Prograf

St. John's Wort (Hypericum perforatum) induces CYP3A4 and P-glycoprotein. Since tacrolimus is a substrate for CYP3A4, there is the potential that the use of St. John's Wort in patients receiving Prograf could result in reduced tacrolimus levels.

As with other immunosuppressive agents, owing to the potential risk of malignant skin changes, exposure to sunlight and ultraviolet (UV) light should be limited by wearing protective clothing and using sunscreen with a high protection factor.

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

Interactions with laboratory tests have not been established.

Immunosuppressants may affect vaccination. Therefore, during treatment with Prograf, 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.

Tacrolimus may affect the pharmacokinetics of other drugs (e.g., phenytoin) and increase their concentration.

Due to the potential for additive or synergistic impairment of renal function, care should be taken when administering Prograf with drugs that may be associated with renal dysfunction. These include, and are not limited to, aminoglycosides, amphotericin B, and cisplatin. NSAIDs may interact with Prograf causing deteriorations in blood pressure (BP) control and serum creatinine levels. Initial clinical experience with Prograf and cyclosporine resulted in additive/synergistic nephrotoxicity when both agents were co-administered. Patients switched from cyclosporine to Prograf should receive the first Prograf 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 or increase bioavailability 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 or decreased bioavailability as indicated by decreased whole blood or plasma levels. Monitoring of blood levels and appropriate dosage adjustments in transplant patients are essential when such drugs are used concomitantly.

Patients receiving Prograf 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 1:1000 should be available at the bedside as well as a source of oxygen.

It is recommended that patients be converted from intravenous to oral Prograf capsules as soon as oral therapy can be tolerated. This usually occurs within 2-3 days. The first dose of oral therapy should be given 8-12 hours after discontinuing the IV infusion. The recommended starting oral dose of Prograf capsules is 0.1-0.15 mg/kg/day administered in two divided daily doses every 12 hours. The initial dose of Prograf 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 Prograf 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.

The recommended starting oral dose of Prograf is 0.075 mg/kg/day administered every 12 hours in two divided doses. It is recommended that patients initiate oral therapy with Prograf capsules if possible. If IV therapy is necessary, conversion from IV to oral Prograf is recommended as soon as oral therapy can be tolerated. This usually occurs within 2-3 days. The initial dose of Prograf should be administered no sooner than 6 hours after transplantation. In a patient receiving an IV infusion, the first dose of oral therapy should be given 8-12 hours after discontinuing the IV infusion.

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

Prograf 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. In situations where more dilute solutions are utilized (e.g., pediatric dosing, etc.), PVC-free tubing should likewise be used to minimize the potential for significant drug adsorption onto the tubing. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Due to the chemical instability of tacrolimus in alkaline media, Prograf injection should not be mixed or coinfused with solutions of pH 9 or greater (e.g., ganciclovir or acyclovir). Prograf Injection is administered as a continuous intravenous infusion.

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

Due to the potential for nephrotoxicity, patients with renal or hepatic impairment should receive doses at the lowest value of the recommended intravenous and oral dosing ranges. Further reductions in dose below these ranges may be required.

Although a formal study to evaluate the pharmacokinetics of tacrolimus in Black transplant patients has not been conducted, a retrospective comparison of Black and Caucasian kidney transplant patients indicated that Black patients required higher tacrolimus doses to attain similar trough concentrations.

Prograf Injection 5 mg/mL (tacrolimus injection) for transplantation only. For Intravenous Infusion only. Anaphylactic reactions have occurred with injectables containing castor oil derivatives (see Warnings and Precautions).

In patients unable to take oral Prograf capsules, therapy may be initiated with Prograf injection. The initial dose of Prograf should be administered no sooner than 6 hours after transplantation. The recommended starting dose of Prograf injection is 0.01 mg/kg/day (heart) or 0.03-0.05 mg/kg/day (liver, kidney) as a continuous intravenous infusion (see Table 11). Adult patients should receive doses at the lower end of the dosing range. Concomitant adrenal corticosteroid therapy is recommended early post transplantation. Continuous intravenous infusion of Prograf injection should be continued until the patient can tolerate oral administration of Prograf capsules.

