Hecoria

Mechanism of Action

Calcineurin inhibitor; inhibits T-cell activation and proliferation, humoral immunity

Macrolide antibiotic; potent immunosuppressant

Absorption

Bioavailability: 7-55% (children); 7-32% (adults)

Peak plasma time: 0.5-6 hr

Distribution

Protein bound: 99%

Vd: 0.5-4.7 L/kg (children); 0.55-2.47 L/kg (adults)

Metabolism

Metabolized in liver by CYP3A4

Metabolites: 13-O-demethyl tacrolimus (major)

P-gp substrate

Elimination

Half-life: 23-46 hr (immediate release); 34.5-41 hr (extended release)

Excretion: Feces (94%); urine (<1%)

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.

Especially tell your doctor if you take:

• cyclosporine (Gengraf, Neoral, and Sandimune)
• sirolimus (Rapamune)
• nelfinavir (Viracept)
• telaprevir (Incivek)
• boceprevir (Victrelis)
• amiodarone (Cordarone, Nexterone, Pacerone)

Ask your doctor or pharmacist if you are not sure if you take any of the medicines listed above.

Tacrolimus may affect the way other medicines work, and other medicines may affect how tacrolimus works.

Know the medicines you take. Keep a list of your medicines and show it to your doctor and pharmacist when you get a new medicine.

Tacrolimus can cause serious side effects, including:

1. Increased risk of cancer. People who take tacrolimus have an increased risk of getting some kinds of cancer, including skin and lymph gland cancer (lymphoma).

2. Increased risk of infection. Tacrolimus is a medicine that affects your immune system. Tacrolimus can lower the ability of your immune system to fight infections. Serious infections can happen in people receiving tacrolimus that can cause death. Call your doctor right away if you have symptoms of an infection such as:

• fever
• sweats or chills
• cough or flu-like symptoms
• muscle aches
• warm, red, or painful areas on your skin

Do not take tacrolimus if you are allergic to tacrolimus or any of the ingredients in tacrolimus.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Abdominal or stomach pain
• abnormal dreams
• agitation
• chills
• confusion
• convulsions (seizures)
• diarrhea
• dizziness
• fever and sore throat
• flu-like symptoms
• frequent urination
• headache
• itching
• loss of appetite
• loss of energy or weakness
• mental depression
• muscle trembling or twitching
• nausea
• pale skin
• seeing or hearing things that are not there
• shortness of breath
• skin rash
• swelling of the feet or lower legs
• tingling
• trembling and shaking of the hands
• trouble sleeping
• unusual bleeding or bruising
• unusual tiredness or weakness
• vomiting

• Blurred vision
• chest pain
• increased sensitivity to pain
• muscle cramps
• numbness or pain in the legs
• ringing in the ears
• sweating

• Enlarged heart
• flushing of the face or neck
• general feeling of discomfort or illness
• weight loss

• Black, tarry stools
• blistering, peeling, loosening of the skin
• bloating
• bloody urine
• constipation
• cough
• drowsiness
• fainting
• fast, slow, or irregular heartbeat
• heartburn
• increased thirst
• indigestion
• joint or muscle pain
• lightheadedness
• lower back or side pain
• pinpoint red spots on the skin
• pounding or rapid pulse
• red skin lesions, often with a purple center
• red, irritated eyes
• skin sores
• ulcers or white spots in the mouth or on the lips
• weakness
• weight gain
• yellow eyes or skin

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Acid or sour stomach
• belching
• difficulty with moving
• lack or loss of strength
• muscle pain or stiffness

