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他克莫司胶囊HECORIA(TACROLIMUS)

2012-12-02 17:59:16  作者:新特药房  来源:互联网  浏览次数:205  文字大小:【】【】【
简介: 部分中文他克莫司处方资料(仅供参考)【别名】他克莫司,大环哌南,普乐可复【外文名】Tacrolimus,Prograf,FK506【药理作用】在分子水平,他克莫司的作用显然是利用与细胞性蛋白质(FKBP12)相结合, ...
关键字:他克莫司胶囊

 部分中文他克莫司处方资料(仅供参考)
【别名】他克莫司,大环哌南,普乐可复
【外文名】Tacrolimus,Prograf,FK506
【药理作用】
在分子水平,他克莫司的作用显然是利用与细胞性蛋白质(FKBP12)相结合,而在细胞内蓄积产生效用。FKBP12-他克莫司复合物会专一性地结合以及抑制calcinurin,其会抑制T细胞中所产生钙离子依赖型讯息传导路径作用,因此防止不连续性淋巴因子基因的转录。本药是具有高度免疫抑制的药物,其活性在体外及体内实验中都已被证实。本药抑制形成主要移值排斥作用之细胞毒性淋巴球的生成 。
本药是具有高度免疫抑制的药物,其活性在体外及体内实验中都已被证实。
本药抑制形成主要移植排斥作用之细胞毒性淋巴球的生成。本药抑制T细胞的活化作用以及T辅助细胞依赖B细胞的增生作用。
也会抑制如白介素-2、白介素-3及γ-干扰素等淋巴因子的生成与白介素-2受体的表达。在分子水平,本药的效应似乎是由结合到细胞性蛋白质(FKBP)所产生,此蛋白质也会造成该化合物累积在细胞间。在体内试验中发现,本药显示出对肝脏及肾脏移植有效。
【适应症】肝脏及肾脏移植患者的首选免疫抑制药物,肝脏及肾脏移植后排斥反应对传统免疫抑制方案耐药者,也可选用该药物。
【用法用量】
下列口服及静脉注射给药之建议剂量只是概略指标,本药的实际剂量应依据个别病人的需要而加以调整,建议剂量只有起始剂量,因此治疗过程中应藉由临床判断并辅以他克莫司血中浓度的监测以调整剂量。口服给药每日剂量分两次投予。最好是在空腹或至少进食前1hr或进食后2-3hr服用胶囊,以达到最大吸收量。
口服胶囊时,通常须连续服用以抑制移植排斥作用。并没有治疗期间的限制。静脉注射给药输注用浓缩液必须在聚乙烯或玻璃瓶中用5%葡萄糖注射或者生理食盐水稀释。所形成的最终输注用溶液的浓度必须在0.004-0.1mg/ml范围间。24hr内输注20-250ml。此溶液不可以一次全量快速注释给药。当患者的状况允许时,应尽快将静脉注射疗法改为口服疗法。静脉注射疗法不应该连续超过7天。首次免疫抑制剂量-成人肝脏移植者为0.1-0.2mg/kg/天,肾脏移植患者为0.15-0.3mg/kg/天,分2次口服。应该在肝脏移植手术后约6hr以及肾脏移植手术24hr内开始给药。如果病患的临床状况不适于口服给药。如果病患的临床状况不适于口服给药,则应该给予连续24hr的静脉输注他克莫司治疗。起始静脉注射剂量对肝脏移植患者为0.01-0.05mg/kg/天,而对肾脏移植患者为0.05-0.1mg/kg/天。

首次免疫抑制剂量-儿童儿童病患通常需要成人建议剂量的1.5-2倍,才能达到相同的治疗血浓度。肝脏及肾脏移植:0.3mg/kg/天,分2次口服。如果不能口服给药时,应该给予连续24hr的静脉输注,对肝脏移植的儿童为0.05mg/kg/天,而对肾脏移植的儿童为0.1mg/kg/天。

维持治疗需要口服本药来达到连续免疫抑制作用以维持移植物的生存。在维持治疗中常可减低剂量。主要是根据各病患个体对于排斥及耐受性的临床评估而调整。

在病患手术后的恢复期,本药的药物动力学可能会改变,因此需要调整本药的剂量。如果疾病发生变化(例如产生排斥现象),必须考虑更换免疫抑制疗法。增加激素、使用短期的单株/多株抗体以及增加本药的剂量都曾被用来控制排斥发作。

如果有中毒征兆(例如明显的不良反应)出现,必须降低本药的剂量。当本药的激素合用时,激素用量通常可以减低,且在少数病例中可以持续地进行单一治疗法。对传统免疫抑制治疗无效如果病患以传本药的治疗应该以该特定移植中首次免疫抑制所建议的初始剂量来开始给药。同时给予环孢素及本药可能会延长环孢素的半衰期,并且产生毒性作用。应该在考虑环孢素的血浓度以及病患的临床状况后,方可开始使用本药治疗。

实际上,通常是在停止给予环孢素后12-24hr才开始使用本药。由于环孢素后的清除率可能会受影响,所以在换药后应该监测环孢素的血药浓度。特殊病人肝功能不全之病患;对于手术前或手术后功能不全,如最初移植功能不良的病患可能需要减低剂量。肾功能不全之病患:由于他克莫司的肾清除率很低,所以依据药物动力学的原则是不需要调整剂量。但是由于其潜在肾毒性,所以建议小心监测包括血肌酐、肌酐清除率的计算及排尿量等肾功能。本药的血中浓度不因透析而降低。

老年病患有限的经验显示其剂量应同成年患者。
【不良反应】由于大部分用药者存在有严重的疾病和同时并用许多其它药物,常很难确定与免疫抑制药物有关之不良反应。
有证据显示,下列许多药物不良反应是可逆转的,并且可经由剂量降低而改善。和静脉给药相比,口服给药发生不良反应的频率明显地较低。下列药物不良反应乃是依据身体系统及其发生频率来编排的。心血管系统-经常性:高血压。偶发生:心绞痛、心悸、渗液(例如心包积液、胸膜积液)。罕见性:包含休克之低血压、心电图异常、心律失常、心房/心室纤颤以及心跳停止、血栓静脉炎、出血(例如胃肠道、大脑)、心力衰竭、心脏扩大、心跳缓慢。

【规格】胶囊1mg*10粒,100粒,5mg*5粒,50粒。注射液5mg/1ml*10安瓿。

FULL PRESCRIBING INFORMATION

BOX WARNING:MALIGNANCIES AND SERIOUS INFECTIONS

  • Increased risk of development of lymphoma and other malignancies, particularly of the skin, due to immunosuppression [see WARNINGS AND PRECAUTIONS (5.2)].
  • Increased susceptibility to bacterial, viral, fungal, and protozoal infections, including opportunistic infections [see WARNINGS AND PRECAUTIONS (5.3, 5.4, 5.5)].
  • Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should prescribe Hecoria (tacrolimus) capsules. 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 [see WARNINGS AND PRECAUTIONS (5.1)]

1 INDICATIONS AND USAGE

1.1 Prophylaxis of Organ Rejection in Kidney Transplant

Hecoria (tacrolimus) capsules are 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 )].

1.2 Prophylaxis of Organ Rejection in Liver Transplant

Hecoria (tacrolimus) capsules are 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 )].

