TACROLIMUS CINFA

Tacrolimus is the active ingredient in tacrolimus extended-release capsules.

Tacrolimus is a calcineurin-inhibitor immunosuppressant produced by Streptomyces tsukubaensis.

Chemically, tacrolimus is designated as [3 S – [3 R [ E (1 S , 3 S , 4 S )], 4 S , 5 R , 8 S , 9 E, 12 R , 14 R , 15 S , 16 R , 18 S , 19 S , 26a R ]] – 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 – methoxycyclo – hexyl) – 1 – methylethenyl] – 14, 16 – dimethoxy – 4, 10, 12, 18 – tetramethyl – 8 – (2 – propenyl) – 15, 19 – epoxy – 3H – pyrido[2, 1 – c ]oxaazacyclotricosine – 1, 7, 20, 21(4H, 23H) – tetrone, monohydrate.

The chemical structure of tacrolimus is

Tacrolimus 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 crystals or crystalline powder.

It is practically insoluble in water, freely soluble in ethanol, and very soluble in methanol and chloroform.

Tacrolimus extended-release capsules is available for oral administration as hard gelatin capsules containing the equivalent of 0.5 mg, 1 mg or 5 mg of anhydrous tacrolimus, USP.

Inactive ingredients include ethylcellulose

NF, hypromellose USP, magnesium stearate NF and lactose monohydrate NF.

The ingredients are directly proportional across all capsule strengths.

The capsule shell contains gelatin

NF, ferric oxide red NF, ferric oxide yellow NF, and titanium dioxide USP. structure.

Tacrolimus extended-release capsules is indicated for the prophylaxis of organ rejection in kidney transplant patients in combination with other immunosuppressants in adult patients who can swallow capsules intact.

Pediatric use information is approved for Astellas Pharma US, Inc.'s ASTAGRAF XL (tacrolimus extended-release capsules).

However, due to Astellas Pharma US, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.

Tacrolimus extended-release capsules is a calcineurin-inhibitor immunosuppressant indicated for the prophylaxis of organ rejection in kidney transplant patients in combination with other immunosuppressants in adult patients who can swallow capsules intact.

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 and the phosphatase activity of calcineurin is 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). 12.3 Pharmacokinetics Table 7 summarizes the pharmacokinetic (PK) parameters of tacrolimus following oral administration of tacrolimus extended-release capsules in healthy subjects and in kidney transplant patients.

Whole blood tacrolimus concentrations in these

PK studies were measured using validated HPLC/MS/MS assays.

Table 7: Pharmacokinetic Parameters of Tacrolimus Extended-Release Capsules (Given Once Daily) in Healthy Subjects and in Kidney Transplant Patients (Under Fasted Conditions) Population Tacrolimus Extended-Release Capsules Dose Healthy adult subjects (actual administered dose of tacrolimus extended-release capsules); adult de novo kidney transplant patients (actual group mean dose of tacrolimus extended-release capsules).

Day Day of tacrolimus extended-release capsules treatment and PK profiling.

PK Parameters of Tacrolimus Extended-Release Capsules C max Arithmetic means ± S.D. (ng/mL) T max Median [range. (hr) AUC 24 (ng•hr/mL) C 24 Tacrolimus trough concentration before the next dose. (ng/mL) Healthy Subjects (N=24) 4 mg 4 mg Day 1 Day 10 6.2 ± 2.1 11.6 ± 3.4 2 [1 to 5] 2 [1 to 3] 74 ± 22 155 ± 46 2.3 ± 0.8 4.7 ± 1.5 Adult Kidney De novo “De novo” refers to immunosuppression starting at the time of transplantation; data from PK substudy of Study 2. (N=17) 0.2 mg/kg 0.19 mg/kg 0.18 mg/kg 0.18 mg/kg Day 1 Day 3 Day 7 Day 14 26 ± 13.7 31 ± 13.9 32.2 ± 10.2 32.7 ± 9 3 [2 to 24] 2 [0.5 to 2] 2 [1 to 6] 2 [1 to 4] 372 ± 202 437 ± 175 405 ± 117 412 ± 109 12.1 ± 7.2 13.5 ± 5.6 11.4 ± 4 11.2 ± 3.9 Adult Kidney (6 months or greater post-transplant) (N=60) 5.2 mg/day Same daily dose of tacrolimus extended-release capsules for 14-day period.

