tacrolimus 5 MG (as anhydrous tacrolimus) Oral Capsule
Generic Name: TACROLIMUS
Brand Name: Tacrolimus
- Substance Name(s):
- TACROLIMUS
DRUG INTERACTIONS
7 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 ) CYP3A Inhibitors: Increased tacrolimus concentrations; monitor concentrations and adjust tacrolimus dose as needed.
( 5.11 , 7.2 ) CYP3A4 Inducers: Decreased tacrolimus concentrations; monitor concentrations and adjust tacrolimus dose as needed.
( 5.11 , 7.2 ) 7.1 Mycophenolic Acid When tacrolimus is prescribed with a given dose of a mycophenolic acid (MPA) product, 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.
Monitor for MPA associated adverse reactions and reduce the dose of concomitantly administered mycophenolic acid products as needed.
7.2 Effects of Other Drugs on Tacrolimus Table 15 displays the effects of other drugs on tacrolimus.
Table 15: Effects of Other Drugs/Substances on Tacrolimus* Drug/Substance Class or Name Drug Interaction Effect Recommendations Grapefruit or grapefruit juice † May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see Warnings and Precautions ( 5.6 , 5.11 , 5.12 )].
Avoid grapefruit or grapefruit juice.
Strong CYP3A Inducers # : Antimycobacterials (e.g., rifampin, rifabutin),anticonvulsants (e.g., phenytoin, carbamazepine and phenobarbital), St John’s Wort May decrease tacrolimus whole blood trough concentrations and increase the risk of rejection [see Warnings and Precautions ( 5.11 )].
Increase tacrolimus dose and monitor tacrolimus whole blood trough concentrations [see Dosage and Administration (2.2, 2.6 ) and Clinical Pharmacology ( 12.3 )].
Strong CYP3A Inhibitors # : Protease inhibitors (e.g, nelfinavir, telaprevir, boceprevir, ritonavir), azole antifungals (e.g., voriconazole, posaconazole, itraconazole, ketoconazole), antibiotics (e.g., clarithromycin, troleandomycin, chloramphenicol), nefazodone, schisandra sphenanthera extracts May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see Warnings and Precautions ( 5.6 , 5.11 , 5.12 )].
Reduce tacrolimus dose (for voriconazole and posaconazole, give one-third of the original dose) and adjust dose based on tacrolimus whole blood trough concentrations [see Dosage and Administration ( 2.2 , 2.6 ) and Clinical Pharmacology ( 12.3 )].
Mild or Moderate CYP3A Inhibitors: Clotrimazole, antibiotics (e.g., erythromycin, fluconazole), calcium channel blockers (e.g., verapamil, diltiazem, nifedipine, nicardipine), amiodarone, danazol, ethinyl estradiol, cimetidine, lansoprazole and omeprazole May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see Warnings and Precautions ( 5.6 , 5.11 , 5.12 )].
Monitor tacrolimus whole blood trough concentrations and reduce tacrolimus dose if needed [see Dosage andAdministration ( 2.2 , 2.6 ) and Clinical Pharmacology ( 12.3 )].
Other drugs, such as: Magnesium and aluminum hydroxideantacids Metoclopramide May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see Warnings and Precautions ( 5.6 , 5.11 , 5.12 )].
Monitor tacrolimus whole blood trough concentrations and reduce tacrolimus dose if needed [see Dosage and Administration ( 2.2 , 2.6 ) and Clinical Pharmacology ( 12.3 )].
Mild or Moderate CYP3A Inducers Methylprednisolone, prednisone May decrease tacrolimus concentrations Monitor tacrolimus whole blood trough concentrations and adjust tacrolimus dose if needed [see Dosage and Administration ( 2.2 , 2.6 )].
* Tacrolimus dosage adjustment recommendation based on observed effect of coadministered drug on tacrolimus exposures [see Clinical Pharmacology ( 12.3 )] , literature reports of altered tacrolimus exposures, or the other drug’s known CYP3A inhibitor/inducer status.
† High dose or double strength grapefruit juice is a strong CYP3A inhibitor; low dose or single strength grapefruit juice is a moderate CYP3A inhibitor.
# Strong CYP3A inhibitor/inducer, based on reported effect on exposures to tacrolimus along with supporting in vitro CYP3A inhibitor/inducer data, or based on drug-drug interaction studies with midazolam (sensitive CYP3A probe substrate).
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 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).
DESCRIPTION
11 Tacrolimus, previously known as FK506, is the active ingredient in Tacrolimus Capsules.
Tacrolimus is a calcineurin-inhibitor 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)-1methylethenyl]-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 an empirical formula of C 44 H 69 NO 12 H 2 O 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.
Tacrolimus Capsules, USP are available for oral administration as capsules (tacrolimus capsules) containing the equivalent of 0.5 mg, 1 mg or 5 mg of tacrolimus USP.
Inactive ingredients include croscarmellose sodium NF, hypromellose USP, lactose anhydrous USNF, and magnesium stearate USNF.
The 0.5 mg capsule shell contains ferric oxide, gelatin and titanium dioxide.
The 1 mg capsule shell contains gelatin and titanium dioxide .
The 5 mg capsule shell contains ferric oxide, gelatin, and titanium dioxide.
structure
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 Transplantation 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 a 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%), African-American (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.
