tacrolimus 1 MG (as anhydrous tacrolimus) Oral Capsule

Generic Name: TACROLIMUS
Brand Name: Tacrolimus
  • Substance Name(s):
  • TACROLIMUS

DRUG INTERACTIONS

7 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 Tacrolimus 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: Can increase MPA exposure after crossover from cyclosporine to tacrolimus; monitor for MPA-related adverse reactions and adjust MMF or MPA-dose as needed (7.1) Nelfinavir and Grapefruit Juice: Increased tacrolimus concentrations via CYP3A inhibition; avoid concomitant use (7.2, 7.3) CYP3A Inhibitors: Increased tacrolimus concentrations; monitor concentrations and adjust tacrolimus dose as needed with concomitant use (5.13, 7.3, 7.4, 7.5, 7.6) CYP3A4 inducers: Decreased tacrolimus concentrations ; monitor concentrations and adjust tacrolimus dose as needed with concomitant use (5.13, 7.7, 7.8, 7.9) 7.1 Mycophenolic Acid Products With a given dose of mycophenolic acid (MPA) products, exposure to MPA is higher with Tacrolimus Capsules USP 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 Tacrolimus 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)].

Whole blood concentrations of tacrolimus are markedly increased when co-administered 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 are recommended when tacrolimus and other protease inhibitors (e.g., ritonavir, telaprevir, boceprevir) 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, amiodarone and methylprednisolone, and herbal products containing schisandra sphenanthera extracts 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.

OVERDOSAGE

10 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 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; (all based on body surface area corrections).

DESCRIPTION

11 Tacrolimus is available for oral administration as capsules (Tacrolimus Capsules USP) containing the equivalent of 0.5 mg, 1 mg or 5 mg of tacrolimus USP.

Inactive ingredients include anhydrous lactose, hypromellose 2910, croscarmellose sodium, and magnesium stearate.

The 0.5 mg capsule shell contains gelatin, titanium dioxide and ferric oxide, the 1 mg capsule shell contains gelatin and titanium dioxide, and the 5 mg capsule shell contains gelatin, titanium dioxide and ferric oxide.

Tacrolimus, previously known as FK506, is the active ingredient in Tacrolimus Capsules USP.

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 USP is: Tacrolimus USP has a molecular formula of C44H69NO12•H2O and a formula weight of 822.03.

Tacrolimus appears as white to off white powder.

It is soluble in acetone, chloroform, ethyl acetate and insoluble in water.

The Dissolution Test criteria of Tacrolimus Capsules USP as outlined below: Tacrolimus Capsules USP, 0.5 mg, 1 mg and 5 mg Complies with USP dissolution test 4 Tacrolimus Capsules USP comply with USP Organic Impurities test criteria as outlined below: Tacrolimus Capsules USP, 0.5 mg, 1 mg and 5 mg USP Procedure 1 and 2

CLINICAL STUDIES

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 Capsules USP /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% Hyperkalemia 31% 32% Diabetes mellitus 24% 9% Hypokalemia 22% 25% Hyperglycemia 22% 16% Edema 18% 19% Hemic and Lymphatic Anemia 30% 24% Leucopenia 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) Diarrhea Urinary tract infection Anemia Hypertension Leucopenia Edema peripheral Hyperlipidemia Tacrolimus Capsules USP (group C) (N=403) 25% 24% 17% 13% 13% 11% 10% Cyclosporine (Group A) (N=384) 16% 28% 19% 14% 10% 12% 15% Cyclosporine (Group B) (N=408) 13% 24% 17% 12% 10% 13% 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 Capsules USP / MMF (N=212) Cyclosporine / MMF (N=212) Gastrointestinal Disorder 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 Disorder Hypomagnesemia 28% 22% Hypophosphatemia 28% 21% Hyperkalemia 26% 19% Hyperglycemia 21% 15% Hyperlipidemia 18% 25% Hypokalemia 16% 18% Nervous System Disorder 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 to70), 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 and IV 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 Capsules USP (N=250) Cyclosporine/AZA (N=250) Tacrolimus Capsules USP (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% Vomitting 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 36% 20% 15% 7% Rash 24% 19% 10% 4% Less frequently observed adverse reactions in both liver transplantation and kidney transplantation patients are described under the subsection Less Frequently Reported Adverse Reactions .