Day 14 16.1 ± 5.3 2 [1 to 6] 222 ± 64 6.7 ± 1.9 Correlation coefficient of AUC to C min r = 0.88.

In de novo adult kidney transplant patients, the tacrolimus systemic exposure, as assessed by AUC 24, for tacrolimus extended-release capsules 0.2 mg/kg once daily on Day 1 post-transplant was 18% (Ratio [SD]: 0.822) lower when compared with Prograf (tacrolimus immediate-release) 0.2 mg/kg/day given twice daily.

By Day 3 post-transplant, the AUC was similar between the two formulations.

On Day 14 (steady state), the AUC for tacrolimus extended-release capsules was 21% (Ratio [SD]: 1.207) higher than that of Prograf (tacrolimus immediate-release), at comparable trough concentrations (C 24 ).

Due to intersubject variability in tacrolimus

PK, individualization of dosing regimen is necessary for optimal therapy.

Pharmacokinetic data indicate that whole blood concentrations rather than plasma concentrations serve as the more appropriate sampling compartment to describe tacrolimus PK.

In healthy subjects, the administration of escalating tacrolimus extended-release capsules doses ranging from 1.5 mg to 10 mg resulted in dose-proportional increases in tacrolimus AUC and C 24h, and no change in elimination half-life.

The presence of a meal affects the absorption of tacrolimus; the rate and extent of absorption is greatest under fasted conditions.

In 24 healthy subjects, administration of tacrolimus extended-release capsules immediately following a high-fat meal (150 protein calories, 250 carbohydrate calories, and to 600 fat calories) reduced the C max, AUC t, and AUC inf of tacrolimus by approximately 25% compared with fasting values.

Food delayed the median

T max from 2 hours in the fasted state to 4 hours in the fed state; however, the terminal half-life remained 36 hours regardless of dosing conditions.

The time when a meal is consumed also affected tacrolimus bioavailability.

In 24 healthy subjects, when tacrolimus extended-release capsules was administered 1.5 hours after consumption of a high-fat breakfast, tacrolimus exposure was decreased approximately 35%.

Administration of tacrolimus extended-release capsules 1 hour prior to a high-fat breakfast reduced tacrolimus exposure by 10%.

Tacrolimus extended-release capsules should be taken, preferably on an empty stomach, at least 1 hour before a meal or at least 2 hours after a meal.

In 23 healthy subjects, a diurnal effect on the absorption of tacrolimus was observed.

Evening dosing of tacrolimus extended-release capsules reduced AUC inf by 35% relative to morning dosing.

Tacrolimus extended-release capsules should be taken consistently at the same time every morning.

The plasma protein binding of tacrolimus is approximately 99% and is independent of concentration over a range of 5 ng/mL to 50 ng/mL.

Tacrolimus is bound mainly to albumin and alpha-1-acid glycoprotein, and has a high level of association with erythrocytes.

The distribution of tacrolimus between whole blood and plasma depends on several factors, such as hematocrit, temperature at the time of plasma separation, drug concentration, and plasma protein concentration.

In a

U.S. trial in which tacrolimus was administered as tacrolimus immediate-release, the ratio of whole blood concentration to plasma concentration averaged 35 (range to 67).

The desired pharmacological activity of tacrolimus is primarily due to the parent drug.

Tacrolimus is extensively metabolized by the mixed-function oxidase system, primarily the cytochrome P-450 system (CYP3A4 and CYP3A5).

A metabolic pathway leading to the formation of 8 possible metabolites has been proposed.

Demethylation and hydroxylation were identified as the primary mechanisms of biotransformation in vitro.

The major metabolite identified in incubations with human liver microsomes is 13-demethyl tacrolimus.

In in vitro studies, a 31-demethyl metabolite has been reported to have the same activity as tacrolimus.

In a mass balance study of orally-administered radiolabeled tacrolimus to 6 healthy subjects, the mean recovery of the radiolabel was 94.9 ± 30.7%.

Fecal elimination accounted for 92.6 ± 30.7% and urinary elimination accounted for 2.3 ± 1.1% of the total radiolabel administered.

The elimination half-life based on radioactivity was 31.9 ± 10.5 hours, whereas it was 48.4 ± 12.3 hours based on tacrolimus concentrations.