Based on reported adverse reactions terms related to decreased renal function, nephrotoxicity was reported in approximately 52% of kidney transplantation patients.
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% Hyperkalemia 31% 32% Diabetes Mellitus 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 Capsules USP (Group C) (N=403) Cyclosporine (Group A) (N=384) Cyclosporine (Group B) (N=408) Diarrhea 25% 16% 13% Urinary tract infection 24% 28% 24% Anemia 17% 19% 17% Hypertension 13% 14% 12% Leucopenia 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 MMF1 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%), African-American (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 kidney transplantation patients are described under the subsection “Less Frequently Reported Adverse Reactions (> 3% and < 15%) in Liver, Kidney, and Heart Transplant Studies”.
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%), African-American (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.
Based on reported adverse reactions terms related to decreased renal function, nephrotoxicity was reported in approximately 40% and 36% of liver transplantation patients receiving tacrolimus in the U.S.
and European randomized trials.
Table 7.
Liver Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus U.S .
TRIAL EUROPEAN TRIAL Tacrolimus (N=250) C yclosporine/AZA (N=250) T acrolimus (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 36% 20% 15% 7% Rash 24% 19% 10% 4% Table 8.
Pediatric Liver Transplantation: Adverse Reactions Occurring in > 10% of Patients Treated with Tacrolimus Granules (STUDY 01-13) Tacrolimus Granules (N=91) Cyclosporine (N=90) Body as a Whole Fever 46% 51% Infection 25% 29% Sepsis 22% 20% CMV Infection 15% 24% EBV Infection 26% 11% Ascites 17% 20% Peritonitis 12% 7% Cardiovascular System Hypertension 39% 47% Digestive System Liver Function Tests Abnormal 37% 28% Diarrhea 26% 26% Vomiting 15% 13% Gastrointestinal Hemorrhage 11% 12% Bile Duct Disorder 12% 8% Gastroenteritis 12% 4% Hemic and Lymphatic System Anemia 29% 19% Metabolic and Nutritional Disorders Hypomagnesemia 40% 29% Acidosis 26% 17% Hyperkalemia 12% 10% Respiratory System Pleural Effusion 22% 19% Bronchitis 11% 8% Urogenital System Kidney Function Abnormal 13% 14% Less frequently observed adverse reactions in liver transplantation patients are described under the subsection “Less Frequently Reported Adverse Reactions (> 3% and < 15%) in Liver, Kidney, and Heart Transplant Studies” 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.
Based on reported adverse reactions terms related to decreased renal function, nephrotoxicity was reported in approximately 59% of heart transplantation patients in the European trial.
Adverse reactions in heart transplant patients in the European trial are presented below: Table 9.
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%), African-American (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.
Other less frequently observed adverse reactions in heart transplantation patients are described under the subsection “Less Frequently Reported Adverse Reactions (> 3% and < 15%) in Liver, Kidney and Heart Transplant Studies.” New Onset Diabetes After Transplant Kidney Transplantation 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 10 ) [see Clinical Studies ( 14.1 ).
Table 10.
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 criterion 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 11 to 14.
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 11 ).
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.
African-American and Hispanic kidney transplant patients were at an increased risk of development of PTDM ( Table 12 ).
Table 11.
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* Tacrolimus/AZA CsA/AZA Patients without pretransplant history of diabetes mellitus.
151 151 New onset PTDM * , 1 st 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 * post 1 year 1 0 Patients with PTDM * at 2 years 16/151 (11%) 5/151 (3%) *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.
T able 12.
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 * Tacrolimus Cyclosporine African-American 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%) * 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.
Liver Transplantation 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 13 ).
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 13.
Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 1 Year in Liver Transplant Recipients Status of PTDM * US Trial European Trial Tacrolimus Cyclosporine Tacrolimus Cyclosporine Patients at risk † 239 236 239 249 New Onset PTDM * 42 (18%) 30 (13%) 26 (11%) 12 (5%) Patients still on insulin at 1 year 23 (10%) 19 (8%) 18 (8%) 6 (2%) *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.
† Patients without pre-transplant history of dibetes mellitus .
Heart Transplantation 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 14 ).
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 14.
Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 1 Year in Heart Transplant Recipients Status of PTDM* US Trial European Trial Tacrolimus MMF Cyclosporine/MM F Tacrolimus/AZA Cyclosporine/AZA Patients at risk † 75 83 132 138 New Onset PTDM* 10 (13%) 6 (7%) 29 (22%) 5 (4%) Patients still on insulin at 1 year ‡ 7 (9%) 1 (1%) 24 (18%) 4 (3%) * Use of insulin for 30 or more consecutive days without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus.
† Patients without pre-transplant history of diabetes mellitus.
‡ 7-12 months for the U.S.
trial.