Prograf capsules should be administered whole and should not be cut, crushed or chewed. Prograf can be administered with or without food however doses should be administeredin a consistent manner, with doses spaced evenly throughout the day.

Due to intersubject variability following dosing with tacrolimus, individualization of the dosing regimen is necessary for optimal therapy.

Additional factors that may impact dosing include, pre-existing conditions, such as renal or hepatic impairment, race, pediatric use and the concomitant use of other medications.

Prograf has been used in combination with azathioprine. Prograf has been used in combination with mycophenolate mofetil (MMF) in patients receiving deceased donor kidney transplants and heart transplants. Because of the risk of anaphylaxis, Prograf injection should be reserved for patients unable to take Prograf capsules orally.

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 IV dose of 0.03-0.05 mg/kg/day and a starting oral dose of 0.15-0.20 mg/kg/day. Dose adjustments may be required. Experience in pediatric kidney and heart transplantation patients is limited.

The recommended adult oral dose of Prograf is 3 mg, administered once a day. Regular monitoring of Prograf treated patients for occurrence of adverse events is mandatory.

If a dose is missed, contact your physician or pharmacist immediately.

The following adverse events were reported in either liver, kidney, and/or heart transplant recipients who were treated with tacrolimus in clinical trials.

bile duct stenosis, colitis, enterocolitis, gastroenteritis, gastrooesophageal reflux disease, hepatic cytolysis, hepatic necrosis, hepatotoxicity, impaired gastric emptying, liver fatty, mouth ulceration, pancreatitis haemorrhagic, pancreatitis necrotizing, stomach ulcer, venoocclusive liver disease.

The following adverse events have been reported from worldwide marketing experience with Prograf. Because these events are reported voluntarily from a population of uncertain size, are associated with concomitant diseases and multiple drug therapies and surgical procedures, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these events in labeling are typically based on one or more of the following factors: (1) seriousness of the event, (2) frequency of the reporting, or (3) strength of causal connection to the drug:

Refer to Warnings and Precautions (Hepatic/Biliary/Pancreatic and Renal) and Monitoring and Laboratory Tests.

disseminated intravascular coagulation, neutropenia, pancytopenia, thrombocytopenic purpura, thrombotic thrombocytopenic purpura.

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

The principal adverse reactions of Prograf (tacrolimus) are tremor, headache, diarrhea, hypertension, nausea, and renal dysfunction. These occur with oral and intravenous administration of Prograf 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 Prograf therapy. Hyperglycemia has been noted in many patients; some may require insulin therapy.

blindness, blindness cortical, hearing loss including deafness, photophobia.

feeling hot and cold, feeling jittery, hot flushes, multi-organ failure, primary graft dysfunction.

acne, alopecia, exfoliative dermatitis, fungal dermatitis, herpes simplex, herpes zoster, hirsutism, pruritus, rash, neoplasm skin benign, skin discolouration, skin disorder, skin ulcer, sweating.

The following nervous system adverse events were also reported at a frequency (<3%): 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%).

abdomen enlarged, abscess, accidental injury, allergic reaction, back pain, cellulitis, chills, fall, feeling abnormal, flu syndrome, generalized edema, hernia, mobility decreased, peritonitis, photosensitivity reaction, sepsis, temperature intolerance, ulcer.

The more common adverse reactions in Prograf-treated heart transplant recipients were kidney function abnormal, hypertension, diabetes mellitus, CMV infection, tremor, hyperglycemia, leukopenia, infection, and hyperlipemia.

acute respiratory distress syndrome, lung infiltration, respiratory distress, respiratory failure.