The mean clearance of radiolabel was 0.226 ± 0.116 L/hr/kg and the mean clearance of tacrolimus was 0.172 ± 0.088 L/hr/kg. The elimination half-life of tacrolimus after oral administration of 4 mg tacrolimus extended-release capsules daily for 10 days was 38 ± 3 hours in 24 healthy subjects.

Pediatric use information is approved for Astellas Pharma US, Inc.’s ASTAGRAF XL (tacrolimus extended-release capsules).

However, due to Astellas Pharma US, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

Tacrolimus pharmacokinetics following a single administration of tacrolimus immediate-release injection (administered as a continuous IV infusion) were determined in 12 patients (7 not on dialysis and on dialysis, serum creatinine of 3.9 ± 1.6 and 12 ± 2.4 mg/dL, respectively) prior to their kidney transplant.

The mean clearance of tacrolimus in patients with renal dysfunction given tacrolimus IV was similar to that in healthy subjects given tacrolimus IV and in healthy subjects given oral tacrolimus immediate-release.

Tacrolimus pharmacokinetics have been determined in six patients with mild hepatic impairment (mean Child-Pugh score: 6.2) following single oral administration of tacrolimus immediate-release.

The mean clearance of tacrolimus in patients with mild hepatic impairment was not substantially different from that in healthy subjects.

Tacrolimus pharmacokinetics were studied in six patients with severe hepatic impairment (mean Child-Pugh score: more than 10).

The mean clearance was substantially lower in patients with severe hepatic impairment.

The pharmacokinetics of tacrolimus was studied following single oral administration of tacrolimus immediate-release (5 mg) in 10 African-American, 12 Latino-American, and 12 Caucasian healthy subjects: The mean (± SD) tacrolimus C max in African-Americans (23.6 ± 12.1 ng/mL) was lower than in Caucasians (40.2 ± 12.6 ng/mL) and Latino-Americans (36.2 ± 15.8 ng/mL).

AUC 0-inf tended to be lower in African-Americans (203 ± 115 ng∙hr/mL) than Caucasians (344 ± 186 ng∙hr/mL) and Latino-Americans (274 ± 150 ng∙hr/mL).

The mean (± SD) absolute oral bioavailability (F) in African-Americans (12 ± 4.5%) and Latino-Americans (14 ± 7.4%) was lower than in Caucasians (19 ± 5.8%).

There was no significant difference in mean terminal half-life among the three ethnic groups (range from approximately to 30 hours).

A formal trial to evaluate the effect of gender on tacrolimus pharmacokinetics has not been conducted; however, there was no difference in total mg daily dosages between male and female patients receiving tacrolimus extended-release capsules in the kidney transplant trials.

A retrospective comparison of pharmacokinetics in healthy subjects, and in kidney transplant patients indicated no gender-based differences.

Drug Interaction Studies Because tacrolimus is metabolized mainly by CYP3A enzymes, drugs or substances known to inhibit these enzymes and/or are known CYP3A substrates may increase tacrolimus whole blood concentrations.

Drugs known to induce

CYP3A enzymes may decrease tacrolimus whole blood concentrations.

Figure and

Figure 2 summarize the PK data from drug interaction studies of tacrolimus extended-release capsules or tacrolimus immediate-release capsules.

These studies assessed the effect of co-administered drugs on tacrolimus PK in healthy subjects.

Dosing adjustments, when using drugs that inhibit or increase CYP3A enzymes, may be necessary.

Figure 1: Effect of Co-administered Drugs on the Pharmacokinetics of Tacrolimus (when Given as Tacrolimus Extended-Release Capsules) Figure 2: Effect of Co-administered Drugs on the Pharmacokinetics of Tacrolimus (when Given as Immediate-Release Tacrolimus) Other Drug Interaction Studies Caspofungin: Caspofungin reduced the blood AUC 0-12 of tacrolimus by approximately 20%, peak blood concentration (C max ) by 16%, and 12-hour blood concentration (C 12hr ) by 26% in healthy adult subjects when tacrolimus (2 doses of 0.1 mg/kg 12 hours apart) was administered on the 10th day of CANCIDAS 70 mg daily, as compared to results.

The following clinically significant adverse drug reactions are discussed in greater detail in other sections of labeling: Lymphoma and Other Malignancies Serious.