Less Frequently Reported Adverse Reactions (> 3% and < 15%) in Liver, Kidney, and Heart Transplant Studies 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 (5.6)] : Abnormal dreams, agitation, amnesia, anxiety, confusion, convulsion, crying, depression, elevated mood, emotional lability, encephalopathy, hemorrhagic 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, esophagitis ulcerative, oral moniliasis, pancreatic pseudocyst, stomatitis Cardiovascular: Abnormal ECG, angina pectoris, arrhythmia, atrial fibrillation, atrial flutter, bradycardia, cardiac fibrillation, cardiopulmonary failure, congestive heart failure, deep thrombophlebitis, echocardiogram abnormal, electrocardiogram QRS complex abnormal, electrocardiogram ST segment abnormal, heart failure, heart rate decreased, hemorrhage, hypotension, phlebitis, postural hypotension, syncope, tachycardia, thrombosis, vasodilatation Urogenital: Acute kidney failure [see Warnings and Precautions ( 5.5 )] , 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, hematocrit increased, hypochromic anemia, leukocytosis, polycythemia, prothrombin decreased, serum iron decreased Miscellaneous: Abdomen enlarged, abscess, accidental injury, allergic reaction, cellulitis, chills, fall, flu syndrome, generalized edema, hernia, mobility decreased, peritonitis, photosensitivity reaction, sepsis, temperature intolerance, ulcer Musculoskeletal: Arthralgia, cramps, generalized spasm, leg cramps, myalgia, myasthenia, osteoporosis Respiratory: Asthma, emphysema, hiccups, lung function decreased, pharyngitis, pneumonia, pneumothorax, pulmonary edema, rhinitis, sinusitis, voice alteration Skin: Acne, alopecia, exfoliative dermatitis, fungal dermatitis, herpes simplex, herpes zoster, hirsutism, neoplasm skin benign, skin discoloration, 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 Note: Tacrolimus capsule are not filled to maximum capsule capacity.
Capsule contains labeled amount.
Store and Dispense Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature].
16.4 Handling and Disposal Tacrolimus can cause fetal harm.
Tacrolimus capsules should not be opened or crushed.
Avoid inhalation or direct contact with skin or mucous membranes of the powder contained in tacrolimus capsules.
If such contact occurs wash the skin thoroughly with soap and water; if ocular contact occurs, rinse eyes with water.
In case a spill occurs, wipe the surface with a wet paper towel.
Follow applicable special handling and disposal procedures 1 .
GERIATRIC USE
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.
DOSAGE FORMS AND STRENGTHS
3 Tacrolimus Capsules, USP are available in the following dosage form and strengths: Oblong shape, hard gelatin capsules for oral administration contains tacrolimus 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 body and cap 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 body and cap 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 body and cap respectively.
Capsules: 0.5 mg, 1 mg and 5 mg ( 3 )
MECHANISM OF ACTION
12.1 Mechanism of Action Tacrolimus binds to an intracellular protein, FKBP-12.
A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin (a ubiquitous mammalian intracellular enzyme) is then formed, after which the phosphatase activity of calcineurin inhibited.
Such inhibition prevents the dephosphorylation and translocation of various factors such as the nuclear factor of activated T-cells (NF-AT), and nuclear factor kappa-light-chain enhancer of activated B-cells (NF-κB).
Tacrolimus inhibits the expression and/or production of several cytokines that include interleukin (IL)-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, gamma interferon, tumor necrosis factor-alpha, and granulocyte macrophage colony stimulating factor.
Tacrolimus also inhibits IL-2 receptor expression and nitric oxide release, induces apoptosis and production of transforming growth factor beta that can lead to immunosuppressive activity.
The net result is the inhibition of T-lymphocyte activation and proliferation as well as T-helper-cell-dependent B-cell response (i.e., immunosuppression).
INDICATIONS AND USAGE
1 Tacrolimus Capsules are a calcineurin-inhibitor immuno-suppressant indicated for the prophylaxis of organ rejection in adult and pediatric patients receiving allogeneic liver, kidney or heart transplants, in combination with other immunosuppressants.
( 1.1 ) 1.1 Prophylaxis of Organ Rejection in Kidney, Liver, and Heart Transplant Tacrolimus Capsules is indicated for the prophylaxis of organ rejection, in patients receiving allogeneic kidney transplant [see Clinical Studies ( 14.1 )] , liver transplants [see Clinical Studies ( 14.2 )] and heart transplant [see Clinical Studies ( 14.3 )] , in combination with other immunosuppressants.
PEDIATRIC USE
8.4 Pediatric Use Safety and effectiveness have been established in pediatric liver, kidney, and heart transplant patients.
Liver transplant: Safety and efficacy using tacrolimus Granules in pediatric de novo liver transplant patients less than 16 years of age are based on evidence from active controlled studies that included 56 pediatric patients, 31 of which received tacrolimus and supported by two pharmacokinetic and safety studies in 151 children who received tacrolimus.
Additionally, 122 pediatric patients were studied in an uncontrolled trial of tacrolimus in living related donor liver transplantation.
Dose adjustments were made in the PK studies based on clinical status and whole blood concentrations.
Pediatric patients generally required higher doses of tacrolimus to maintain blood trough concentrations of tacrolimus similar to adult patients [see Dosage and Administration ( 2.3 ), Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3 ) and Clinical Studies ( 14.2 )].
Kidney and heart transplant: Use of Tacrolimus capsules and tacrolimus Granules in pediatric kidney and heart transplant patients is supported by adequate and well-controlled studies and pharmacokinetic data in adult kidney and heart transplant patients with additional pharmacokinetic data in pediatric kidney and heart transplant patients and safety data in pediatric liver transplant patients [see Dosage and Administration ( 2.3 ) and Clinical Pharmacology ( 12.3 )].