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 deceased donor kidney transplants. Within six weeks post-transplant there were no deaths or graft losses. Six patients (19.4%) experienced acute rejection, with one 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%) (Transpl Int 1995;8:86-90). 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 (Clin Transplantation 1994;8:508-515). The one 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 deceased donor 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 deceased donor kidney transplants randomized to three 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 six weeks post-transplant there were no patient deaths, and one 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%-62%).

Data on the safety and efficacy of tacrolimus in combination with immunosuppressants other than steroids in liver transplant patients is 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, one died and one lost their graft in the first year post-transplant.

(See Warnings and Precautions) diabetes mellitus, cushing's syndrome.

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.

arthralgia, cramps, generalized spasm, joint disorder, leg cramps, myalgia, myasthenia, osteoporosis.

carpal tunnel syndrome, cerebral infarction, hemiparesis, leukoencephalopathy, mental disorder, mutism, quadriplegia, speech disorder, syncope.

acute renal failure, cystitis haemorrhagic, hemolytic-uremic syndrome, micturition disorder.

There have been rare spontaneous reports of myocardial hypertrophy associated with clinically manifested ventricular dysfunction in patients receiving Prograf therapy (see Warnings and Precautions).

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.

asthma, bronchitis, cough increased, emphysema, hiccups, lung disorder, lung function decreased, pharyngitis, pneumothorax, pneumonia, pulmonary edema, respiratory disorder, rhinitis, sinusitis, voice alteration.

Stevens-Johnson syndrome, toxic epidermal necrolysis.

glycosuria, increased amylase including pancreatitis, weight decreased.

The adverse events associated with Prograf treatment in rheumatoid arthritis patients, occurred at a lower rate of incidence than seen in transplant patients receiving Prograf. The majority of adverse events were mild or moderate in intensity, of limited duration and did not result in discontinuation of the study drug.

Less frequently observed adverse reactions in both kidney and liver transplantation patients are described under Less Common Clinical Trial Adverse Drug Reactions.

The incidence of hyperlipidemia or hypercholesteremia as an adverse event at any time during the 18 month study was significantly lower in the tacrolimus group (45/157, 28.7%) than in the cyclosporine group (63/157, 40.1%) (p=0.043, Fisher's exact test).

In the US study, mean serum creatinine levels at 1 year posttransplant were significantly lower in the tacrolimus/MMF group compared with those in either the cyclosporine/MMF group (p=0.002, one-way ANOVA) or the tacrolimus/sirolimus group (p=0.020, one-way ANOVA).

atrial fibrillation, atrial flutter, cardiac arrhythmia, cardiac arrest, electrocardiogram t wave abnormal, flushing, myocardial infarction, myocardial ischaemia, pericardial effusion, QT prolongation with or without Torsade de Pointes, venous thrombosis deep limb, ventricular extrasystoles, ventricular fibrillation.

Experience with Prograf in pediatric kidney and heart transplant patients is limited. Successful liver transplants have been performed in pediatric patients (ages 4 months up to 16 years) using Prograf, with the majority of these patients under 5 years of age (see Warnings and Precautions).

Prograf is not indicated for the use of rheumatoid arthritis in children younger than 18 years of age.

The safety and efficacy of Prograf in patients older than 65 years of age has not been established.

Prograf (tacrolimus) is indicated for:

• prophylaxis of organ rejection in patients receiving allogeneic liver, kidney or heart transplants.

  
  

• treatment of refractory rejection in patients receiving allogeneic liver or kidney transplants.

  
  

Prograf is to be used concomitantly with adrenal corticosteroids and other immunosuppressive agents.

Only physicians experienced in immunosuppressive therapy and management of organ transplant should prescribe Prograf (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.

Prograf (tacrolimus), capsule monotherapy is indicated for:

• treatment of active rheumatoid arthritis in adult patients for whom anti-rheumatic drug (DMARD) therapy is ineffective or inappropriate.

  
  

Prograf may be used in combination with non-steroidal anti-inflammatory drugs (NSAIDs) and/or steroids, although the possibility of increased toxicity has not been fully explored (see Warnings and Precautions and Drug Interactions).