1.4 Limitations of Use

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

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

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

2 DOSAGE AND ADMINISTRATION

2.1 Dosage in Adult Kidney, or Liver Transplant Patients

The initial oral dosage recommendations for adult patients with kidney, or liver transplants along with recommendations for whole blood trough concentrations are shown in Table 1. The initial dose of Hecoria (tacrolimus) capsules should be administered no sooner than 6 hours after transplantation in the liver 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

Patient Population

Recommended Hecoria Initial Oral Dosage

Note: daily doses should be administered as two divided doses, every 12 hours
Observed Tacrolimus Whole Blood Trough Concentrations

Adult kidney transplant patients

In combination with azathioprine
0.2 mg/kg/day

month 1 to 3: 7 to 20 ng/mL

month 4 to 12: 5 to 15 ng/mL
In combination with MMF/IL-2
receptor antagonista
0.1 mg/kg/day month 1 to 12: 4 to 11 ng/mL
Adult liver transplant patients 0.10 to 0.15 mg/kg/day month 1 to 12: 5 to 20 ng/mL
a In 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 month 1 to 3 and 5 to 12 ng/mL during month 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).

Table 2. Comparative Dose and Trough Concentrations Based on Race
Time After Transplant  

Caucasian

n=114
 

Black

n=56
 

Dose

(mg/kg)
 

Trough Concentrations

(ng/mL)
 

Dose

(mg/kg)
Trough Concentrations (ng/mL)
Day 7 0.18 12 0.23 10.9
Month 1 0.17 12.8 0.26 12.9
Month 6 0.14 11.8 0.24 11.5
Month 12 0.13 10.1 0.19 11
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. Tacrolimus injection should be discontinued as soon as the patient can tolerate oral administration of Hecoria, 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 (tacrolimus) capsules 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 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)].

2.2 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.

Table 3. Summary of Initial Oral Dosage Recommendations and Observed Whole Blood Trough Concentrations in Children
Patient Population

Recommended Hecoria Initial Oral Dosage

Note: daily doses should be administered as two divided doses, every 12 hours
Observed Tacrolimus Whole Blood Trough Concentrations
Pediatric liver transplant patients 0.15 to 0.20 mg/kg/day Month 1 to 12: 5 to 20 ng/mL
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 transplantation patients is limited.

2.3 Dosage Adjustment in Patients with Renal Impairment

Due to its potential for nephrotoxicity, 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 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.

2.4 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. 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)].

2.5 Administration Instructions

It is recommended that patients initiate oral therapy with Hecoria (tacrolimus) capsules 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 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)].

Hecoia 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, 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.

2.6 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.

3 DOSAGE FORMS AND STRENGTHS

Hecoria (tacrolimus) capsules are available in 0.5 mg, 1 mg, and 5 mg strengths.

Hecoria (tacrolimus) capsules, containing white to off white powder equivalent to 0.5 mg of anhydrous tacrolimus, are hard gelatin capsules with white opaque body and ivory cap. The body is imprinted “0.5 mg” and cap is imprinted “HECORIA” in black ink.

Hecoria (tacrolimus) capsules, containing white to off white powder equivalent to 1 mg of anhydrous tacrolimus, are hard gelatin capsules with white opaque body and brown cap. The body is imprinted “1 mg” and cap is imprinted “HECORIA” in black ink.

Hecoria (tacrolimus) capsules, containing white to off white powder equivalent to 5 mg of anhydrous tacrolimus, are hard gelatin capsules with white opaque body and orange cap. The body is imprinted “5 mg” and cap is imprinted “HECORIA” in black ink.

4 CONTRAINDICATIONS

Hecoria (tacrolimus) capsules are contraindicated in patients with a hypersensitivity to tacrolimus. Hypersensitivity symptoms reported include dyspnea, rash, pruritus, and acute respiratory distress syndrome [see ADVERSE REACTIONS (6)].

5 WARNINGS AND PRECAUTIONS

5.1 Management of Immunosuppression

Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should use Hecoria (tacrolimus) capsules. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physicians responsible for maintenance therapy should have complete information requisite for the follow up of the patient [see BOX WARNING].

5.2 Lymphoma and Other Malignancies

Patients receiving immunosuppressants, including Hecoria (tacrolimus) capsules, are at increased risk of developing lymphomas and other malignancies, particularly of the skin [see BOX WARNING]. The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent.

As usual for patients with increased risk for skin cancer, exposure to sunlight and UV light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.

Post transplant lymphoproliferative disorder (PTLD) has been reported in immunosuppressed organ transplant recipients. The majority of PTLD events appear related to Epstein Barr Virus (EBV) infection. The risk of PTLD appears greatest in those individuals who are EBV seronegative, a population which includes many young children.

5.3 Serious Infections

Patients receiving immunosuppressants, including Hecoria (tacrolimus) capsules, are at increased risk of developing bacterial, viral, fungal, and protozoal infections, including opportunistic infections [see BOX WARNING and WARNINGS AND PRECAUTIONS (5.4, 5.5)]. These infections may lead to serious, including fatal, outcomes. Because of the danger of oversuppression of the immune system which can increase susceptibility to infection, combination immunosuppressant therapy should be used with caution.

5.4 Polyoma Virus Infections

Patients receiving immunosuppressants, including Hecoria (tacrolimus) capsules, are at increased risk for opportunistic infections, including polyoma virus infections. Polyoma virus infections in transplant patients may have serious, and sometimes fatal, outcomes. These include polyoma virus-associated nephropathy (PVAN), mostly due to BK virus infection, and JC virus-associated progressive multifocal leukoencephalopathy (PML) which have been observed in patients receiving tacrolimus  [see ADVERSE REACTIONS (6.2)].

PVAN is associated with serious outcomes, including deteriorating renal function and kidney graft loss [see ADVERSE REACTIONS (6.2)]. Patient monitoring may help detect patients at risk for PVAN.

Cases of PML have been reported in patients treated with Hecoria. PML, which is sometimes fatal, commonly presents with hemiparesis, apathy, confusion, cognitive deficiencies and ataxia. Risk factors for PML include treatment with immunosuppressant therapies and impairment of immune function. In immunosuppressed patients, physicians should consider PML in the differential diagnosis in patients reporting neurological symptoms and consultation with a neurologist should be considered as clinically indicated.

Reductions in immunosuppression should be considered for patients who develop evidence of PVAN or PML. Physicians should also consider the risk that reduced immunosuppression represents to the functioning allograft.

5.5 Cytomegalovirus (CMV) Infections

Patients receiving immunosuppressants, including Hecoria (tacrolimus) capsules, are at increased risk of developing CMV viremia and CMV disease. The risk of CMV disease is highest among transplant recipients seronegative for CMV at time of transplant who receive a graft from a CMV seropositive donor. Therapeutic approaches to limiting CMV disease exist and should be routinely provided. Patient monitoring may help detect patients at risk for CMV disease. Consideration should be given to reducing the amount of immunosuppression in patients who develop CMV viremia and/or CMV disease.

5.6 New Onset Diabetes After Transplant

Tacrolimus was shown to cause new onset diabetes mellitus in clinical trials of kidney and liver transplantation. New onset diabetes after transplantation may be reversible in some patients. Black and Hispanic kidney transplant patients are at an increased risk. Blood glucose concentrations should be monitored closely in patients using Hecoria (tacrolimus) capsules [see ADVERSE REACTIONS (6.1)].