BOXED WARNING
– MALIGNANCIES AND SERIOUS INFECTIONS Increased risk for developing serious infections and malignancies with tacrolimus or other immunosuppressants that may lead to hospitalization or death.
( 5.1 , 5.2 ) WARNING: MALIGNANCIES AND SERIOUS INFECTIONS See full prescribing information for complete boxed warning Increased risk for developing serious infections and malignancies with tacrolimus capsules or other immunosuppressants that may lead to hospitalization or death.
(5.1 , 5.2 )
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Not Interchangeable with Extended Release Tacrolimus Products- Medication Errors: Instruct patients or caregivers to recognize the appearance of tacrolimus capsules ( 5.3 ) New Onset Diabetes After Transplant: Monitor blood glucose.
( 5.4 ) Nephrotoxicity: (acute and/or chronic); Reduce the dose; use caution with other nephrotoxic drugs.
( 5.5 ) Neurotoxicity: Including risk of Posterior Reversible Encephalopathy Syndrome (PRES); monitor for neurologic abnormalities; reduce or discontinue tacrolimus capsules and other immunosuppressants.
( 5.6 ) Hyperkalemia: Monitor serum potassium levels.
Consider carefully before using with other agents also associated with hyperkalemia.
( 5.7 ) Hypertension: May require antihypertensive therapy.
Monitor relevant drug-drug interactions.
( 5.8 ) Anaphylactic Reactions with IV formulation: Observe patients receiving tacrolimus injection for signs and symptoms of anaphylaxis.
( 5.9 ) Not recommended for use with Sirolimus: Not recommended in liver and heart transplant due to increased risk of serious adverse reactions.
( 5.10 ) Myocardial Hypertrophy: Consider dose reduction/ discontinuation.
( 5.13 ) Immunizations: Avoid live vaccines.
( 5.14 ) Pure Red Cell Aplasia: Consider discontinuation of tacrolimus capsules.
( 5.15 ) 5.1 Lymphoma and Other Malignancies Patients receiving immunosuppressants, including Tacrolimus 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, examine patients for skin changese; xposure to sunlight and UV light should be limited by wearing protective clothing and using a broad spectrum 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.
Monitor EBV serology during treatment.
5.2 Serious Infections Patients receiving immunosuppressants, including tacrolimus are at increased risk of developing bacterial, viral, fungal, and protozoal infections, including opportunistic infections.
These infections may lead to serious, including fatal, outcomes.
Serious viral infections reported include: Polyoma virus-associated nephropathy (PVAN), mostly due to BK virus infection JC virus-associated progressive multifocal leukoencephalopathy (PML) Cytomegalovirus infections: CMV seronegative transplant patients who receive an organ from a CMV seropositive donor disease are at higher risk of developing CMV viremia and CMV disease.
Monitor for the development of infection and adjust the immunosuppressive regimen to balance the risk of rejection with the risk of infection [see Adverse Reactions ( 6.1 , 6.2 )].
5.3 Not Interchangeable With Extended-Release Tacrolimus Products – Medication Errors Medication errors, including substitution and dispensing errors, between tacrolimus immediate-release products and tacrolimus extended-release products were reported outside the U.S.
This led to serious adverse reactions, including graft rejection, or other adverse reactions due to under-or over-exposure to tacrolimus.
Tacrolimus is not interchangeable or substitutable with tacrolimus extended-release products.
Changes between tacrolimus immediate-release and extended-release dosage forms must occur under physician supervision.
Instruct patients and caregivers to recognize the appearance of tacrolimus capsules dosage forms [see Dosage Forms and Strengths ( 3 )] and to confirm with the healthcare provider if a different product is dispensed.
5.4 New Onset Diabetes After Transplant Tacrolimus 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.
African-American 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 )] .
5.5 Nephrotoxicity Tacrolimus like other calcineurin inhibitors, can cause acute or chronic nephrotoxicity.
Nephrotoxicity was reported in clinical trials [see Adverse Reactions ( 6.1 )].
Consider dosage reduction in patients with elevated serum creatinine and tacrolimus whole blood trough concentrations greater than the recommended range.
The risk for nephrotoxicity may increase when tacrolimus is concomitantly administered with CYP3A inhibitors (by increasing tacrolimus whole blood concentrations) or drugs associated with nephrotoxicity (e.g., aminoglycosides, ganciclovir, amphotericin B, cisplatin, nucleotide reverse transcriptase inhibitors, protease inhibitors) [see Drug Interactions ( 7.2 )] .
Monitor renal function and consider dosage reduction if nephrotoxicity occurs.
5.6 Neurotoxicity Tacrolimus may cause a spectrum of neurotoxicities.
The most severe neurotoxicities include posterior reversible encephalopathy syndrome (PRES), delirium, seizure and coma; others include tremors, paresthesias, headache, mental status changes, and changes in motor and sensory functions [see Adverse Reactions ( 6.1 , 6.2 )] .
As symptoms may be associated with tacrolimus whole blood trough concentrations at or above the recommended range, monitor for neurologic symptoms and consider dosage reduction or discontinuation of tacrolimus capsules if neurotoxicity occurs.