Combined use of Prograf with gold, penicillamine, hydroxychloroquine, sulfasalazine or azathioprine has not been studied. There is currently insufficient data to support the concomitant use of Prograf and methotrexate.

Careful monitoring of Prograf treated patients is mandatory. Prograf should only be prescribed for rheumatoid arthritis by physicians experienced with the use of immunosuppressants.

Each oblong, white capsule, branded with red “1 mg” on cap and “ 617” on capsule body contains: anhydrous tacrolimus 1 mg. Nonmedicinal ingredients: croscarmellose sodium, hydroxypropylmethylcellulose, lactose and magnesium stearate; capsule shell: gelatin and titanium dioxide. Bottles of 100 or 10 blister packs of 10.

Each oblong, light yellow capsule, branded with red “0.5 mg” on cap and “ 607” on capsule body contains: anhydrous tacrolimus 0.5 mg. Nonmedicinal ingredients: croscarmellose sodium, hydroxypropylmethylcellulose, lactose and magnesium stearate; capsule shell: ferric oxide, gelatin and titanium dioxide. Bottles of 100 or 10 blister packs of 10.

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

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.

Prograf may cause 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 Prograf in the U.S. and European randomized trials, respectively, and in 59% of heart transplantation patients in a European randomized trial (see Adverse Reactions). 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 Prograf 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 Prograf-based regimen, cyclosporine should be discontinued at least 24 hours prior to initiating Prograf. Prograf dosing may be further delayed in the presence of elevated cyclosporine levels (see Drug Interactions). When switching from tacrolimus to cyclosporine, tacrolimus should be discontinued for at least 24 hours.

For patients with renal insufficiency some evidence suggests that the use of lower doses may be warranted. (See Action and Clinical Pharmacology and Dosage and Administration.)

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 Prograf in the U.S. and European randomized trials, respectively, and in 8% of heart transplant recipients in a European randomized trial and may require treatment (see Adverse Reactions). Serum potassium levels should be monitored and potassium sparing diuretics should not be used during Prograf therapy. (See Warnings and Precautions, Monitoring and Laboratory Tests.)

Hyperkalemia has also been noted in patients with rheumatoid arthritis. Tacrolimus should be discontinued in patients in whom hypertension and hyperkalemia cannot be controlled. The adverse events associated with Prograf treatment in rheumatoid arthritis patients occurred at a lower rate of incidence than seen in transplant patients receiving Prograf. The majority of adverse events were mild or moderate in intensity, of limited duration and did not result in discontinuation of the study drug.

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 Prograf 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.

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.

Data from a European Phase III study indicates that trough concentrations of tacrolimus in whole blood, as measured by IMx were most variable during the first week of dosing. From 1 week to 3 months, 80% of patients maintained trough concentrations between 8-20 ng/mL and, from 3 months through 18 months, 80% of patients maintained trough concentrations between 6-18 ng/mL.

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.

Prograf used in the treatment of rheumatoid arthritis patients has resulted in a lower incidence rate of adverse events than previously seen in transplant patients. Trough blood levels of tacrolimus in this patient population have been demonstrated to be very close to the lower limit of quantitation in assays used to evaluate tacrolimus levels. The lower incidence rates of adverse events as well as the lower levels of tacrolimus detected in rheumatoid arthritis patients may be due to the lower daily dose of Prograf administered to this patient population. Consequently, monitoring tacrolimus trough levels in rheumatoid arthritis patients has not proven to be the most effective approach of managing this patient population. Management of these patients has proven to be effective based on the incidence of adverse events and monitoring serum creatinine levels. Current data further supports the fact that nephrotoxicity associated with Prograf is predictable and can be managed through the careful monitoring of serum creatinine, adjustments of concomitant medications and if necessary, withdrawal of treatment. Since Prograf can impair renal function, a reliable baseline level of serum creatinine should be established by at least two measurements prior to treatment. Serum creatinine should be monitored every 2 weeks during the first month of therapy and every four weeks for the next three months, then quarterly thereafter.