Heart Transplantation The incidence of adverse reactions was determined based on two trials in primary orthotopic heart transplantation.

In a trial conducted in Europe, 314 patients received a regimen of antibody induction, corticosteroids and azathioprine (AZA) in combination with Tacrolimus (n=157) or cyclosporine (n=157) for 18 months.

The trial population had a mean age of 51 years (range 18 to 65), the distribution was 82% male, and the composition was White (96%), Black (3%) and other (1%).

The most common adverse reactions (≥ 15%) observed in tacrolimus-treated heart transplant patients are: abnormal renal function, hypertension, diabetes mellitus, CMV infection, tremor, hyperglycemia, leukopenia, infection, anemia, bronchitis, pericardial effusion, urinary tract infection and hyperlipemia.

Adverse reactions in heart transplant patients in the European trial are presented below: Table 8.

Heart Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus Capsules USP in Conjunction with Azathioprine (AZA) Tacrolimus Capsules USP/AZA (n=157) Cyclosporine/AZA (n=157) Cardiovascular System Hypertension 62% 69% Pericardial Effusion 15% 14% Body as a Whole CMV Infection 32% 30% Infection 24% 21% Metabolic and Nutritional Disorders Diabetes Mellitus 26% 16% Hyperglycemia 23% 17% Hyperlipemia 18% 27% Hemic and Lymphatic System Anemia 50% 36% Leukopenia 48% 39% Urogenital System Kidney Function Abnormal 56% 57% Urinary Tract Infection 16% 12% Respiratory System Bronchitis 17% 18% Nervous System Tremor 15% 6% In the European trial, the cyclosporine trough concentrations were above the pre-defined target range (i.e., 100 to 200 ng/mL) at Day 122 and beyond in 32 to 68% of the patients in the cyclosporine treatment arm, whereas the tacrolimus trough concentrations were within the pre-defined target range (i.e., 5 to 15 ng/mL) in 74 to 86% of the patients in the tacrolimus treatment arm.

In a U.S.

trial, the incidence of adverse reactions was based on 331 heart transplant patients that received corticosteroids and tacrolimus in combination with sirolimus (n=109), tacrolimus in combination with MMF (n=107) or cyclosporine modified in combination with MMF (n=115) for 1 year.

The trial population had a mean age of 53 years (range 18 to 75), the distribution was 78% male, and the composition was White (83%), Black (13%) and other (4%).

Only selected targeted treatment-emergent adverse reactions were collected in the U.S.

heart transplantation trial.

Those reactions that were reported at a rate of 15% or greater in patients treated with tacrolimus and MMF include the following: any target adverse reactions (99%), hypertension (89%), hyperglycemia requiring antihyperglycemic therapy (70%), hypertriglyceridemia (65%), anemia (hemoglobin 140 mg/dL (on two separate occasions) (61%), hypercholesterolemia (57%), hyperlipidemia (34%), WBCs <3000 cells/mcL (34%), serious bacterial infections (30%), magnesium <1.2 mEq/L (24%), platelet count <75,000 cells/mcL (19%), and other opportunistic infections (15%).

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 9 ) [see Clinical Studies (14.1)].

Table 9.

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 Capsules USP / 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 10 to 13.

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 10).

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 11 ).

Table 10.

Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 2 Years in Kidney Transplant Recipients in a Phase 3 Trial using Azathioprine (AZA) Status of PTDM 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.

Tacrolimus Capsules USP/AZA CsA/AZA Patients without pretransplant history of diabetes mellitus.

151 151 New onset PTDM 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.

, 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 PTDM 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.

post 1 year 1 0 Patients with PTDM 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.

at 2 years 16/151 (11%) 5/151 (3%) Table 11.

Development of Post-Transplant Diabetes Mellitus by Race or Ethnicity and by Treatment Group During First Year Post Kidney Transplantation in a Phase 3 Trial Patient Race Patients Who Developed PTDM 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.