5.7 Hyperkalemia Hyperkalemia has been reported with tacrolimus 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 )] .
Monitor serum potassium levels periodically during treatment 5.8 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 ( 5.7 )].
Calcium-channel blocking agents may increase tacrolimus blood concentrations and therefore require dosage reduction of tacrolimus [see Drug Interactions ( 7.2 )].
5.9 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 orally.
Monitor patients for anaphylaxis when using the intravenous route of administration [ see Dosage and Administration ( 2.1 )].
5.10 Not Recommended for Use with Sirolimus Tacrolimus capsules are not recommended for use with sirolimus: The 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.
The 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 )].
5.11 Interactions with CYP3A4 Inhibitors and Inducers When co-administering 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 )].
5.12 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 co-administering 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 )].
5.13 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 should be considered [see Adverse Reactions ( 6.2 )].
5.14 Immunizations Whenever possible, administer the complete complement of vaccines before transplantation and treatment with Tacrolimus.
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.
Inactivated vaccines noted to be safe for administration after transplantation may not be sufficiently immunogenic during treatment with tacrolimus.
5.15 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 should be considered [see Adverse Reactions ( 6.2 )].
INFORMATION FOR PATIENTS
Patient Information Tacrolimus Capsules, USP (ta-KROE-li-mus) Read this Patient Information before you start taking tacrolimus capsules and each time you get a refill.
There may be new information.
This information does not take the place of talking with your healthcare provider about your medical condition or your treatment.
If you have any questions about tacrolimus capsules ask your healthcare provider or pharmacist.
What is the most important information I should know about tacrolimus capsules? Tacrolimus capsules can cause serious side effects, including: Increased risk of cancer.
People who take tacrolimus capsules have an increased risk of getting some kinds of cancer, including skin and lymph gland cancer (lymphoma).
Increased risk of infection .
Tacrolimus capsules is a medicine that affects your immune system.
Tacrolimus capsules can lower the ability of your immune system to fight infections.
Serious infections can happen in people receiving tacrolimus capsules that can cause death.
Call your healthcare provider right away if you have any symptoms of an infection, including: fever muscle aches sweats or chills warm, red, or painful areas on your skin cough or flu-like symptoms What is tacrolimus capsules? Tacrolimus capsules is a prescription medicine used with other medicines to help prevent organ rejection in people who have had a kidney, liver, or heart transplant.
Tacrolimus capsules are types of tacrolimus immediate-release drugs and they are not the same as tacrolimus extended-release tablets or tacrolimus extended-release capsules.
Your healthcare provider should decide what medicine is right for you.
Who should not take tacrolimus Capsules? Do not take tacrolimus Capsules if you are allergic to tacrolimus or any of the ingredients in tacrolimus capsules.
See the end of this leaflet for a complete list of ingredients in tacrolimus capsules.
What should I tell my healthcare provider before taking tacrolimus Capsules? Before you take tacrolimus capsules, tell your healthcare provider about all of your medical conditions, including if you: plan to receive any live vaccines.
People taking tacrolimus capsules should not receive live vaccines have or have had liver, kidney, or heart problems.
are pregnant or plan to become pregnant.
Tacrolimus capsules can harm your unborn baby.
If you are able to become pregnant, you should use effective birth control before and during treatment with tacrolimus capsules.
Talk to your healthcare provider before starting treatment with tacrolimus capsules about birth control methods that may be right for you.
Males who have female partners who are able to become pregnant should also use effective birth control before and during treatment with tacrolimus capsules.
Talk to your healthcare provider before starting treatment with tacrolimus capsules about birth control methods that may be right for you.
There is a pregnancy registry for females who become pregnant and males who have fathered a pregnancy during treatment with tacrolimus capsules, USP.
The purpose of this registry is to collect information about the health of you and your baby.
To enroll in this voluntary registry, call 1-877-955-6877 or go to https://www.transplantpregnancyregistry.org/ .
are breastfeeding or plan to breastfeed.
Tacrolimus Capsules passes into your breast milk.
You and your healthcare provider should decide if you will breastfeed while taking tacrolimus Capsules.
Tell your healthcare provider about all the medicines you take, and when you start a new medicine or stop taking a medicine, including prescription and over-the-counter medicines, vitamins, natural, herbal or nutritional supplements.
Especially tell your healthcare provider if you take: sirolimus (RAPAMUNE) cyclosporine (GENGRAF, NEORAL, and SANDIMMUNE) medicines called aminoglycosides that are used to treat bacterial infections ganciclovir (CYTOVENE IV, VALCYTE) amphotericin B (ABELCET, AMBISOME) cisplatin antiviral medicines called nucleoside reverse transcriptase inhibitors antiviral medicines called protease inhibitors water pill (diuretic) medicine to treat high blood pressure nelfinavir (VIRACEPT) telaprevir (INCIVEK) boceprevir ritonavir (KALETRA, NORVIR, TECHNIVIE, VIEKIRA PAK, VIEKIRA XR) letermovir (PREVYMIS) ketoconazole itraconazole (ONMEL, SPORANOX) voriconazole (VFEND) clarithromycin (BIAXIN, BIAXIN XL, PREVPAC) rifampin (RIFADIN, RIFAMATE, RIFATER, RIMACTANE) rifabutin (MYCOBUTIN) amiodarone (NEXTERONE, PACERONE) Ask your healthcare provider or pharmacist if you are not sure if you take any of the medicines listed above.