Infections Increased Mortality in Female Liver Transplant Patients New Onset Diabetes after Transplant Nephrotoxicity due to Tacrolimus Extended-Release Capsules and Drug Interactions Neurotoxicity Hyperkalemia Hypertension QT Prolongation Pure Red Cell Aplasia Thrombotic Microangiopathy, Including Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura The most common adverse reactions (≥ 30%) are: diarrhea, constipation, nausea, peripheral edema, tremor and anemia.

To report SUSPECTED ADVERSE

REACTIONS, contact eVenus Pharmaceutical Laboratories, Inc.fda.gov/medwatch. 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 patients were treated with tacrolimus extended-release capsules (N=214) or tacrolimus immediate-release product (N=212) and concomitant immunosuppressants (median duration of exposure of 12 months) in a randomized, open-label, active-controlled trial of mostly U.S. patients (Study 1) .

The types of adverse reactions seen in Study were similar to the adverse reactions seen in Study 2 [non-U.S. trial in kidney transplant patients treated with tacrolimus extended-release capsules (N=331) or tacrolimus immediate-release product (N=336) and concomitant immunosuppressants.

In Study 1, the proportion of patients who discontinued treatment due to adverse reactions was 9% and 11% in the tacrolimus extended-release capsules and tacrolimus immediate-release treatment groups, respectively, through 12 months of treatment.

The most common adverse reactions leading to discontinuation in tacrolimus extended-release capsules-treated patients were related to infections or renal/urinary disorders.

Infections The overall incidence of infections, serious infections, and infections with identified etiology reported in patients treated with the tacrolimus extended-release capsules or tacrolimus immediate-release product in Study are shown in Table 2.

Table 2: Percentage of Patients with.

Infections in Study 1 Study was not designed to support comparative claims of tacrolimus extended-release capsules compared to tacrolimus immediate-release product for the adverse reactions reported in this table.

Tacrolimus extended-release capsules, MMF, steroids, basiliximab induction N=214 Tacrolimus immediate-release product, MMF, steroids, basiliximab induction N=212 All.

Infections 69% 69% Respiratory.

Infections 34% 31% Urinary Tract.

Infections 16% 25% Cytomegalovirus.

Infections 10% 11% Bacterial.

Infections 8% 12% Gastroenteritis 7% 3% Polyomavirus.

Infections 3% 5% Serious.

Infections 22% 23% New Onset Diabetes After Transplant (NODAT) The incidence of new onset diabetes after transplantation (defined by the composite occurrence of ≥ 2 fasting plasma glucose values that were more than 126 mg/dL at ≥ 30 days apart, insulin use for ≥ 30 consecutive days, oral hypoglycemic use for ≥ 30 consecutive days, and/or HbA 1C ≥ 6.5%) is summarized in Table 3 below for Study 1 through one year post-transplant.

Table 3: Percentage of Patients with NODAT Through One Year Post-Kidney Transplant in Study 1 Study was not designed to support comparative claims of tacrolimus extended-release capsules compared to tacrolimus immediate-release product for the adverse reactions reported in this table.

Tacrolimus extended-release capsules, MMF, steroids, basiliximab induction N=162 Tacrolimus immediate-release product, MMF, steroids, basiliximab induction N=151 Composite NODAT 36% 35% ≥ 2 Fasting Plasma Glucose Values ≥ 126 mg/dL ≥ 30 days apart 26% 23% HbA 1C ≥ 6.5% 19% 22% Oral hypoglycemic use ≥ 30 consecutive days 14% 9% Insulin use ≥ 30 consecutive days 6% 8% Hyperkalemia In Study 1, 73 of 214 (34.1%) patients on tacrolimus extended-release capsules had a serum potassium level greater than 5.4 up to 6.4 mEq/L, and 8 out of 214 (3.7%) patients had a serum potassium level greater than 6.4 mEq/L.

The most common (≥ 30%) adverse reactions observed with tacrolimus extended-release capsules in Study were: diarrhea, constipation, nausea, peripheral edema, tremor, and anemia.

The incidence of adverse reactions that occurred in ≥ 15% of tacrolimus extended-release capsules-treated patients compared to tacrolimus immediate-release product through one year of treatment in Study is shown by treatment groups in Table 4.