Tacrolimus Capsules USP Cyclosporine Black 15/41 (37%) 3 (8%) Hispanic 5/17 (29%) 1 (6%) Caucasian 10/82 (12%) 1 (1%) Other 0/11 (0%) 1 (10%) Total 30/151 (20%) 6 (4%) 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 12).

Hyperglycemia was associated with the use of Tacrolimus Capsules USP 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 12.

Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 1 Year in Liver Transplant Recipients Status of PTDM 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.

US Trial European Trial Tacrolimus Capsules USP Cyclosporine Tacrolimus Capsules USP Cyclosporine Patients at risk b) Patients without pre-transplant history of diabetes mellitus 239 236 239 249 New Onset PTDM 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.

42 (18%) 30 (13%) 26 (11%) 12 (5%) Patients still on insulin at 1 year 23 (10%) 19 (8%) 18 (8%) 6 (2%) Heart Transplant Insulin-dependent PTDM was reported in 13% and 22% of tacrolimus-treated heart transplant patients receiving mycophenolate mofetil (MMF) or azathioprine (AZA) and was reversible in 30% and 17% of these patients at one year post-transplant, in the U.S.

and European randomized trials, respectively (Table 13).

Hyperglycemia defined as two fasting plasma glucose levels ≥126 mg/dL was reported with the use of tacrolimus plus MMF or AZA in 32% and 35% of heart transplant recipients in the U.S.

and European randomized trials, respectively, and may require treatment [see Adverse Reactions (6.1)].

Table 13.

Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 1 Year in Heart Transplant Recipients Status of PTDM a) Use of insulin for 30 or more consecutive days without a prior history of insulin-dependent diabetes mellitus or non- insulin dependent diabetes mellitus.

US Trial European Trial Tacrolimus Capsules USP/MMF Cyclosporine/MMF Tacrolimus Capsules USP/AZA Cyclosporine/AZA Patients at risk b) Patients without pre-transplant history of diabetes mellitus.

75 83 132 138 New Onset PTDM a) Use of insulin for 30 or more consecutive days without a prior history of insulin-dependent diabetes mellitus or non- insulin dependent diabetes mellitus.

10 (13%) 6 (7%) 29 (22%) 5 (4%) Patients still on insulin at 1 year c) 7-12 months for the U.S.

trial.

7 (9%) 1 (1%) 24 (18%) 4 (3%) Less Frequently Reported Adverse Reactions (>3% and <15%) The following adverse reactions were reported in either liver, kidney and/or heart 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

HOW SUPPLIED

16 / STORAGE AND HANDLING 16.1 Tacrolimus Capsules USP Tacrolimus Capsules USP, 0.5 mg: Light yellow color, oblong shape, size “5” hard gelatin capsules printed with “PBT” and “0.5” in red ink on cap and body respectively.

Capsules are supplied as follows: NDC 69452-153-20 Bottle of 100 Tacrolimus Capsules USP, 1 mg: White color, oblong shape, size “5” hard gelatin capsules printed with “PBT” and “1.0” in red ink on cap and body respectively.

Capsules are supplied as follows: NDC 69452-154-20 Bottle of 100 Tacrolimus Capsules USP, 5 mg: Pink color, oblong shape, size “4” hard gelatin capsules printed with “PBT” and “5.0” in red ink on cap and body respectively.

Capsules are supplied as follows: NDC 69452-155-20 Bottle of 100 Storage: Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F)

DOSAGE FORMS AND STRENGTHS

3 Oblong shape, hard gelatin capsules for oral administration contains tacrolimus USP as follows: Tacrolimus Capsules USP, 0.5 mg: Light yellow color, oblong shape , size “5” hard gelatin capsules printed with “PBT” and “0.5” in red ink on cap and body respectively.

Tacrolimus Capsules USP, 1 mg: White color, oblong shape, size “5” hard gelatin capsules printed with “PBT” and “1.0” in red ink on cap and body respectively.

Tacrolimus Capsules USP, 5 mg: Pink color, oblong shape, size “4” hard gelatin capsules printed with “PBT” and “5.0” in red ink on cap and body respectively.