5.7 Nephrotoxicity

Hecoria (tacrolimus) capsules, like other calcineurin-inhibitors, can cause acute or chronic nephrotoxicity, particularly when used in high doses. Acute nephrotoxicity is most often related to vasoconstriction of the afferent renal arteriole, is characterized by increasing serum creatinine, hyperkalemia, and/or a decrease in urine output, and is typically reversible. Chronic calcineurin-inhibitor nephrotoxicity is associated with increased serum creatinine, decreased kidney graft life, and characteristic histologic changes observed on renal biopsy; the changes associated with chronic calcineurin-inhibitor nephrotoxicity are typically progressive. Patients with impaired renal function should be monitored closely as the dosage of tacrolimus may need to be reduced. In patients with persistent elevations of serum creatinine who are unresponsive to dosage adjustments, consideration should be given to changing to another immunosuppressive therapy.

Based on reported adverse reactions terms related to decreased renal function, nephrotoxicity was reported in approximately 52% 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 REACTIONS (6.1)].

Due to the potential for additive or synergistic impairment of renal function, care should be taken when administering Hecoria with drugs that may be associated with renal dysfunction. These include, but are not limited to, aminoglycosides, ganciclovir, amphotericin B, cisplatin, nucleotide reverse transcriptase inhibitors (e.g., tenofovir) and protease inhibitors (e.g., ritonavir, indinavir). Similarly, care should be exercised when administering with CYP3A4 inhibitors such as antifungal drugs (e.g., ketoconazole), calcium channel blockers (e.g., diltiazem, verapamil), and macrolide antibiotics (e.g., clarithromycin, erythromycin, troleandomycin) which will result in increased tacrolimus whole blood concentrations due to inhibition of tacrolimus metabolism [see DRUG INTERACTIONS (7.3,7.4, 7.5, 7.6)].

5.8 Neurotoxicity

Hecoria (tacrolimus) capsules may cause a spectrum of neurotoxicities, particularly when used in high doses. The most severe neurotoxicities include posterior reversible encephalopathy syndrome (PRES), delirium, and coma. Patients treated with tacrolimus have been reported to develop PRES. Symptoms indicating PRES include headache, altered mental status, seizures, visual disturbances and hypertension. Diagnosis may be confirmed by radiological procedure. If PRES is suspected or diagnosed, blood pressure control should be maintained and immediate reduction of immunosuppression is advised. This syndrome is characterized by reversal of symptoms upon reduction or discontinuation of immunosuppression.

Coma and delirium, in the absence of PRES, have also been associated with high plasma concentrations of tacrolimus. Seizures have occurred in adult and pediatric patients receiving Hecoria [see ADVERSE REACTIONS (6.1)].

Less severe neurotoxicities, include tremors, parathesias, headache, and other changes in motor function, mental status, and sensory function [see ADVERSE REACTIONS (6.1)] . Tremor and headache have been associated with high whole-blood concentrations of tacrolimus and may respond to dosage adjustment.

5.9 Hyperkalemia

Hyperkalemia has been reported with Hecoria (tacrolimus) capsule use. Serum potassium levels should be monitored. Careful consideration should be given prior to use of other agents also associated with hyperkalemia (e.g., potassium-sparing diuretics, ACE inhibitors, angiotensin receptor blockers) during Hecoria therapy [see ADVERSE REACTIONS (6.1)].

5.10 Hypertension

Hypertension is a common adverse effect of Hecoria (tacrolimus) capsules therapy and may require antihypertensive therapy [see ADVERSE REACTIONS (6.1)]. The control of blood pressure can be accomplished with any of the common antihypertensive agents, though careful consideration should be given prior to use of antihypertensive agents associated with hyperkalemia (e.g., potassium-sparing diuretics, ACE inhibitors, angiotensin receptor blockers) [see WARNINGS AND PRECAUTIONS (5.9)]. Calcium-channel blocking agents may increase tacrolimus blood concentrations and therefore require dosage reduction of Hecoria [see DRUG INTERACTIONS (7.5)].

5.11 Anaphylactic Reactions with Tacrolimus Injection

Anaphylactic reactions have occurred with injectables containing castor oil derivatives, including tacrolimus, in a small percentage of patients (0.6%). The exact cause of these reactions is not known. Tacrolimus injection should be reserved for patients who are unable to take tacrolimus capsules [see INDICATIONS AND USAGE (1.4)].

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 should be available at the bedside as well as a source of oxygen.

5.12 Use with Sirolimus

The safety and efficacy of Hecoria (tacrolimus) capsules with sirolimus has not been established in kidney transplant patients.

Use of sirolimus with tacrolimus in studies of de novo liver transplant patients was associated with an excess mortality, graft loss, and hepatic artery thrombosis (HAT) and is not recommended [see INDICATIONS AND USAGE (1.4)].

5.13 Use with Strong Inhibitors and Inducers of CYP3A

Co-administration with strong CYP3A4-inhibitors (e.g., ritonavir, ketoconazole, itraconazole, voriconazole, clarithromycin) and strong inducers (e.g., rifampin, rifabutin) is not recommended without close monitoring of tacrolimus whole blood trough concentrations [see DRUG INTERACTIONS (7)].

5.14 Myocardial Hypertrophy

Myocardial hypertrophy has been reported in infants, children, and adults, particularly those with high tacrolimus trough concentrations, and is generally manifested by echocardiographically demonstrated concentric increases in left ventricular posterior wall and interventricular septum thickness. This condition appears reversible in most cases following dose reduction or discontinuance of therapy. In patients who develop renal failure or clinical manifestations of ventricular dysfunction while receiving tacrolimus therapy, echocardiographic evaluation should be considered. If myocardial hypertrophy is diagnosed, dosage reduction or discontinuation of Hecoria (tacrolimus) capsules should be considered [see ADVERSE REACTIONS (6.2)].

5.15 Immunizations

The use of live vaccines should be avoided during treatment with tacrolimus; examples include (not limited to) the following: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.

5.16 Pure Red Cell Aplasia

Cases of pure red cell aplasia (PRCA) have been reported in patients treated with tacrolimus. A mechanism for tacrolimus-induced PRCA has not been elucidated. All patients reported risk factors for PRCA such as parvovirus B19 infection, underlying disease, or concomitant medications associated with PRCA. If PRCA is diagnosed, discontinuation of Hecoria (tacrolimus) capsules should be considered [see ADVERSE REACTIONS (6.2)].

6 ADVERSE REACTIONS

The following serious and otherwise important adverse drug reactions are discussed in greater detail in other sections of labeling:

  • Lymphoma and Other Malignancies [see BOX WARNING, WARNINGS AND PRECAUTIONS (5.2)]
  • Serious Infections [see BOX WARNING, WARNINGS AND PRECAUTIONS (5.3)]
  • Polyoma Virus Infections [see BOX WARNING, WARNINGS AND PRECAUTIONS (5.4)]
  • CMV Infections [see BOX WARNING, WARNINGS AND PRECAUTIONS (5.5)]
  • New Onset Diabetes After Transplant [see WARNINGS AND PRECAUTIONS (5.6)]
  • Nephrotoxicity [see WARNINGS AND PRECAUTIONS (5.7)]
  • Neurotoxicity [see WARNINGS AND PRECAUTIONS (5.8)]
  • Hyperkalemia [see WARNINGS AND PRECAUTIONS (5.9)]
  • Hypertension [see WARNINGS AND PRECAUTIONS (5.10)]
  • Myocardial Hypertrophy [see WARNINGS AND PRECAUTIONS (5.14)]
  • Pure Red Cell Aplasia [see WARNINGS AND PRECAUTIONS (5.16)]

6.1 Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In addition, the clinical trials were not designed to establish comparative differences across study arms with regards to the adverse reactions discussed below.