Tacrolimus capsules may affect the way other medicines work, and other medicines may affect how tacrolimus capsules works.
Know the medicines you take.
Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine.
How should I take tacrolimus capsules? Take tacrolimus capsules exactly as your healthcare provider tells you to take it.
Your healthcare provider will tell you how much tacrolimus capsules to take and when to take it.
Your healthcare provider may change your tacrolimus capsules dose if needed.
Do not stop taking or change your dose of tacrolimus capsules without talking to your healthcare provider.
Take tacrolimus capsules with or without food.
Take tacrolimus capsules the same way every day.
For example, if you choose to take tacrolimus capsules with food, you should always take tacrolimus capsules with food.
Take tacrolimus capsules at the same time each day, 12 hours apart.
For example, if you take your first dose at 7:00 a.m., you should take your second dose at 7:00 p.m.
Taking tacrolimus capsules at the same time each day helps to keep the amount of medicine in your body at a steady level.
Do not eat graperuit or drink grapefruit juice while taking tacrolimus capsules.
If you take too much tacrolimus capsules, call your healthcare provider or go to the nearest hospital emergency room right away.
Tacrolimus capsules: • Do not open or crush tacrolimus capsules.
What should I avoid while taking tacrolimus capsules? While you take tacrolimus capsules you should not receive any live vaccines.
Limit the amount of time you spend in sunlight and avoid exposure to ultraviolet (UV) light, such as tanning machines.
Wear protective clothing and use a sunscreen with a high sun protection factor (SPF).
What are the possible side effects of tacrolimus Capsules? Tacrolimus capsules may cause serious side effects, including: See “What is the most important information I should know about tacrolimus Capsules?” problems from medicine errors.
People who take tacrolimus capsules have sometimes been given the wrong type of tacrolimus product.
Tacrolimus extended-release medicines are not the same as tacrolimus capsules and cannot be substituted for each other, unless specifically prescribed by your healthcare provider, who will send you to get blood tacrolimus levels at a lab.
Check your tacrolimus capsules when you get a new prescription and before you take it to make sure you have received tacrolimus capsules.
Check with the pharmacist and call your healthcare provider if you think you were given the wrong medicine.
high blood sugar (diabetes).
Your healthcare provider may do blood tests to check for diabetes while you take tacrolimus capsules.
Call your healthcare provider right away if you have any symptoms of high blood sugar, including: frequent urination drowsiness increased thirst or hunger loss of appetite blurred vision fruity smell on your breath confusion nausea, vomiting, or stomach pain kidney problems.
Kidney problems are a serious and common side effect of tacrolimus capsules.
Your healthcare provider may do blood tests to check your kidney function while you take tacrolimus capsules.
nervous system problems.
Nervous system problems are a serious and common side effect of tacrolimus capsules.
Call your healthcare provider right away if you get any of these symptoms while taking tacrolimus capsules.
These could be signs of a serious nervous system problem: headache changes in behavior confusion coma seizures tremors changes in your vision numbness and tingling high levels of potassium in your blood.
Your healthcare provider may do blood tests to check your potassium level while you take tacrolimus capsules.
high blood pressure.
High blood pressure is a serious and common side effect of tacrolimus capsules.
Your healthcare provider will monitor your blood pressure while you take tacrolimus capsules and may prescribe blood pressure medicine for you, if needed.
Your healthcare provider may instruct you to check your blood pressure at home.
changes in the electrical activity of your heart (QT prolongation).
heart problems (myocardial hypertrophy).
Tell your healthcare provider right away if you get any of these symptoms of heart problems while taking tacrolimus capsules: shortness of breath feel lightheaded chest pain feel faint severe low red blood cell count (anemia).
The most common side effects of tacrolimus Capsules in people who have received a kidney, liver or heart transplant are: infections in general, including cytomegalovirus (CMV) infection swelling of the hands, legs, ankles, or feet weakness tremors(shaking of the body) pain constipation high levels of fat in your blood diarrhea high levels of potassium in your blood headache low red blood cell count (anemia) stomach pain low white blood cell count trouble sleeping fever nausea numbness or tingling in your hands and feet high blood sugar (diabetes) inflammation of your airway (bronchitis) low levels of magnesium in your blood fluid around your heart low levels of phosphate in your blood Tell your healthcare provider if you have any side effect that bothers you or that does not go away.
These are not all the possible side effects of tacrolimus capsules.
For more information, ask your healthcare provider or pharmacist.
Call your healthcare provider for medical advice about side effects.
You may report side effects to FDA at 1-800-FDA1088.
How should I store tacrolimus capsules? tacrolimus capsules Store Tacrolimus Capsules, USP at room temperature between 68°F to 77°F (20°C to 25°C).
Keep tacrolimus capsules and all medicines out of the reach of children.
General information about the safe and effective use of tacrolimus capsules.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet.
Do not use tacrolimus capsules for a condition for which it was not prescribed.