Capsules: 0.5 mg, 1 mg and 5 mg (3)

INDICATIONS AND USAGE

1 Tacrolimus Capsules USP is a calcineurin-inhibitor immunosuppressant indicated for Prophylaxis of organ rejection in patients receiving allogeneic liver, kidney or heart transplants (1.1, 1.2, 1.3) Use concomitantly with adrenal corticosteroids; in kidney and heart transplant, use in conjunction with azathioprine or mycophenolate mofetil (MMF) (1.1, 1.2, 1.3) Limitations of Use (1.4): Do not use simultaneously with cyclosporine.

Intravenous use reserved for patients who can not tolerate capsules orally.

Use with sirolimus is not recommended in liver and heart transplant; use with sirolimus in kidney transplant has not been established.

1.1 Prophylaxis of Organ Rejection in Kidney Transplant Tacrolimus Capsules USP are indicated for the prophylaxis of organ rejection in patients receiving allogeneic kidney transplants.

It is recommended that Tacrolimus 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 Tacrolimus Capsules USP [see Dosage and Administration (2.6)].

1.2 Prophylaxis of Organ Rejection in Liver Transplant Tacrolimus Capsules USP are indicated for the prophylaxis of organ rejection in patients receiving allogeneic liver transplants.

It is recommended that Tacrolimus be used concomitantly with adrenal corticosteroids [see Clinical Studies (14.2)].

Therapeutic drug monitoring is recommended for all patients receiving Tacrolimus Capsules USP [see Dosage and Administration (2.6)].

1.3 Prophylaxis of Organ Rejection in Heart Transplant Tacrolimus Capsules USP are indicated for the prophylaxis of organ rejection in patients receiving allogeneic heart transplants.

It is recommended that Tacrolimus Capsules USP 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 Tacrolimus Capsules USP [see Dosage and Administration (2.6)].

1.4 Limitations of Use 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 Tacrolimus Capsules USP orally [see Dosage and Administration (2.1) and see Warnings and Precautions (5.11)].

Use with sirolimus is not recommended in liver and heart transplant.

The safety and efficacy of Tacrolimus with sirolimus has not been established in kidney transplant [see Warnings and Precautions (5.12)].

BOXED 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 Tacrolimus Capsules USP.

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)] .

WARNING: MALIGNANCIES AND SERIOUS INFECTIONS See full prescribing information for complete boxed warning Increased risk of development of lymphoma and other malignancies, particularly of the skin, due to immunosuppression (5.2) Increased susceptibility to bacterial, viral, fungal, and protozoal infections, including opportunistic infections (5.3, 5.4, 5.5) Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should prescribe Tacrolimus Capsules USP (5.1)

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Lymphoma and Other Malignancies: Risk of lymphomas, including post transplant lymphoproliferative disorder (PLTD); appears related to intensity and duration of use.

Avoid prolonged exposure to UV light and sunlight (5.2) Serious infections: Increased risk of bacterial, viral, fungal and protozoal infections, including opportunistic infections: combination immunosuppression should be used with caution (5.3) Polyoma Virus Infections: Serious, sometimes fatal outcomes, including polyoma virus-associated nephropathy (PVAN), mostly due to BK virus, and JC virus-associated progressive multifocal leukoencephalopathy (PML); consider reducing immunosuppression (5.4) Cytomegalovirus (CMV) Infections: Increased risk of CMV viremia and disease; consider reducing immunosuppression (5.5) New Onset Diabetes After Transplant: Monitor blood glucose (5.6) Nephrotoxicity: Acute and/or chronic; reduce the dose; use caution with other nephrotoxic drugs (5.7) Neurotoxicity: Risk of Posterior Reversible Encephalopathy Syndrome, monitor for neurologic abnormalities; reduce or discontinue Tacrolimus Capsules USP and other immunosuppressants (5.8) Hyperkalemia: Monitor serum potassium levels.

Careful consideration should be given prior to use of other agents also associated with hyperkalemia (5.9) Hypertension: May require antihypertensive therapy.