Kidney Transplant

The incidence of adverse reactions was determined in three randomized kidney transplant trials. One of the trials used azathioprine (AZA) and corticosteroids and two of the trials used mycophenolate mofetil (MMF) and corticosteroids concomitantly for maintenance immunosuppression.

Tacrolimus-based immunosuppression in conjunction with azathioprine and corticosteroids following kidney transplantation was assessed in trial where 205 patients received tacrolimus based immunosuppression and 207 patients received cyclosporine based immunosuppression. The trial population had a mean age of 43 years (mean±sd was 43±13 years on tacrolimus and 44±12 years on cyclosporine arm), the distribution was 61% male, and the composition was White (58%), Black (25%), Hispanic (12%) and Other (5%). The 12 month post-transplant information from this trial is presented below.

The most common adverse reactions ( ≥ 30%) observed in tacrolimus-treated kidney transplant patients are: infection, tremor, hypertension, abnormal renal function, constipation, diarrhea, headache, abdominal pain, insomnia, nausea, hypomagnesemia, urinary tract infection, hypophosphatemia, peripheral edema, asthenia, pain, hyperlipidemia, hyperkalemia and anemia.

Adverse reactions that occurred in ≥ 15% of kidney transplant patients treated with tacrolimus in conjunction with azathioprine are presented below:

Table 4. Kidney Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus in Conjunction with Azathioprine (AZA)

Tacrolimus /AZA

(N=205)
Cyclosporine/AZA
(N=207)
Nervous System
Tremor 54% 34%
Headache 44% 38%
Insomnia 32% 30%
Paresthesia 23% 16%
Dizziness 19% 16%
Gastrointestinal
Diarrhea 44% 41%
Nausea 38% 36%
Constipation 35% 43%
Vomiting 29% 23%
Dyspepsia 28% 20%
Cardiovascular
Hypertension 50% 52%
Chest Pain 19% 13%
Urogenital
Creatinine Increased 45% 42%
Urinary Tract Infection 34% 35%
Metabolic and Nutritional
Hypophosphatemia 49% 53%
Hypomagnesemia 34% 17%
Hyperlipemia 31% 38%
Diabetes Mellitus 31% 32%
Hyperkalemia 24% 9%
Hypokalemia 22% 25%
Hyperglycemia 22% 16%
Edema 18% 19%
Hemic and Lymphatic
Anemia 30% 24%
Leukopenia 15% 17%
Miscellaneous
Infection 45% 49%
Peripheral Edema 36% 48%
Asthenia 34% 30%
Abdominal Pain 33% 31%
Pain 32% 30%
Fever 29% 29%
Back Pain 24% 20%
Respiratory System
Dyspnea 22% 18%
Cough Increased 18% 15%
Musculoskeletal
Arthralgia 25% 24%
Skin
Rash 17% 12%
Pruritus 15% 7%
Two trials were conducted for tacrolimus -based immunosuppression in conjunction with MMF and corticosteroids. In the non-US trial (Study 1), the incidence of adverse reactions was based on 1195 kidney transplant patients that received tacrolimus (Group C, n=403), or one of two cyclosporine (CsA) regimens (Group A, n=384 and Group B, n=408) in combination with MMF and corticosteroids; all patients, except those in one of the two cyclosporine groups, also received induction with daclizumab. The trial population had a mean age of 46 years (range 17 to 76), the distribution was 65% male, and the composition was 93% Caucasian. The 12 month post-transplant information from this trial is presented below.

Adverse reactions that occurred in ≥ 10% of kidney transplant patients treated with tacrolimus in conjunction with MMF in Study 1 [Note: This trial was conducted entirely outside of the United States. Such trials often report a lower incidence of adverse reactions in comparison to U.S. trials] are presented below:

Table 5. Kidney Transplantation: Adverse Reactions Occurring in ≥ 10% of Patients Treated with Tacrolimus in Conjunction with MMF (Study 1)
  Tacrolimus (Group C) Cyclosporine (Group A) Cyclosporine (Group B)
  (N=403) (N=384) (N=408)
Diarrhea 25% 16% 13%
Urinary Tract Infection 24% 28% 24%
Anemia 17% 19% 17%
Hypertension 13% 14% 12%
Leukopenia 13% 10% 10%
Edema Peripheral 11% 12% 13%
Hyperlipidemia 10% 15% 13%
Key: Group A = CsA/MMF/CS, B = CsA/MMF/CS/Daclizumab, C= Tac/MMF/CS/Daclizumab
CsA= Cyclosporine, CS = Corticosteroids, Tac = Tacrolimus, MMF = mycophenolate mofetil
In the U.S. trial (Study 2) with tacrolimus-based immunosuppression in conjunction with MMF and corticosteroids, 424 kidney transplant patients received tacrolimus (n=212) or cyclosporine (n=212) in combination with MMF 1 gram twice daily, basiliximab induction, and corticosteroids. The trial population had a mean age of 48 years (range 17 to 77), the distribution was 63% male, and the composition was White (74%), Black (20%), Asian (3%) and other (3%). The 12 month post-transplant information from this trial is presented below.

Adverse reactions that occurred in ≥15% of kidney transplant patients treated with tacrolimus in conjunction with MMF in Study 2 are presented below:

Table 6. Kidney Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus in Conjunction with MMF (Study 2)
  Tacrolimus /MMF Cyclosporine/MMF
  (N=212) (N=212)
Gastrointestinal Disorders
Diarrhea 44% 26%
Nausea 39% 47%
Constipation 36% 41%
Vomiting 26% 25%
Dyspepsia 18% 15%
Injury, Poisoning, and Procedural Complications
Post-Procedural Pain 29% 27%
Incision Site Complication 28% 23%
Graft Dysfunction 24% 18%
Metabolism and Nutrition Disorders
Hypomagnesemia 28% 22%
Hypophosphatemia 28% 21%
Hyperkalemia 26% 19%
Hyperglycemia 21% 15%
Hyperlipidemia 18% 25%
Hypokalemia 16% 18%
Nervous System Disorders
Tremor 34% 20%
Headache 24% 25%
Blood and Lymphatic System Disorders
Anemia 30% 28%
Leukopenia 16% 12%
Miscellaneous
Edema Peripheral 35% 46%
Hypertension 32% 35%
Insomnia 30% 21%
Urinary Tract Infection 26% 22%
Blood Creatinine Increased 23% 23%
Less frequently observed adverse reactions in both liver transplantation and kidney transplantation patients are described under the subsection Less Frequently Reported Adverse Reactions.

Liver Transplantation

There were two randomized comparative liver transplant trials. In the U.S. trial, 263 adult and pediatric patients received tacrolimus and steroids and 266 patients received cyclosporine-based immunosuppressive regimen (CsA/AZA). The trial population had a mean age of 44 years (range 0.4 to 70), the distribution was 52% male, and the composition was White (78%), Black (5%), Asian (2%), Hispanic (13%) and Other (2%). In the European trial, 270 patients received tacrolimus and steroids and 275 patients received CsA/AZA. The trial population had a mean age of 46 years (range 15 to 68), the distribution was 59% male, and the composition was White (95.4%), Black (1%), Asian (2%) and Other (2%).