Do not give tacrolimus capsules to other people, even if they have the same symptoms that you have.
It may harm them.
You can ask your pharmacist or healthcare provider for information about tacrolimus capsules that is written for health professionals.
This Patient Information leaflet summarizes the most important information about tacrolimus capsules.
If you would like more information, talk to your healthcare provider.
What are the ingredients in tacrolimus capsules? Active ingredient: Tacrolimus USP Inactive ingredients: Tacrolimus capsules: croscarmellose sodium, hypromellose, lactose anhydrous, and magnesium stearate.
The 0.5 mg capsule shell contains ferric oxide, gelatin, and titanium dioxide.
The 1 mg capsule shell contains gelatin and titanium dioxide.
The 5 mg capsule shell contains ferric oxide, gelatin, and titanium dioxide.
Manufactured by: Panacea Biotec Pharma Limited, Malpur, Baddi, Distt.
Solan (H.P.) – 173205, India All other trademarks and registered trademarks are the property of their respective owners.
Mfg.Lic.No: MB/05/203 Distributed by: Bionpharma Inc., 600 Alexander Road, Princeton, NJ 08540, USA.
Item Code: PPIT082B For more information, call Bionpharma, Inc.
at 1-888-235-BION or 1-888-235-2466.
This Patient Information has been approved by the U.S.
Food and Drug Administration.
Revised Date: October 2020
DOSAGE AND ADMINISTRATION
2 Patient Population Initial Oral Dosage (formulation) Whole Blood Trough Concentration range ADULT Kidney Transplant with azathioprine 0.2 mg/kg/day capsules divided in two doses, every 12 hours Month 1-3: 7-20 ng/mL Month 4-12: 5-15 ng/mL With MMF/IL-2 receptor antagonist 0.1 mg/kg/day capsules, divided in two doses, every 12 hours Month 1-12: 4-11 ng/mL Liver Transplant With corticosteroids only 0.1-0.15 mg/kg/day capsules, divided in two doses, every 12 hours Month 1-12: 5-20 ng/mL Heart Transplant With azathioprine or MMF 0.075 mg/kg/day capsules, divided in two doses, every 12 hours Month 1-3: 10-20 ng/mL Month ≥ 4: 5-15 ng/mL PEDIATRIC Kidney Transplant 0.3 mg/kg/day capsules, divided in two doses, every 12 hours Month 1-12: 5-20 ng/mL Liver Transplant 0.15-0.2 mg/kg/day capsules 0.2 mg/kg/day, divided in two doses, every 12 hours Month 1-12: 5-20 ng/mL Heart Transplant 0.3 mg/kg/day* capsules divided in two doses, every 12 hours Month 1-12: 5-20 ng/mL MMF= Mycophenolate mofetil *0.1 mg/kg/day if cell depleting induction treatment is administered Administer capsules consistently with or without food.
( 2.1 ) Therapeutic drug monitoring is recommended.
( 2.1 , 2.6 ) Avoid eating grapefruit or drinking grapefruit juice.
( 2.1 ) See dosing adjustments for African-American patients ( 2.2 ), hepatic and renal impaired.
( 2.4 , 2.5 ) For complete dosing information see the full prescribing information 2.1 Important Administration Instructions Tacrolimus Capsules should not be used without supervision by a physician with experience in immunosuppressive therapy.
Tacrolimus capsules and tacrolimus granules are not interchangeable or substitutable for other tacrolimus extended-release products.
This is because rate of absorption following the administration of an extended-release tacrolimus product is not equivalent to that of an immediate-release tacrolimus drug product.
Under-or overexposure to tacrolimus may result in graft rejection or other serious adverse reactions.
Changes between tacrolimus immediate-release and extended-release dosage forms must occur under physician supervision [see Warnings and Precautions ( 5.3 )].
Intravenous Formulation -Administration Precautions due to Risk of Anaphylaxis Intravenous use is recommended for patients who cannot tolerate oral formulations, and conversion from intravenous to oral tacrolimus capsules are recommended as soon as oral therapy can be tolerated to minimize the risk of anaphylactic reactions that occurred with injectables containing castor oil derivatives [see Warnings and Precautions ( 5.9 )].
Oral Formulations (Capsules) If patients are able to initiate oral therapy, the recommended starting doses should be initiated.
Tacrolimus capsules may be taken with or without food.
However, since the presence of food affects the bioavailability of tacrolimus capsules, if taken with food, it should be taken consistently the same way each time [see Clinical Pharmacology ( 12.3 )].
General Administration Instructions Patients should not eat grapefruit or drink grapefruit juice in combination with tacrolimus capsules [see Drug Interactions ( 7.2 )].
Tacrolimus capsules should not be used simultaneously with cyclosporine.
Tacrolimus capsules or cyclosporine should be discontinued at least 24 hours before initiating the other.
In the presence of elevated tacrolimus capsules or cyclosporine concentrations, dosing with the other drug usually should be further delayed.
Therapeutic drug monitoring (TDM) is recommended for all patients receiving tacrolimus capsules [see Dosage and Administration ( 2.6 )].
2.2 Dosing for Adult Kidney, Liver, or Heart Transplant Patients – Capsules Capsules If patients are able to tolerate oral therapy, the recommended oral starting doses should be initiated.