• Body aches or pain
• burning or stinging of the skin
• cracks in the skin
• crying
• delusions
• dementia
• depersonalization
• dysphoria
• euphoria
• excessive muscle tone
• feeling of constant movement of self or surroundings
• feeling that others are watching you or controlling your behavior
• feeling that others can hear your thoughts
• increased sensitivity of the skin to sunlight
• large, flat, blue or purplish patches in the skin
• loss of strength or energy
• muscle tension or tightness
• painful blisters on the trunk of the body
• painful cold sores or blisters on the lips, nose, eyes, or genitals
• paranoia
• quick to react or overreact emotionally
• rapidly changing moods
• redness or other discoloration of the skin
• restlessness
• scaly skin
• sensation of spinning
• severe mood or mental changes
• severe sunburn
• sleepiness or unusual drowsiness
• sore mouth or tongue
• sores on the skin
• swelling or inflammation of the mouth
• tender, swollen glands in the neck
• unusual behavior
• white patches in the mouth, tongue, or throat

• Change in color vision
• decreased weight
• difficulty seeing at night
• feeling hot and cold
• hearing loss
• sudden sweating

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

• Store at room temperature.
• Store in a dry place. Do not store in a bathroom.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

Prophylaxis of Organ Rejection in Kidney Transplant

Hecoria (tacrolimus capsules, USP) is indicated for the prophylaxis of organ rejection in patients receiving allogeneic kidney transplants. It is recommended that Hecoria be used concomitantly with azathioprine or mycophenolate mofetil (MMF) and adrenal corticosteroids [see CLINICAL STUDIES (14.1)]. Therapeutic drug monitoring is recommended for all patients receiving Hecoria [see DOSAGE AND ADMINISTRATION (2.6)].

Prophylaxis of Organ Rejection in Liver Transplant

Hecoria (tacrolimus capsules, USP) is indicated for the prophylaxis of organ rejection in patients receiving allogeneic liver transplants. It is recommended that Hecoria be used concomitantly with adrenal corticosteroids [see CLINICAL STUDIES (14.2)]. Therapeutic drug monitoring is recommended for all patients receiving Hecoria [see DOSAGE AND ADMINISTRATION (2.6)].

Prophylaxis of Organ Rejection in Heart Transplant

Hecoria (tacrolimus capsules, USP) is indicated for the prophylaxis of organ rejection in patients receiving allogeneic heart transplants. It is recommended that Hecoria be used concomitantly with azathioprine or mycophenolate mofetil (MMF) and adrenal corticosteroids [see CLINICAL STUDIES (14.3)]. Therapeutic drug monitoring is recommended for all patients receiving Hecoria [see DOSAGE AND ADMINISTRATION (2.6)].

Limitations of Use

Hecoria (tacrolimus capsules, USP) should not be used simultaneously with cyclosporine [see DOSAGE AND ADMINISTRATION (2.5)].

Tacrolimus injection should be reserved for patients unable to take Hecoria capsules orally [see DOSAGE AND ADMINISTRATION (2.1) and WARNINGS AND PRECAUTIONS (5.11)].

Use with sirolimus is not recommended in liver and heart transplant. The safety and efficacy of Hecoria with sirolimus has not been established in kidney transplant [see WARNINGS AND PRECAUTIONS (5.12)].

Dosage in Adult Kidney, Liver, or Heart Transplant Patients

The initial oral dosage recommendations for adult patients with kidney, liver, or heart transplants along with recommendations for whole blood trough concentrations are shown in Table 1. The initial dose of Hecoria (tacrolimus capsules, USP) should be administered no sooner than 6 hours after transplantation in the liver and heart transplant patients. In kidney transplant patients, the initial dose of Hecoria may be administered within 24 hours of transplantation, but should be delayed until renal function has recovered. For blood concentration monitoring details see DOSAGE AND ADMINISTRATION (2.6).

Table 1. Summary of Initial Oral Dosage Recommendations and Observed Whole Blood Trough Concentrations in Adults

 aIn a second smaller trial, the initial dose of tacrolimus was 0.15 to 0.2 mg/kg/day and observed tacrolimus concentrations were 6 to 16 ng/mL during months 1 to 3 and 5 to 12 ng/mL during months 4 to 12 [see CLINICAL STUDIES (14.1)].

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

The data in kidney transplant patients indicate that the Black patients required a higher dose to attain comparable trough concentrations compared to Caucasian patients (Table 2).