The proportion of patients reporting more than one adverse event was > 99% in both the tacrolimus group and the CsA/AZA group. Precautions must be taken when comparing the incidence of adverse reactions in the U.S. trial to that in the European trial. The 12-month post-transplant information from the U.S. trial and from the European trial is presented below. The two trials also included different patient populations and patients were treated with immunosuppressive regimens of differing intensities. Adverse reactions reported in ≥15% in tacrolimus patients (combined trial results) are presented below for the two controlled trials in liver transplantation.

The most common adverse reactions (≥ 40%) observed in tacrolimus-treated liver transplant patients are: tremor, headache, diarrhea, hypertension, nausea, abnormal renal function, abdominal pain, insomnia, paresthesia, anemia, pain, fever, asthenia, hyperkalemia, hypomagnesemia, and hyperglycemia. These all occur with oral administration of tacrolimus and some may respond to a reduction in dosing (e.g., tremor, headache, paresthesia, hypertension). Diarrhea was sometimes associated with other gastrointestinal complaints such as nausea and vomiting.

Table 7. Liver Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus
U.S. TRIAL EUROPEAN TRIAL
Tacrolimus (N=250) Cyclosporine/AZA (N=250) Tacrolimus (N=264) Cyclosporine/AZA (N=265)
Nervous System
Headache 64% 60% 37% 26%
Insomnia 64% 68% 32% 23%
Tremor 56% 46% 48% 32%
Paresthesia 40% 30% 17% 17%
Gastrointestinal

Diarrhea

72%

47%

37%

27%

Nausea

46%

37%

32%

27%

LFT Abnormal 36% 30% 6% 5%
Anorexia 34% 24% 7% 5%
Vomiting 27% 15% 14% 11%
Constipation 24% 27% 23% 21%
Cardiovascular
Hypertension 47% 56% 38% 43%
Urogenital
Kidney Function Abnormal 40% 27% 36% 23%
Creatinine Increased 39% 25% 24% 19%
BUN Increased 30% 22% 12% 9%
Oliguria 18% 15% 19% 12%
Urinary Tract Infection 16% 18% 21% 19%
Metabolic and Nutritional
Hypomagnesemia 48% 45% 16% 9%
Hyperglycemia 47% 38% 33% 22%
Hyperkalemia 45% 26% 13% 9%
Hypokalemia 29% 34% 13% 16%
Hemic and Lymphatic
Anemia 47% 38% 5% 1%
Leukocytosis 32% 26% 8% 8%
Thrombocytopenia 24% 20% 14% 19%
Miscellaneous
Pain 63% 57% 24% 22%
Abdominal Pain 59% 54% 29% 22%
Asthenia 52% 48% 11% 7%
Fever 48% 56% 19% 22%
Back Pain 30% 29% 17% 17%
Ascites 27% 22% 7% 8%
Peripheral Edema 26% 26% 12% 14%
Respiratory System
Pleural Effusion 30% 32% 36% 35%
Dyspnea 29% 23% 5% 4%
Atelectasis 28% 30% 5% 4%
Skin and Appendages

Pruritus

Rash

36%

24%

20%

19%

15%

10%

7%

4%
Less frequently observed adverse reactions in both liver transplantation and kidney transplantation patients are described under the subsection Less Frequently Reported Adverse Reactions.

Other targeted treatment-emergent adverse reactions in tacrolimus-treated patients occurred at a rate of less than 15%, and include the following: Cushingoid features, impaired wound healing, hyperkalemia, Candida infection, and CMV infection/syndrome.

New Onset Diabetes After Transplant

Kidney Transplant  

New Onset Diabetes After Transplant (NODAT) is defined as a composite of fasting plasma glucose ≥126 mg/dL,
HbA1C ≥ 6%, insulin use ≥ 30 days or oral hypoglycemic use. In a trial in kidney transplant patients (Study 2), NODAT was observed in 75% in the tacrolimus-treated and 61% in the Neoral-treated patients without pre-transplant history of diabetes mellitus ( Table 8 ) [see CLINICAL STUDIES (14.1)].

Table 8. Incidence of New Onset Diabetes After Transplant at 1 year in Kidney Transplant Recipients in a Phase 3 Trial (Study 2)
Parameter Treatment Group

Tacrolimus/MMF

(n = 212)

Neoral/MMF

(n = 212)
NODAT 112/150 (75%) 93/152 (61%)

Fasting Plasma Glucose ≥ 126 mg/dL

96/150 (64%) 80/152 (53%)
HbA1C ≥ 6% 59/150 (39%) 28/152 (18%)
Insulin Use ≥ 30 days 9/150 (6%) 4/152 (3%)
Oral Hypoglycemic Use 15/150 (10%) 5/152 (3%)
In early trials of tacrolimus, Post-Transplant Diabetes Mellitus (PTDM) was evaluated with a more limited criteria of “use of insulin for 30 or more consecutive days with < 5 day gap” in patients without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus. Data are presented in Tables 9 to 11. PTDM was reported in 20% of tacrolimus/Azathioprine (AZA)-treated kidney transplant patients without pre-transplant history of diabetes mellitus in a Phase 3 trial (Table 9). The median time to onset of PTDM was 68 days. Insulin dependence was reversible in 15% of these PTDM patients at one year and in 50% at 2 years post-transplant. Black and Hispanic kidney transplant patients were at an increased risk of development of PTDM (Table 10).

Table 9. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 2 Years in Kidney Transplant Recipients in a Phase 3 Trial using Azathioprine (AZA)
a Use of insulin for 30 or more consecutive days, with < 5 day gap, without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus.
Status of PTDMa Tacrolimus/AZA CsA/AZA
Patients without pre-transplant history of diabetes mellitus 151 151
New onset PTDMa, 1st Year 30/151 (20%) 6/151 (4%)
Still insulin-dependent at one year in those without prior history of diabetes 25/151 (17%) 5/151 (3%)
New onset PTDMa post 1 year 1 0
Patients with PTDMa at 2 years 16/151 (11%) 5/151 (3%)
Liver Transplant  

Insulin-dependent PTDM was reported in 18% and 11% of tacrolimus-treated liver transplant patients and was reversible in 45% and 31% of these patients at 1 year post-transplant, in the U.S. and European randomized trials, respectively, (Table 11).   Hyperglycemia was associated with the use of tacrolimus in 47% and 33% of liver transplant recipients in the U.S. and European randomized trials, respectively, and may require treatment [see ADVERSE REACTIONS (6.1)].