Monitor relevant drug-drug interactions (5.10) Anaphylactic Reactions with IV formulation: Observe patients receiving Tacrolimus injection for signs and symptoms of anaphylaxis (5.11) Use with Sirolimus: Not recommended in liver and heart transplant due to increased risk of serious adverse reactions (5.12) Myocardial Hypertrophy: Consider dosage reduction or discontinuation (5.15) Immunizations: Use of live vaccines should be avoided (5.16) Pure Red Cell Aplasia: Discontinuation should be considered (5.17) 5.1 Management of Immunosuppression Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should use Tacrolimus Capsules USP.

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 Boxed Warning].

5.2 Lymphoma and Other Malignancies Patients receiving immunosuppressants, including Tacrolimus Capsules USP, are at increased risk of developing lymphomas and other malignancies, particularly of the skin [see Boxed 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 Tacrolimus Capsules USP, are at increased risk of developing bacterial, viral, fungal, and protozoal infections, including opportunistic infections [see Boxed 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 Tacrolimus Capsules USP, 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 Tacrolimus Capsules USP.

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 Tacrolimus Capsules USP, 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 Capsules USP was shown to cause new onset diabetes mellitus in clinical trials of kidney, liver, and heart 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 tacrolimus [see Adverse Reactions (6.1)].

5.7 Nephrotoxicity Tacrolimus Capsules USP, 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 Capsules USP 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 Capsules USP in the U.S.

and European randomized trials, respectively, and in 59% of heart transplantation patients in a European randomized trial [see Adverse Reactions (6.1)].

Due to the potential for additive or synergistic impairment of renal function, care should be taken when administering Tacrolimus Capsules USP 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 Tacrolimus Capsules USP 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 tacrolimus [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 Tacrolimus Capsules USP 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 tacrolimus therapy [see Adverse Reactions (6.1)].

5.10 Hypertension Hypertension is a common adverse effect of tacrolimus 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 tacrolimus [see Drug Interactions (7.5)].

5.11 Anaphylactic Reactions with Tacrolimus Injection Anaphylactic reactions have occurred with injectables containing castor oil derivatives, including Tacrolimus Capsules USP, 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 USP [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 tacrolimus 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)].

Use of sirolimus (2 mg per day) with tacrolimus in heart transplant patients in a U.S.

trial was associated with increased risk of renal function impairment, wound healing complications, and insulin-dependent post-transplant diabetes mellitus, and is not recommended [see Clinical Studies (14.3)].

5.13 Use with CYP3A4 Inhibitors and Inducers When coadministering Tacrolimus with strong CYP3A4-inhibitors (e.g., telaprevir, boceprevir, ritonavir, ketoconazole, itraconazole, voriconazole, clarithromycin) and strong inducers (e.g., rifampin, rifabutin) adjustments in the dosing regimen of Tacrolimus and subsequent frequent monitoring of tacrolimus whole blood trough concentrations and tacrolimus-associated adverse reactions are recommended [see Drug Interactions (7)].

5.14 QT Prolongation Tacrolimus may prolong the QT/QTc interval and may cause Torsade de Pointes.

Avoid Tacrolimus in patients with congenital long QT syndrome.

In patients with congestive heart failure, bradyarrhythmias, those taking certain antiarrhythmic medications or other medicinal products that lead to QT prolongation, and those with electrolyte disturbances such as hypokalemia, hypocalcemia, or hypomagnesemia, consider obtaining electrocardiograms and monitoring electrolytes (magnesium, potassium, calcium) periodically during treatment.

When coadministering tacrolimus with other substrates and/or inhibitors of CYP3A4 that also have the potential to prolong the QT interval, a reduction in tacrolimus dose, frequent monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended.

Use of tacrolimus with amiodarone has been reported to result in increased tacrolimus whole blood concentrations with or without concurrent QT prolongation [see Drug Interactions (7)].

5.15 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 Tacrolimus Capsules USP should be considered [see Adverse Reactions (6.2)].

5.16 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.

5.17 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 Tacrolimus Capsules USP should be considered [see Adverse Reactions ( 6.2 )].

5.18 Gastrointestinal Perforation Gastrointestinal perforation has been reported in patients treated with Tacrolimus; all reported cases were considered to be a complication of transplant surgery or accompanied by infection, diverticulum, or malignant neoplasm.

As gastrointestinal perforation may be serious or life-threatening, appropriate medical/surgical management should be instituted promptly [see Adverse Reactions ( 6.1 )].

