blood Level Monitoring: Monitoring of tacrolimus blood levels in conjunction with other laboratory and clinical parameters is considered an essential aid to patient management. During the immediate postoperative period trough blood concentrations should be measured every 1 to 3 days. More intensive monitoring may be required in patients with hepatic or renal dysfunction. Following discharge from the hospital, the frequency of patient monitoring will decrease with time post-transplant.

Although there is a lack of direct correlation between tacrolimus levels and drug efficacy, data from Phase II and III studies of kidney and liver transplant patients has shown an increasing incidence of adverse events with increasing trough blood concentrations. Most stable patients are maintained with 12 hours trough whole blood levels of 5 to 20 ng/mL. Long-term post-transplant patients often are maintained at the low end of this target range.

Two methods are available for the assay of tacrolimus: microparticle enzyme immuno assay (MEIA) and enzyme linked immuno sorbent assay (ELISA). Both methods use the same monoclonal antibody for the tacrolimus parent compound. Whole blood is the matrix of choice and specimens should be collected into tubes containing ethylene diamine tetraacetic acid (EDTA) anticoagulant. Heparin anticoagulation is not recommended because of the tendency to form clots on storage. Samples which are not analyzed immediately should be stored in a refrigerator and assayed within 3 days; if samples are to be kept longer they should be deep frozen -20°C for up to 12 months.

Kidney Transplantation: Data from the U.S. and European studies indicate that trough concentrations of tacrolimus in whole blood, as measured by IMx, were most variable during the first week of dosing. During the first 3 months, 80% of the patients maintained trough concentrations between 7 to 20 ng/mL, and then between 5 to 15 ng/mL, through 1 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.

Liver Transplantation: 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 1 year post-transplantation, ranged from 9.8 to 19.4 ng/mL.

Availability And Storage: Capsules: 1 mg: Each oblong, white capsule, branded with red “1 mg” on cap and Fujisawa logo ” 617″ on capsule body contains: anhydrous tacrolimus 1 mg. Nonmedicinal ingredients: croscarmellose sodium, hydroxypropylmethylcellulose 2910, lactose and magnesium stearate; capsule shell: gelatin and titanium dioxide. Bottles of 100 and blister cards of 10´10.

5 mg: Each oblong, greyish/red capsule, branded with white “5 mg” on cap and Fujisawa logo ” 657″ on capsule body, contains: anhydrous tacrolimus 5 mg. Nonmedicinal ingredients: croscarmellose sodium, hydroxypropylmethylcellulose 2910, lactose and magnesium stearate; capsule shell: gelatin, ferric oxide and titanium dioxide. Bottles of 100 and blister cards of 10´10.

Store and dispense at controlled room temperature, 15 to 30°C.

Injection: Each mL of sterile solution contains: the equivalent of anhydrous tacrolimus 5 mg. Nonmedicinal ingredients: dehydrated alcohol, USP, 83% v/v and polyoxyl 60 hydrogenated castor oil (HCO-60). Ampuls of 1 mL, boxes of 10. Store in carton and protect from light and dispense ampuls between 15 and 25°C.

PROGRAF® Fujisawa Tacrolimus Immunosuppressant

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