Table 11. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 1 Year in Liver Transplant Recipients
a  Use of insulin for 30 or more consecutive days, with < 5 day gap, without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus.
b Patients without pre-transplant history of diabetes mellitus.
Status of PTDMa US Trial European Trial
Tacrolimus Cyclosporine Tacrolimus Cyclosporine
Patients at riskb 239 236 239 249
New Onset PTDMa 42 (18%) 30 (13%) 26 (11%) 12 (5%)
Patients still on insulin at 1 year 23 (10%) 19 (8%) 18 (8%) 6 (2%)

  Less Frequently Reported Adverse Reactions (>3% and <15%)

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

Nervous System [see WARNINGS AND PRECAUTIONS (5.8)]

Abnormal dreams, agitation, amnesia, anxiety, confusion, convulsion, crying, depression, elevated mood, emotional lability, encephalopathy, haemorrhagic stroke, hallucinations, hypertonia, incoordination, monoparesis, myoclonus, nerve compression, nervousness, neuralgia, neuropathy, paralysis flaccid, psychomotor skills impaired, psychosis, quadriparesis, somnolence, thinking abnormal, vertigo, writing impaired

Special Senses

Abnormal vision, amblyopia, ear pain, otitis media, tinnitus

Gastrointestinal

Cholangitis, cholestatic jaundice, duodenitis, dysphagia, esophagitis, flatulence, gastritis, gastroesophagitis, gastrointestinal hemorrhage, GGT increase, GI disorder, GI perforation, hepatitis, hepatitis granulomatous, ileus, increased appetite, jaundice, liver damage, oesophagitis ulcerative, oral moniliasis, pancreatic pseudocyst, rectal disorder, stomatitis,

Cardiovascular

Abnormal ECG, angina pectoris, arrhythmia, atrial fibrillation, atrial flutter, bradycardia, cardiac fibrillation, cardiopulmonary failure, cardiovascular disorder, congestive heart failure, deep thrombophlebitis, echocardiogram abnormal, electrocardiogram QRS complex abnormal, electrocardiogram ST segment abnormal, heart failure, heart rate decreased, hemorrhage, hypotension, peripheral vascular disorder, phlebitis, postural hypotension, syncope, tachycardia, thrombosis, vasodilatation

Urogenital

Acute kidney failure [see WARNINGS AND PRECAUTIONS (5.7 )], albuminuria, BK nephropathy, bladder spasm, cystitis, dysuria, hematuria, hydronephrosis, kidney failure, kidney tubular necrosis, nocturia, pyuria, toxic nephropathy, urge incontinence, urinary frequency, urinary incontinence, urinary retention, vaginitis

Metabolic/Nutritional

Acidosis, alkaline phosphatase increased, alkalosis, ALT (SGPT) increased, AST (SGOT) increased, bicarbonate decreased, bilirubinemia, dehydration, GGT increased, gout, healing abnormal, hypercalcemia, hypercholesterolemia, hyperphosphatemia, hyperuricemia, hypervolemia, hypocalcemia, hypoglycemia, hyponatremia, hypoproteinemia, lactic dehydrogenase increase, weight gain

Endocrine

Cushing’s syndrome

Hemic/Lymphatic

Coagulation disorder, ecchymosis, haematocrit increased, haemoglobin abnormal, hypochromic anemia, leukocytosis, polycythemia, prothrombin decreased, serum iron decreased

Miscellaneous

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

Musculoskeletal

Arthralgia, cramps, generalized spasm, joint disorder, leg cramps, myalgia, myasthenia, osteoporosis

Respiratory

Asthma, emphysema, hiccups, lung disorder, lung function decreased, pharyngitis, pneumonia, pneumothorax, pulmonary edema, respiratory disorder, rhinitis, sinusitis, voice alteration

Skin

Acne, alopecia, exfoliative dermatitis, fungal dermatitis, herpes simplex, herpes zoster, hirsutism, neoplasm skin benign, skin discoloration, skin disorder, skin ulcer, sweating

6.2 Postmarketing Adverse Reactions

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

Other reactions include:

Cardiovascular

Atrial fibrillation, atrial flutter, cardiac arrhythmia, cardiac arrest, electrocardiogram T wave abnormal, flushing, myocardial infarction, myocardial ischaemia, pericardial effusion, QT prolongation, Torsade de Pointes, venous thrombosis deep limb, ventricular extrasystoles, ventricular fibrillation, myocardial hypertrophy  [see WARNINGS AND PRECAUTIONS (5.14)].

Gastrointestinal

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

Hemic/Lymphatic

Disseminated intravascular coagulation, neutropenia, pancytopenia, thrombocytopenic purpura, thrombotic thrombocytopenic purpura, pure red cell aplasia [see WARNINGS AND PRECAUTIONS (5.16)]

Infections

Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal; -polyoma virus-associated nephropathy, (PVAN) including graft loss [see WARNINGS AND PRECAUTIONS (5.4)]

Metabolic/Nutritional

Glycosuria, increased amylase including pancreatitis, weight decreased

Miscellaneous

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

Nervous System

Carpal tunnel syndrome, cerebral infarction, hemiparesis, leukoencephalopathy, mental disorder, mutism, posterior reversible encephalopathy syndrome (PRES)  [see WARNINGS AND PRECAUTIONS (5.8)], progressive multifocal leukoencephalopathy (PML) [see WARNINGS AND PRECAUTIONS (5.4)], quadriplegia, speech disorder, syncope

Respiratory

Acute respiratory distress syndrome, interstitial lung disease, lung infiltration, respiratory distress, respiratory failure

Skin

Stevens-Johnson syndrome, toxic epidermal necrolysis

Special Senses

Blindness, blindness cortical, hearing loss including deafness, photophobia

Urogenital

Acute renal failure, cystitis haemorrhagic, hemolytic-uremic syndrome, micturition disorder

7 DRUG INTERACTIONS

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)].

7.1 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.

7.2 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)].

7.3 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)]. Monitoring of whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended when tacrolimus and other protease inhibitors (e.g., ritonavir) are used concomitantly.

7.4 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.

7.5 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.

7.6 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.

7.7 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.

7.8 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 phenytoin plasma concentrations and adjusting the phenytoin dose as needed are recommended when tacrolimus and phenytoin are administered concomitantly.

7.9 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 co-administered.

7.10 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.

7.11 Others

Bromocriptine, nefazodone, metoclopramide, danazol, ethinyl estradiol 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 co-administered.

8 USE IN SPECIFIC POPULATIONS

8.1 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.

8.3 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.

8.4 Pediatric Use

The safety and efficacy of Hecoria (tacrolimus) capsules in pediatric kidney 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)].

8.5 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.

8.6 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 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) ].

8.7 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)].

10 OVERDOSAGE

Limited overdosage experience is available. Acute overdosages of up to 30 times the intended dose have been reported. Almost all cases have been asymptomatic and all patients recovered with no sequelae. Acute overdosage was sometimes followed by adverse reactions consistent with those listed in ADVERSE REACTIONS (6) (including tremors, abnormal renal function, hypertension, and peripheral edema); in one case of acute overdosage, transient urticaria and lethargy were observed. Based on the poor aqueous solubility and extensive erythrocyte and plasma protein binding, it is anticipated that tacrolimus is not dialyzable to any significant extent; there is no experience with charcoal hemoperfusion. The oral use of activated charcoal has been reported in treating acute overdoses, but experience has not been sufficient to warrant recommending its use. General supportive measures and treatment of specific symptoms should be followed in all cases of overdosage.

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

11 DESCRIPTION

Hecoria (tacrolimus) is available for oral administration as capsules (tacrolimus capsules) containing the equivalent of 0.5 mg, 1 mg or 5 mg of anhydrous tacrolimus. In addition, each capsule contains the following inactive ingredients: croscarmellose sodium, hypromellose, lactose monohydrate, and magnesium stearate.

The Hecoria (tacrolimus) capsule shell for 0.5 mg strength consists of gelatin, titanium dioxide and yellow iron oxide.

The Hecoria (tacrolimus) capsule shell for 1 mg strength consists of black iron oxide, gelatin, red iron oxide, titanium dioxide, and yellow iron oxide.

The Hecoria (tacrolimus) capsule shell for 5 mg strength consists of red iron oxide, gelatin, and titanium dioxide.