DOSAGE AND ADMINISTRATION

2 Summary of Initial Oral Dosage Recommendation and Observed Whole Blood Trough Concentrations (2.1, 2.2).

Patient Population Recommended Initial Oral Dosage (two divided doses every 12 hours) Observed Whole Blood Trough Concentrations Adult Kidney transplant In combination with azathioprine In combination with MMF/IL-2 receptor antagonist 0.2 mg/kg/day 0.1 mg/kg/day month 1-3: 7-20 ng/mL month 4-12: 5-15 ng/mL month 1-12: 4-11 ng/mL Adult Liver transplant Pediatric Liver transplant 0.10-0.15 mg/kg/day 0.15-0.20 mg/kg/day month 1-12: 5-20 ng/mL month 1-12: 5-20 ng/mL Adult Heart transplant 0.075 mg/kg/day month 1-3: 10-20 ng/mL month ≥4: 5-15 ng/mL Careful and frequent monitoring of tacrolimus trough concentrations is recommended; Black patients may require higher doses in order to achieve comparable trough concentrations (2.1) Hepatic/Renal impaired patients should receive doses at the lowest value of recommended initial oral dosing range (2.3, 2.4) Administer capsules consistently with or without food; do not drink grapefruit juice (2.5, 7.2) 2.1 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 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 Tacrolimus Capsules USP 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 Tacrolimus Capsules USP 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 In combination with MMF/IL-2 receptor antagonist a 0.2 mg/kg/day 0.1 mg/kg/day month 1-3: 7-20 ng/mL month 4-12: 5-15 ng/mL month 1-12: 4-11 ng/mL Adult liver transplant patients 0.10-0.15 mg/kg/day month 1-12: 5-20 ng/mL Adult heart transplant patients 0.075 mg/kg/day month 1-3: 10-20 ng/mL month ≥4: 5-15 ng/mL a) In a second smaller trial, the initial dose of tacrolimus was 0.15-0.2 mg/kg/day and observed tacrolimus concentrations were 6-16 ng/mL during month 1-3 and 5-12 ng/mL during month 4-12 [see Clinical Studies (14.1)].

Dosing should be titrated based on clinical assessments of rejection and tolerability.

Lower tacrolimus 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 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 11.0 Initial Dose – Injection Tacrolimus injection should be used only as a continuous IV infusion and when the patient cannot tolerate oral administration of Tacrolimus Capsules USP.

Tacrolimus injection should be discontinued as soon as the patient can tolerate oral administration of Tacrolimus Capsules USP, usually within 2-3 days.

In a patient receiving an IV infusion, the first dose of oral therapy should be given 8-12 hours after discontinuing the IV infusion.

The observed trough concentrations described above pertain to oral administration of Tacrolimus Capsules USP only; while monitoring tacrolimus 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 0.03-0.05 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)].

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 0.03-0.05 mg/kg/day.

Table 3.

Summary of Initial Oral Dosage Recommendations and Observed Whole Blood Trough Concentrations in Children Patient Population Recommended Tacrolimus Capsules USP 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- 0.20 mg/kg/day Month 1-12: 5-20 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 and heart 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 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 Tacrolimus Capsules USP 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 Tacrolimus.

Close monitoring of blood concentrations is warranted.

The use of Tacrolimus Capsules USP 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 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 Tacrolimus Capsules USP consistently every day either with or without food because the presence and composition of food decreases the bioavailability of tacrolimus [see Clinical Pharmacology (12.3)].

Patients should not eat grapefruit or drink grapefruit juice in combination with tacrolimus [see Drug Interactions (7.2)].

Tacrolimus Capsules USP should not be used simultaneously with cyclosporine.

Tacrolimus Capsules USP or cyclosporine should be discontinued at least 24 hours before initiating the other.

In the presence of elevated tacrolimus or cyclosporine concentrations, dosing with the other drug usually should be further delayed.

In patients unable to take oral 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 Capsules USP is recommended as soon as oral therapy can be tolerated.

This usually occurs within 2-3 days.

In patients receiving an IV infusion, the first dose of oral therapy should be given 8-12 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.