If serum creatinine is increased by more than 40% above baseline, the serum creatinine should be repeated in one week. If the repeated serum creatinine remains increased by more than 40% from baseline, dosing of Prograf should be interrupted for 14 days and the serum creatinine measurement should again be repeated. If the serum creatinine returns to a value less than a 40% increase from baseline, dosing with Prograf may be resumed. If the serum creatinine remains elevated by more than 40% from baseline, Prograf should be discontinued. These recommendations apply even if the patient's values still lie within the laboratory normal range.

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 0.33× and 1.0× (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 1.0 and 3.2 mg/kg (equivalent to 0.5× and 1.5×), 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 1.0 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 post-implantation 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. Prograf 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, eleven female transplant patients maintained on tacrolimus therapy throughout pregnancy delivered twelve babies, with one patient conceiving twice. These patients received tacrolimus from week one to 20 months prior to conception. Ten of the pregnancies were successful, four with C-sections. The neonates showed no growth retardation or congenital anomalies. Hyperkalemia was observed in the majority of babies, but resolved within 24-48 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 one newborn who had temporary anuria associated with high cord blood tacrolimus concentration, however, renal function was normal within one 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.

Patients receiving Prograf 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 1:1000 should be available at the bedside as well as a source of oxygen.

Monitoring of tacrolimus blood levels in conjunction with other laboratory and clinical parameters is considered an essential aid to transplant patient management. During the immediate post-operative period trough blood concentrations should be measured every 1-3 days. In patients with hepatic or renal dysfunction or in those receiving or discontinuing concomitant interacting medications, more intensive monitoring may be required, since tacrolimus clearance may be affected under each of these circumstances. More frequent monitoring may also be required in patients early after transplantation since it is at this time patients experience the highest risk of rejection. Blood concentration monitoring is not a replacement for renal and liver function monitoring and tissue biopsies. 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 hour 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: 1) microparticle enzyme immuno assay (MEIA) and 2) enzyme linked immuno sorbent assay (ELISA). Both methods use the same monoclonal anti-body 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) 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 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.

Data from the U.S. and European Phase III 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 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.

No formal studies have been performed to evaluate the effect of Prograf specifically in the geriatric patient population.

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

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

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

In de novo heart transplant recipients, new onset glucose intolerance (no history/no diabetes at baseline; fasting plasma glucose ≥126 mg/dL; oral hypoglycemic agent use; and/or insulin use ≥30 days) was observed in 63% (83/132) of transplant recipients in the tacrolimus group and 54% (74/138) in the cyclosporine group in the European trial (p=0.139, Fisher's exact test). In the US trial in de novo heart transplant recipients, new onset glucose intolerance was observed in 68% (58/85) of transplant recipients in the tacrolimus/sirolimus group, 61% (46/75) in the tacrolimus/MMF group and 58% (48/83) in the cyclosporine/MMF group.

Hyperglycemia, elevations in HgbA1c, and overt diabetes have also been noted in rheumatoid arthritis patients treated with tacrolimus. Tacrolimus should be discontinued in patients in whom blood sugars cannot be controlled.

Prograf may cause neurotoxicity and the likelihood increases with higher blood levels.

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 Prograf-treated kidney transplant patients in the U.S. and European studies (54 and 35%, respectively), and heart transplant patients (15%) compared with cyclosporine-treated patients. The incidence of other neurological events in the two treatment groups in both kidney studies and heart transplant patients was similar. 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 Prograf. Coma and delirium also have been associated with high plasma concentrations of tacrolimus.

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

Heart failure, cardiomegaly and increased thickness of the myocardium have been reported in patients taking Prograf. 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 Prograf should be considered in cases where the perceived risk to the patient outweighs the benefit.

The two randomized active-controlled trials of Prograf in primary liver transplantation included 56 pediatric patients. Thirty-one patients were randomized to Prograf 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 Prograf to maintain blood trough concentrations of tacrolimus similar to adult patients (see Dosage and Administration). 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.