Hecoria (tacrolimus) capsules 0.5 mg, 1 mg and 5 mg are printed with edible black ink. The black ink is comprised of ammonia, black iron oxide, butyl alcohol, potassium hydroxide, propylene glycol, and shellac.

Tacrolimus, previously known as FK506, is the active ingredient in Hecoria (tacrolimus) capsules. Tacrolimus is a macrolide immunosuppressant produced by Streptomyces tsukubaensis. Chemically, tacrolimus is designated as [3S-[3R*[E(1S*,3S*,4S*)],4S*,5R*,8S*,9E,12R∗  ,14R, 15S*,16R*,18S*,19S*,26aR*]] 5,6,8,11,12,13,14,15,16,17,18,19, 24,25,26,26a-hexadecahydro-5,19-dihydroxy-3-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylethenyl]-14,16-dimethoxy-4,10,12,18-tetramethyl-8-(2-propenyl)-15,19-epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclotricosine-1,7,20,21(4H,23H)-tetrone, monohydrate.

The chemical structure of tacrolimus is:

Tacrolimus has a molecular formula of C44H69NO12•H2O and a formula weight of 822.03. Tacrolimus appears as white crystals or crystalline powder. It is practically insoluble in water, freely soluble in ethanol, and very soluble in methanol and chloroform.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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

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

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

12.3 Pharmacokinetics

Tacrolimus activity is primarily due to the parent drug. The pharmacokinetic parameters (mean±S.D.) of tacrolimus have been determined following intravenous (IV) and/or oral (PO) administration in healthy volunteers, and in kidney transplant and liver transplant patients (Table 12).

Table 12. Pharmacokinetics Parameters (mean±S.D.) of Tacrolimus in Healthy Volunteers and Patients
anot applicable
bAUC0-120
c  AUC0-72
dCorrected for individual bioavailability
eAUC0-inf
fnot available
gAUC0-t
hDetermined after the first dose
iMedian [range]
jAUC0-12

Population

N

Route

(Dose)

Parameters

Cmax

(ng/mL)

Tmax

(hr)

AUC

(ng•hr/mL)

t1/2

(hr)

CI

(L/hr/kg)

V

(L/kg)

Healthy

Volunteers

8

IV

(0.025 mg/kg/4hr)

a

a

598b

± 125

34.2

± 7.7

0.040

± 0.009

1.91

± 0.31

16

PO

(5 mg)

29.7

± 7.2

1.6

± 0.7

243c

± 73

34.8

± 11.4

0.041d

± 0.008

1.94d

± 0.53

Kidney

Transplant

Patients

26

IV

(0.02 mg/kg/12 hr)
a a

294e

± 262

18.8

± 16.7

0.083

± 0.050

1.41

± 0.66

PO

(0.2 mg/kg/day)

19.2

± 10.3

3

203e

± 42

f f f

PO

(0.3 mg/kg/day)

24.2

± 15.8

1.5

288e

± 93
f f f

Liver

Transplant

Patients

17

IV

(0.05 mg/kg/12 hr)

a

a

3300e

± 2130

11.7

± 3.9

0.053

± 0.017

0.85

± 0.30

PO

(0.3 mg/kg/day)

68.5

± 30

2.3

± 1.5

519e

± 179
f f f
Due to intersubject variability in tacrolimus pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy [see DOSAGE AND ADMINISTRATION (2.6)]. Pharmacokinetic data indicate that whole blood concentrations rather than plasma concentrations serve as the more appropriate sampling compartment to describe tacrolimus pharmacokinetics.

Absorption

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

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

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

Food Effects

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

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

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

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

Hecoria (tacrolimus) capsules should be taken consistently every day either with or without food because the presence and composition of food decreases the bioavailability of Hecoria [see DOSAGE AND ADMINISTRATION (2.5)].

Distribution

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 mainly to albumin and alpha-1-acid glycoprotein, and has a high level of association with erythrocytes. The distribution of tacrolimus between whole blood and plasma depends on several factors, such as hematocrit, temperature at the time of plasma separation, drug concentration, and plasma protein concentration. In a U.S. trial, the ratio of whole blood concentration to plasma concentration averaged 35 (range 12 to 67).

Metabolism

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

Excretion
The mean clearance following IV administration of tacrolimus is 0.040, 0.083, and 0.053, and 0.051 L/hr/kg in healthy volunteers, adult kidney transplant patients, adult liver transplant patients, and adult heart transplant patients, respectively. In man, less than 1% of the dose administered is excreted unchanged in urine.

In a mass balance study of IV administered radiolabeled tacrolimus to 6 healthy volunteers, the mean recovery of radiolabel was 77.8±12.7%. Fecal elimination accounted for 92.4±1% and the elimination half-life based on radioactivity was 48.1±15.9 hours whereas it was 43.5±11.6 hours based on tacrolimus concentrations. The mean clearance of radiolabel was 0.029±0.015 L/hr/kg and clearance of tacrolimus was 0.029±0.009 L/hr/kg. When administered PO, the mean recovery of the radiolabel was 94.9±30.7%. Fecal elimination accounted for 92.6±30.7%, urinary elimination accounted for 2.3±1.1% and the elimination half-life based on radioactivity was 31.9±10.5 hours whereas it was 48.4±12.3 hours based on tacrolimus concentrations. The mean clearance of radiolabel was 0.226±0.116 L/hr/kg and clearance of tacrolimus 0.172±0.088 L/hr/kg.

Specific Populations  

Pediatric

Pharmacokinetics of tacrolimus have been studied in liver transplantation patients, 0.7 to 13.2 years of age. Following oral administration to 9 patients, mean AUC and Cmax were 337±167 ng·hr/mL and 48.4±27.9 ng/mL, respectively. The absolute bioavailability was 31±24%.

Whole blood trough concentrations from 31 patients less than 12 years old showed that pediatric patients needed higher doses than adults to achieve similar tacrolimus trough concentrations [see DOSAGE AND ADMINISTRATION (2.2)].

Pharmacokinetics of tacrolimus have also been studied in kidney transplantation patients, 8.2±2.4 years of age. Following oral administration, mean AUC and Cmax were 181±65 (range 81 to 300) ng·hr/mL and 30±11 (range 14 to 49) ng/mL, respectively. The absolute bioavailability was 19±14 (range 5.2 to 56) %.

Renal and Hepatic Impairment
The mean pharmacokinetic parameters for tacrolimus following single administrations to patients with renal and hepatic impairment are given in Table 13.

Table 13. Pharmacokinetic In Renal and Hepatic Impaired Patients
a corrected for bioavailability
b 1 patient did not receive the PO dose

Population

(No. of Patients)
Dose

AUC0-t

(ng·hr/mL)

t1/2

(hr)

V

(L/kg)

CI

L/hr/kg)

Renal

Impairment

(n=12)

0.02

mg/kg/4hr

IV

393±123

(t=60 hr)

26.3±9.2

1.07

±0.20

0.038

±0.014

Mild Hepatic

Impairment

(n=6)

0.02

mg/kg/4hr

IV

367±107

(t=72 hr)

60.6±43.8

Range: 27.8 to 141

3.1±1.6

0.042

±0.02

7.7 mg

PO

488±320

(t=72 hr)

66.1±44.8

Range: 29.5 to 138
3.7±4.7a

0.034

±0.019a

Severe

Hepatic

Impairment

(n=6, IV)

0.02 mg/kg/4hr

IV (n=2)

0.01 mg/kg/8hr

IV (n=4)

762±204

(t=120 hr)

289±117

(t=144 hr)

198±158

Range: 81 to 436

3.9±1

0.017

±0.013

(n=5, PO)b

8 mg PO

(n=1)

5 mg PO

(n=4)

4 mg PO

(n=1)

658

(t=120 hr)

533±156 (t=144 hr)

119±35

Range: 85 to 178
3.1±3.4a

0.016

±0.011a
Renal Impairment: Tacrolimus pharmacokinetics following a single IV administration were determined in 12 patients (7 not on dialysis and 5 on dialysis, serum creatinine of 3.9±1.6 and 12±2.4 mg/dL, respectively) prior to their kidney transplant. The pharmacokinetic parameters obtained were similar for both groups. The mean clearance of tacrolimus in patients with renal dysfunction was similar to that in normal volunteers (Table 15) [see DOSAGE AND ADMINISTRATION (2.3) and USE IN SPECIFIC POPULATIONS (8.6)].