The initial dose of tacrolimus capsules 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 may be administered within 24 hours of transplantation, but should be delayed until renal function has recovered.
The initial oral tacrolimus dosage recommendations for adult patients with kidney, liver, or heart transplants and whole blood trough concentration range are shown in Table 1 .
Perform therapeutic drug monitoring (TDM) to ensure that patients are within the ranges listed in Table 1 .
Table 1.
Summary of Initial Oral Tacrolimus capsules Dosing Recommendations and Whole Blood Trough Concentration Range in Adults Patient Population Tacrolimus Capsules* Initial Oral Dosage Whole Blood Trough Concentration Range kidney Transplant With azathioprine 0.2 mg/kg/day, divided in two doses, administered every 12 hours Month 1-3: 7-20 ng/mL Month 4-12: 5-15 ng/mL With MMF/IL-2 receptor antagonist† 0.1 mg/kg/day, divided in two doses, administered every 12 hours Month 1-12: 4-11 ng/mL Liver Transplant With corticosteroids only 0.10-0.15 mg/kg/day, divided in two doses, administered every 12 hours Month 1-12: 5-20 ng/mL Heart Transplant With azathioprine or MMF 0.075 mg/kg/day, divided in two doses, administered every 12 hours Month 1-3: 10-20 ng/mL Month ≥ 4: 5-15 ng/mL *African-American patients may require higher doses compared to Caucasians (see Table 2) † 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 capsules 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 African-American patients required a higher dose to attain comparable trough concentrations compared to Caucasian patients ( Table 2 ) [see Use in Specific Populations ( 8.8 ) and Clinical Pharmacology ( 12.3 )].
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 Intravenous Injection Tacrolimus injection should be used only as a continuous intravenous infusion and should be discontinued as soon as the patient can tolerate oral administration.
The first dose of tacrolimus capsules should be given 8-12 hours after discontinuing the intravenous infusion.
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 intravenous infusion.
Adult patients should receive doses at the lower end of the dosing range.
Concomitant adrenal corticosteroid therapy is recommended early post-transplantation.
The whole blood trough concentration range described in Table 1 pertain to oral administration of tacrolimus capsules only; while monitoring tacrolimus concentrations in patients receiving tacrolimus injection as a continuous intravenous 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.
Anaphylactic reactions have occurred with injectables containing castor oil derivatives, such as Tacrolimus injection.
Therefore, monitoring for signs and symptoms of anaphylaxis is recommended [see Warnings and Precautions ( 5.9 )].
2.3 Dosing for Pediatric Kidney, Liver, and Heart Transplant Patients Oral formulation (capsules) Pediatric patients in general need higher tacrolimus doses compared to adults: the higher dose requirements may decrease as the child grows older.
Recommendations for the initial oral dosing for pediatric transplant patients and whole blood trough concentration range are shown in Table 3 .
Perform TDM to ensure that patients are within the ranges listed in Table 3 .
Table 3.
Summary of Initial Tacrolimus capsules Dosing Recommendations and Whole Blood Trough Concentration Range in Children Patient Population Initial Tacrolimus Capsules USP Whole Blood Trough Concentration Range Pediatric kidney transplant patients † 0.3 mg/kg/day capsules, divided in two doses, administered every 12 hours Month 1-12: 5-20 ng/mL Pediatric liver transplant patients ‡ 0.15- 0.2 mg/kg/day, divided in two doses, administered every 12 hours Month 1-12: 5-20 ng/ mL Pediatric heart transplant patients † 0.3 mg/kg/day* capsules, divided in two doses, administered every 12 hours Month 1-12: 5-20 ng/mL *0.1 mg/kg/day if cell depleting induction treatment is administered † See Clinical Pharmacology ( 12.3 ) , Tacrolimus Granules Pharmacokinetics in Pediatric Patients ‡ See Clinical Studies ( 14.2 ) , Liver Transplantation For conversion of pediatric patients from tacrolimus granules to tacrolimus capsules or from tacrolimus capsules to tacrolimus granules, the total daily dose should remain the same.
Following conversion from one formulation to another formulation of tacrolimus, therapeutic drug monitoring is recommended [see Dosage and Administration ( 2.6 )] .
If a patient is unable to receive an oral formulation, the patient may be started on tacrolimus injection.
For pediatric liver transplant patients, the intravenous dose is 0.03-0.05 mg/kg/day.
2.4 Dosage Adjustment in Patients with Renal Impairment Due to its potential for nephrotoxicity, consideration should be given to dosing tacrolimus capsules at the lower end of the therapeutic dosing range in patients who have received a liver or heart transplant and have pre-existing renal impairment.
Further reductions in dose below the targeted range may be required.
In kidney transplant patients with post-operative oliguria, the initial dose of tacrolimus capsules 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 [see Dosage and Administration ( 2.2 ) , Warnings and Precautions ( 5.5 ) , Use in Specific Populations ( 8.6 ) , and Clinical Pharmacology ( 12.3 )] .
2.5 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 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 ( 2.2 ), Warnings and Precautions ( 5.5 ), Use in Specific Populations ( 8.7 ), and Clinical Pharmacology ( 12.3 )].
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.
Whole blood trough concentration range 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.