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 0.5× the clinical dose. (See Warnings and Precautions.)

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

Hypertension is a common side effect of Prograf (tacrolimus) therapy (see Adverse Reactions). 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 Prograf-associated hypertension, care should be taken since interference with tacrolimus metabolism may require a dosage reduction in the transplant patient (see Drug Interactions). Hypertension and hyperkalemia has also been noted in patients with rheumatoid arthritis. Tacrolimus should be discontinued in patients in whom hypertension and hyperkalemia cannot be controlled.

Heart failure, myocardial hypertrophy and arrhythmia have been reported in association with the administration of Prograf. Myocardial hypertrophy 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 transplant 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, 4-46 ng/mL in children (n=7) age 2-15 years and 11-24 ng/mL in adults (N=3) age 37-53 years.

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

Store in the carton and protect from light. Dispense Prograf ampoules between 15 and 25°C.

Prograf Injection must be diluted to a concentration between 0.004 mg/mL and 0.02 mg/mL with 0.9% Sodium Chloride Injection or 5% Dextrose Injection before use. The diluted infusion solution should be stored at 15-25°C 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.

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, 23.6 hours in heart transplant patients receiving a single intravenous dose of Prograf and 34.2 hours in healthy volunteers following intravenous administration. In rheumatoid arthritis patients the administration of a single intravenous and oral dose of Prograf, produced a mean terminal elimination half-life of 34.9 and 35.2 hrs respectively.

In transplant patients the intersubject variability in tacrolimus pharmacokinetics, has resulted in the need for the dosing regimen to be individualized. Dosing individualization can be achieved by therapeutic drug monitoring of tacrolimus blood concentrations and evaluation of clinical status (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.

Tacrolimus, the active ingredient in Prograf, is a macrolide immunosuppressant produced by S. tsukubaensis.

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 nM-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).

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.

The clearance of tacrolimus is 0.040, 0.083, 0.042 and 0.049 L/h/kg in healthy volunteers, adult kidney transplant patients, adult liver transplant patients, and adult rheumatoid arthritis patients, respectively. In man, less than 1% of the dose administered is excreted unchanged in urine.

A formal study to evaluate the effect of gender on tacrolimus pharmacokinetics has not been conducted however, there was no differences noted in dosing by gender in the kidney transplant trial. A retrospective comparison of pharmacokinetics in healthy volunteers, and in kidney and liver transplant patients indicated no gender-based differences.

Tacrolimus is extensively metabolized by the mixed-function oxidase system, primarily the cytochrome P-450 enzyme 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; the 13-demethyl, 15-demethyl and 15- and 31- double-demethylated metabolites were shown to retain an activity of less than 10%.

A study in liver transplantation has been conducted in sixteen pediatric patients (age range: 0.7-13.2 years). A mean terminal elimination half-life of 11.5 hours was determined following an intravenous dose of 0.037 mg/kg/day in twelve patients; the volume of distribution was 2.6 L/kg, whereas clearance was 0.135 L/h/kg. In nine patients receiving capsule formulation, a mean C_max of 48.4 ng/mL was attained at a mean T_max of 2.7 hours following an oral dose of 0.152 mg/kg as Prograf capsules. The AUC_{(0-72 h)} 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 and Administration).

The pharmacokinetics of tacrolimus has not been established in the geriatric population.

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.)

The 1 mg and 5 mg dose strengths of tacrolimus capsules are bioequivalent as indicated in Table 12.

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 approximately 25% in rheumatoid arthritis patients. In healthy volunteers the absolute bioavailability of tacrolimus was found to be approximately 18% (Table 15).

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 to proteins, mainly 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 ranged from 12 to 67 (mean 35).

In 18 kidney transplant patients, tacrolimus trough concentrations from 3 to 30 ng/mL measured at 10-12 hours post dose (C_min) 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. In 25 heart transplant patients, the correlation coefficient was 0.89 after an oral dose of 0.075 or 0.15 mg/kg/day at steady-state.