Hepatic Impairment: Tacrolimus pharmacokinetics have been determined in six patients with mild hepatic dysfunction (mean Pugh score: 6.2) following oral administrations. The mean clearance of tacrolimus in patients with mild hepatic dysfunction was not substantially different from that in normal volunteers (see previous table). Tacrolimus pharmacokinetics were studied in 6 patients with severe hepatic dysfunction (mean Pugh score: >10). The mean clearance was substantially lower in patients with severe hepatic dysfunction, irrespective of the route of administration [see DOSAGE AND ADMINISTRATION (2.4) and USE IN SPECIFIC POPULATIONS (8.7)].

Race
The pharmacokinetics of tacrolimus have been studied following single IV and oral administration of tacrolimus to 10 African-American, 12 Latino-American, and 12 Caucasian healthy volunteers. There were no significant pharmacokinetic differences among the three ethnic groups following a 4-hour IV infusion of 0.015 mg/kg. However, after single oral administration of 5 mg, mean (±SD) tacrolimus Cmax in African-Americans (23.6±12.1 ng/mL) was significantly lower than in Caucasians (40.2±12.6 ng/mL) and the Latino-Americans (36.2±15.8 ng/mL) (p<0.01). Mean AUC0-inf tended to be lower in African-Americans (203±115 ng·hr/mL) than Caucasians (344±186 ng·hr/mL) and Latino-Americans (274±150 ng·hr/mL). The mean (±SD) absolute oral bioavailability (F) in African-Americans (12±4.5%) and Latino-Americans (14±7.4%) was significantly lower than in Caucasians (19±5.8%, p=0.011). There was no significant difference in mean terminal T1/2 among the three ethnic groups (range from approximately 25 to 30 hours). A retrospective comparison of African-American and Caucasian kidney transplant patients indicated that African-American patients required higher tacrolimus doses to attain similar trough concentrations [see DOSAGE AND ADMINISTRATION (2.1)].

Gender
A formal trial to evaluate the effect of gender on tacrolimus pharmacokinetics has not been conducted, however, there was no difference 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.

Drug Interactions

Frequent monitoring of whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended when concomitant use of the following drugs with tacrolimus is initiated or discontinued [see DRUG INTERACTIONS (7)].

Nelfinavir: Based on a clinical study of 5 liver transplant recipients, co-administration of tacrolimus with nelfinavir increased blood concentrations of tacrolimus significantly and, as a result, a reduction in the tacrolimus dose by an average of 16-fold was needed to maintain mean trough tacrolimus blood concentrations of 9.7 ng/mL. It is recommended to avoid concomitant use of Hecoria (tacrolimus) capsules and nelfinavir unless the benefits outweigh the risks [see DRUG INTERACTIONS (7.3)].

Rifampin: In a study of 6 normal volunteers, a significant decrease in tacrolimus oral bioavailability (14±6% vs. 7±3%) was observed with concomitant rifampin administration (600 mg). In addition, there was a significant increase in tacrolimus clearance (0.036±0.008 L/hr/kg vs. 0.053±0.010 L/hr/kg) with concomitant rifampin administration [see DRUG INTERACTIONS(7.7 )].

Magnesium-aluminum-hydroxide: In a single-dose crossover study in healthy volunteers, co-administration of tacrolimus and magnesium-aluminum-hydroxide resulted in a 21% increase in the mean tacrolimus AUC and a 10% decrease in the mean tacrolimus Cmax relative to tacrolimus administration alone [see DRUG INTERACTIONS (7.10 )].

Ketoconazole: In a study of 6 normal volunteers, a significant increase in tacrolimus oral bioavailability (14±5% vs. 30±8%) was observed with concomitant ketoconazole administration (200 mg). The apparent oral clearance of tacrolimus during ketoconazole administration was significantly decreased compared to tacrolimus alone (0.430±0.129 L/hr/kg vs. 0.148±0.043 L/hr/kg). Overall, IV clearance of tacrolimus was not significantly changed by ketoconazole co-administration, although it was highly variable between patients [see DRUG INTERACTIONS (7.4)].

Voriconazole (see complete prescribing information for Voriconazole): Repeat oral dose administration of voriconazole (400 mg every 12 hours for one day, then 200 mg every 12 hours for 6 days) increased tacrolimus (0.1 mg/kg single dose) Cmax and AUCτ in healthy subjects by an average of 2-fold (90% CI: 1.9, 2.5) and 3-fold (90% CI: 2.7, 3.8), respectively [see DRUG INTERACTIONS (7.4)].

Posaconazole (see complete prescribing information for Noxafil®): Repeat oral administration of posaconazole (400 mg twice daily for 7 days) increased tacrolimus (0.05 mg/kg single dose) Cmax and AUC in healthy subjects by an average of 2-fold (90% CI: 2.01, 2.42) and 4.5-fold (90% CI 4.03, 5.19), respectively [see DRUG INTERACTIONS (7.4)].

Caspofungin (see complete prescribing information for CANCIDAS®): Caspofungin reduced the blood AUC0-12 of tacrolimus by approximately 20%, peak blood concentration (Cmax) by 16%, and 12-hour blood concentration (C12hr) by 26% in healthy adult subjects when tacrolimus (2 doses of 0.1 mg/kg 12 hours apart) was administered on the 10th day of CANCIDAS® 70 mg daily, as compared to results from a control period in which tacrolimus was admin


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原产地英文商品名:
HECORIA 5mg/cap 100caps/box
原产地英文药品名:
TACROLIMUS
中文参考商品译名:
HECORIA 5毫克/胶囊 100胶囊/盒
中文参考药品译名:
他克莫司
生产厂家中文参考译名:
诺华
生产厂家英文名:
NOVARTIS


---------------------------------------------------------------
原产地英文商品名:
HECORIA 1mg/cap 100caps/box
原产地英文药品名:
TACROLIMUS
中文参考商品译名:
HECORIA 1毫克/胶囊 100胶囊/盒
中文参考药品译名:
他克莫司
生产厂家中文参考译名:
诺华
生产厂家英文名:
NOVARTIS


---------------------------------------------------------------
原产地英文商品名:
HECORIA 0.5mg/cap 100caps/box
原产地英文药品名:
TACROLIMUS
中文参考商品译名:
HECORIA 0.5毫克/胶囊 100胶囊/盒
中文参考药品译名:
他克莫司
生产厂家中文参考译名:
诺华
生产厂家英文名:
NOVARTIS

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