Initial Dose – Injection 

Tacrolimus injection should be used only as a continuous IV infusion and when the patient cannot tolerate oral administration of Hecoria (tacrolimus capsules, USP). Tacrolimus injection should be discontinued as soon as the patient can tolerate oral administration of Hecoria capsules, usually within 2 to 3 days. In a patient receiving an IV infusion, the first dose of oral therapy should be given 8 to 12 hours after discontinuing the IV infusion.

The observed trough concentrations described above pertain to oral administration of Hecoria only; while monitoring Hecoria concentrations in patients receiving tacrolimus injection as a continuous IV infusion may have some utility, the observed concentrations will not represent comparable exposures to those estimated by the trough concentrations observed in patients on oral therapy.

The recommended starting dose of tacrolimus injection is 0.03 to 0.05 mg/kg/day in kidney and liver transplant and 0.01 mg/kg/day in heart transplant given as a continuous IV infusion. Adult patients should receive doses at the lower end of the dosing range. Concomitant adrenal corticosteroid therapy is recommended early post-transplantation.

Anaphylactic reactions have occurred with injectables containing castor oil derivatives, such as tacrolimus injection [see WARNINGS AND PRECAUTIONS (5.11)].

Dosage in Pediatric Liver Transplant Patients

The initial oral dosage recommendations for pediatric patients with liver transplants along with recommendations for whole blood trough concentrations are shown in Table 3. For blood concentration monitoring details see DOSAGE AND ADMINISTRATION (2.6). If necessary, pediatric patients may start on an IV dose of 0.03 to 0.05 mg/kg/day.

 Pediatric liver transplantation patients without pre-existing renal or hepatic dysfunction have required and tolerated higher doses than adults to achieve similar blood concentrations.

Experience in pediatric kidney and heart transplantation patients is limited.

Dosage Adjustment in Patients with Renal Impairment

Due to its potential for nephrotoxicity, consideration should be given to dosing Hecoria (tacrolimus capsules, USP) at the lower end of the therapeutic dosing range in patients who have received a liver or heart transplant and have pre-existing renal impairment. Further reductions in dose below the targeted range may be required.

In kidney transplant patients with post-operative oliguria, the initial dose of Hecoria should be administered no sooner than 6 hours and within 24 hours of transplantation, but may be delayed until renal function shows evidence of recovery.

Dosage Adjustments in Patients with Hepatic Impairment

Due to the reduced clearance and prolonged half-life, patients with severe hepatic impairment (Child Pugh ≥ 10) may require lower doses of Hecoria (tacrolimus capsules, USP). Close monitoring of blood concentrations is warranted.

The use of Hecoria in liver transplant recipients experiencing post-transplant hepatic impairment may be associated with increased risk of developing renal insufficiency related to high whole-blood concentrations of tacrolimus. These patients should be monitored closely and dosage adjustments should be considered. Some evidence suggests that lower doses should be used in these patients [see DOSAGE AND ADMINISTRATION (2.1), USE IN SPECIFIC POPULATIONS (8.7) and CLINICAL PHARMACOLOGY (12.3)].

Administration Instructions

It is recommended that patients initiate oral therapy with Hecoria (tacrolimus capsules, USP) if possible.

Initial dosage and observed tacrolimus whole blood trough concentrations for adults are shown in Table 1 and for pediatrics in Table 3 [see DOSAGE AND ADMINISTRATION (2.1, 2.2)]; for blood concentration monitoring details in kidney transplant patients [see DOSAGE AND ADMINISTRATION (2.1)].

It is important to take Hecoria capsules consistently every day either with or without food because the presence and composition of food decreases the bioavailability of Hecoria [see CLINICAL PHARMACOLOGY (12.3)].

Patients should not eat grapefruit or drink grapefruit juice in combination with Hecoria [see DRUG INTERACTIONS (7.2)].
 

Hecoria should not be used simultaneously with cyclosporine. Hecoria or cyclosporine should be discontinued at least 24 hours before initiating the other. In the presence of elevated Hecoria or cyclosporine concentrations, dosing with the other drug usually should be further delayed.

In patients unable to take oral Hecoria (tacrolimus capsules, USP), therapy may be initiated with tacrolimus injection as a continuous IV infusion. If IV therapy is necessary, conversion from IV to oral tacrolimus is recommended as soon as oral therapy can be tolerated. This usually occurs within 2 to 3 days. In patients receiving an IV infusion, the first dose of oral therapy should be given 8 to 12 hours after discontinuing the IV infusion.

Therapeutic Drug Monitoring

Monitoring of tacrolimus blood concentrations in conjunction with other laboratory and clinical parameters is considered an essential aid to patient management for the evaluation of rejection, toxicity, dose adjustments and compliance. Observed whole blood trough concentrations can be found in Table 1. Factors influencing frequency of monitoring include but are not limited to hepatic or renal dysfunction, the addition or discontinuation of potentially interacting drugs and the post-transplant time. Blood concentration monitoring is not a replacement for renal and liver function monitoring and tissue biopsies. Data from clinical trials show that tacrolimus whole blood concentrations were most variable during the first week post-transplantation.

The relative risks of toxicity and efficacy failure are related to tacrolimus whole blood trough concentrations. Therefore, monitoring of whole blood trough concentrations is recommended to assist in the clinical evaluation of toxicity and efficacy failure.

Methods commonly used for the assay of tacrolimus include high performance liquid chromatography with tandem mass spectrometric detection (HPLC/MS/MS) and immunoassays. Immunoassays may react with metabolites as well as parent compound. Therefore assay results obtained with immunoassays may have a positive bias relative to results of HPLC/MS. The bias may depend upon the specific assay and laboratory. Comparison of the concentrations in published literature to patient concentrations using the current assays must be made with detailed knowledge of the assay methods and biological matrices employed. Whole blood is the matrix of choice and specimens should be collected into tubes containing ethylene diamine tetraacetic acid (EDTA) anti-coagulant. Heparin anti-coagulation is not recommended because of the tendency to form clots on storage. Samples which are not analyzed immediately should be stored at room temperature or in a refrigerator and assayed within 7 days; see assay instructions for specifics. If samples are to be kept longer they should be deep frozen at -20°C. One study showed drug recovery >90% for samples stored at -20°C for 6 months, with reduced recovery observed after 6 months.

Since tacrolimus is metabolized mainly by CYP3A enzymes, drugs or substances known to inhibit these enzymes may increase tacrolimus whole blood concentrations. Drugs known to induce CYP3A enzymes may decrease tacrolimus whole blood concentrations [see WARNINGS AND PRECAUTIONS (5.13) and CLINICAL PHARMACOLOGY (12.3)]. Dose adjustments may be needed along with frequent monitoring of tacrolimus whole blood trough concentrations when Hecoria is administered with CYP3A inhibitors or inducers. In addition, patients should be monitored for adverse reactions including changes in renal function and QT prolongation [see WARNINGS AND PRECAUTIONS (5.7) and (5.14)].

Mycophenolic Acid Products

With a given dose of mycophenolic acid (MPA) products, exposure to MPA is higher with tacrolimus co-administration than with cyclosporine co-administration because cyclosporine interrupts the enterohepatic recirculation of MPA while tacrolimus does not. Clinicians should be aware that there is also a potential for increased MPA exposure after crossover from cyclosporine to Hecoria (tacrolimus) capsules in patients concomitantly receiving MPA-containing products.

Grapefruit Juice

Grapefruit juice inhibits CYP3A-enzymes resulting in increased tacrolimus whole blood trough concentrations, and patients should avoid eating grapefruit or drinking grapefruit juice with tacrolimus [see DOSAGE AND ADMINISTRATION (2.5)].

Protease Inhibitors

Most protease inhibitors inhibit CYP3A enzymes and may increase tacrolimus whole blood concentrations. It is recommended to avoid concomitant use of tacrolimus with nelfinavir unless the benefits outweigh the risks [see CLINICAL PHARMACOLOGY (12.3)]. Whole blood concentrations of tacrolimus are markedly increased when coadministered with telaprevir or with boceprevir [see CLINICAL PHARMACOLOGY (12.3)]. Monitoring of tacrolimus whole blood concentrations and tacrolimus-associated adverse reactions, and appropriate adjustments in the dosing regimen of tacrolimus are recommended when tacrolimus and protease inhibitors (e.g., ritonavir, telaprevir, boceprevir) are used concomitantly.

Antifungal Agents

Frequent monitoring of whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended when concomitant use of the following antifungal drugs with tacrolimus is initiated or discontinued [see CLINICAL PHARMACOLOGY (12.3)].

Azoles: Voriconazole, posaconazole, itraconazole, ketoconazole, fluconazole and clotrimazole inhibit CYP3A metabolism of tacrolimus and increase tacrolimus whole blood concentrations. When initiating therapy with voriconazole or posaconazole in patients already receiving tacrolimus, it is recommended that the tacrolimus dose be initially reduced to one-third of the original dose and the subsequent tacrolimus doses be adjusted based on the tacrolimus whole blood concentrations.

Caspofungin is an inducer of CYP3A and decreases whole blood concentrations of tacrolimus.

Calcium Channel Blockers

Verapamil, diltiazem, nifedipine, and nicardipine inhibit CYP3A metabolism of tacrolimus and may increase tacrolimus whole blood concentrations. Monitoring of whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended when these calcium channel blocking drugs and tacrolimus are used concomitantly.

Antibacterials

Erythromycin, clarithromycin, troleandomycin and chloramphenicol inhibit CYP3A metabolism of tacrolimus and may increase tacrolimus whole blood concentrations. Monitoring of blood concentrations and appropriate dosage adjustments of tacrolimus are recommended when these drugs and tacrolimus are used concomitantly.

Antimycobacterials

Rifampin [see CLINICAL PHARMACOLOGY (12.3)] and rifabutin are inducers of CYP3A enzymes and may decrease tacrolimus whole blood concentrations. Monitoring of whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended when these antimycobacterial drugs and tacrolimus are used concomitantly.

Anticonvulsants

Phenytoin, carbamazepine and phenobarbital induce CYP3A enzymes and may decrease tacrolimus whole blood concentrations. Monitoring of whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended when these drugs and tacrolimus are used concomitantly.

Concomitant administration of phenytoin with tacrolimus may also increase phenytoin plasma concentrations. Thus, frequent monitoring of phenytoin plasma concentrations and adjusting the phenytoin dose as needed are recommended when tacrolimus and phenytoin are administered concomitantly.

St. John’s Wort (Hypericum perforatum)

St. John’s Wort induces CYP3A enzymes and may decrease tacrolimus whole blood concentrations. Monitoring of whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended when St. John’s Wort and tacrolimus are coadministered.

Gastric Acid Suppressors/Neutralizers

Lansoprazole and omeprazole, as CYP2C19 and CYP3A4 substrates, may potentially inhibit the CYP3A4 metabolism of tacrolimus and thereby substantially increase tacrolimus whole blood concentrations, especially in transplant patients who are intermediate or poor CYP2C19 metabolizers, as compared to those patients who are efficient CYP2C19 metabolizers.

Cimetidine may also inhibit the CYP3A4 metabolism of tacrolimus and thereby substantially increase tacrolimus whole blood concentrations.

Coadministration with magnesium and aluminum hydroxide antacids increase tacrolimus whole blood concentrations [see CLINICAL PHARMACOLOGY (12.3)]. Monitoring of whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended when these drugs and tacrolimus are used concomitantly.

Others

Bromocriptine, nefazodone, metoclopramide, danazol, ethinyl estradiol, amiodarone and methylprednisolone may inhibit CYP3A metabolism of tacrolimus and increase tacrolimus whole blood concentrations. Monitoring of blood concentrations and appropriate dosage adjustments of tacrolimus are recommended when these drugs and tacrolimus are coadministered.

Pregnancy

Pregnancy Category C - There are no adequate and well-controlled studies in pregnant women. Tacrolimus is transferred across the placenta. The use of tacrolimus during pregnancy in humans has been associated with neonatal hyperkalemia and renal dysfunction. Tacrolimus given orally to pregnant rabbits at 0.5 to 4.3 times the clinical dose and pregnant rats at 0.8 to 6.9 times the clinical dose was associated with an increased incidence of fetal death in utero, fetal malformations (cardiovascular, skeletal, omphalocele, and gallbladder agenesis) and maternal toxicity. Hecoria (tacrolimus) capsules should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.

In pregnant rabbits, tacrolimus at oral doses of 0.32 and 1 mg/kg, 0.5 to 4.3 times the clinical dose range (0.075 to 0.2 mg/kg) based on body surface area, was associated with maternal toxicity as well as an increased incidence of abortions. At the 1 mg/kg dose, fetal rabbits showed an increased incidence of malformations (ventricular hypoplasia, interventricular septal defect, bulbous aortic arch, stenosis of ductus arteriosis, interrupted ossification of vertebral arch, vertebral and rib malformations, omphalocele, and gallbladder agenesis) and developmental variations. In pregnant rats, tacrolimus at oral doses of 3.2 mg/kg, 2.6 to 6.9 times the clinical dose range was associated with maternal toxicity, an increase in late resorptions, decreased numbers of live births, and decreased pup weight and viability. Tacrolimus, given orally to pregnant rats after organogenesis and during lactation at 1 and 3.2 mg/kg, 0.8 to 6.9 times the recommended clinical dose range was associated with reduced pup weights and pup viability (3.2 mg/kg only); among the high dose pups that died early, an increased incidence of kidney hydronephrosis was observed.

Nursing Mothers

Tacrolimus is excreted in human milk. As the effect of chronic exposure to tacrolimus in healthy infants is not established, patients maintained on Hecoria (tacrolimus) capsules should discontinue nursing taking into consideration importance of drug to the mother.

Pediatric Use

The safety and efficacy of Hecoria (tacrolimus) capsules in pediatric kidney and heart transplant patients have not been established. Successful liver transplants have been performed in pediatric patients (ages up to 16 years) using tacrolimus. Two randomized active-controlled trials of tacrolimus in primary liver transplantation included 56 pediatric patients. Thirty-one patients were randomized to tacrolimus-based and 25 to cyclosporine-based therapies. Additionally, a minimum of 122 pediatric patients were studied in an uncontrolled trial of tacrolimus in living related donor liver transplantation. Pediatric patients generally required higher doses of tacrolimus to maintain blood trough concentrations of tacrolimus similar to adult patients [see DOSAGE AND ADMINISTRATION (2.2)].

Geriatric Use

Clinical trials of tacrolimus did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Use in Renal Impairment

The pharmacokinetics of tacrolimus in patients with renal impairment was similar to that in healthy volunteers with normal renal function. However, consideration should be given to dosing Hecoria (tacrolimus) capsules at the lower end of the therapeutic dosing range in patients who have received a liver or heart transplant and have pre-existing renal impairment. Further reductions in dose below the targeted range may be required [see DOSAGE AND ADMINISTRATION (2.3) and CLINICAL PHARMACOLOGY (12.3)].

Use in Hepatic Impairment

The mean clearance of tacrolimus was substantially lower in patients with severe hepatic impairment (mean Child-Pugh score: >10) compared to healthy volunteers with normal hepatic function. Close monitoring of tacrolimus trough concentrations is warranted in patients with hepatic impairment [see CLINICAL PHARMACOLOGY (12.3)].

The use of Hecoria (tacrolimus) capsules in liver transplant recipients experiencing post-transplant hepatic impairment may be associated with increased risk of developing renal insufficiency related to high whole-blood trough concentrations of tacrolimus. These patients should be monitored closely and dosage adjustments should be considered. Some evidence suggests that lower doses should be used in these patients [see DOSAGE AND ADMINISTRATION (2.3) and CLINICAL PHARMACOLOGY (12.3)].