Table 4: Adverse Reactions (≥ 15%) in Kidney Transplant Patients Through One Year Post-Transplant in Study 1 Study was not designed to support comparative claims of tacrolimus extended-release capsules compared to tacrolimus immediate-release for the adverse reactions reported in this table.

Tacrolimus extended-release capsules, MMF, steroids, basiliximab induction N=214 Tacrolimus immediate-release product, MMF, steroids, basiliximab induction N=212 Diarrhea 45% 44% Constipation 40% 32% Nausea 36% 35% Peripheral Edema 36% 34% Tremor 35% 34% Anemia 33% 29% Hypertension 28% 30% Vomiting 25% 25% Hypomagnesemia 24% 27% Insomnia 24% 28% Hypophosphatemia 23% 28% Headache 22% 24% Hyperkalemia 20% 23% Increased Blood Creatinine 19% 23% Fatigue 16% 10% Leukopenia 16% 16% Hyperlipidemia 16% 17% Hyperglycemia 16% 18% Less Frequently Reported Adverse Reactions (less than 15% in tacrolimus extended-release capsules-treated patients) by System Organ Class The following adverse reactions were reported in clinical studies of kidney transplant patients who were treated with tacrolimus extended-release capsules, MMF, and steroids (Studies and 2): Blood and Lymphatic System.

Disorders: Hemolytic anemia, leukocytosis, neutropenia, thrombocytopenia, thrombotic microangiopathy Cardiac.

Disorders: Atrial fibrillation, atrial flutter, tachycardia Ear.

Disorders: Vision blurred, conjunctivitis Gastrointestinal.

Disorders: Abdominal distension, abdominal pain, aphthous stomatitis, dyspepsia, esophagitis, flatulence, gastritis, gastroesophageal reflux disease General.

Disorders and Administration Site Conditions: Anasarca, asthenia, edema, pyrexia Hepatobiliary.

Disorders: Abnormal hepatic function, cholestasis, hepatitis (acute and chronic), hepatotoxicity.

Infections and Infestations: Condyloma acuminatum, tinea versicolor Injury: Fall.

Investigations: Increased blood lactate dehydrogenase, increased blood urea, increased hepatic enzyme Metabolism and Nutrition.

Disorders: Anorexia, hyperphosphatemia, hyperuricemia, hypokalemia, hyponatremia, metabolic acidosis Musculoskeletal and Connective Tissue.

Disorders: Arthralgia, osteopenia, osteoporosis Neoplasms: Kaposi’s sarcoma Nervous System.

Disorders: Convulsion, dizziness, hypoesthesia, neurotoxicity, paresthesia, peripheral neuropathy Psychiatric.

Disorders: Agitation, anxiety, confusional state, depression, hallucination, mood swings, nightmare Renal and Urinary.

Disorders: Anuria, oliguria, proteinuria, renal failure, renal tubular necrosis, toxic nephropathy Respiratory, Thoracic and Mediastinal.

Disorders: Acute respiratory distress syndrome, dyspnea, pulmonary edema, productive cough Skin and Subcutaneous Tissue.

Disorders: Acne, alopecia, dermatitis, hyperhidrosis, hypotrichosis, pruritus, rash Vascular.

Disorders: Deep vein thrombosis, flushing Pediatrics Pediatric use information is approved for Astellas Pharma US, Inc.'s ASTAGRAF XL (tacrolimus extended-release capsules).

However, due to Astellas Pharma US, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information. 6.2 Postmarketing Experience The following adverse reactions have been reported from marketing experience with tacrolimus in the U.S. and outside the U.S. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

These reactions have been chosen for inclusion due to either their seriousness, frequency of reporting or causal connection to tacrolimus extended-release capsules: Blood and Lymphatic System.

Disorders: Agranulocytosis, disseminated intravascular coagulation, hemolytic uremic syndrome, febrile neutropenia, pancytopenia, pure red cell aplasia, coagulopathy, thrombotic thrombocytopenic purpura, prolonged activated partial thromboplastin time, decreased blood fibrinogen Cardiac.

Disorders: Cardiac arrest, myocardial infarction, ventricular fibrillation, congestive cardiac failure, hypertrophic cardiomyopathy, pericardial effusion, angina pectoris, supraventricular extrasystoles, supraventricular tachycardia, bradycardia, Torsades de pointes, QT prolongation Ear.

Disorders: Hearing loss Eye.

Disorders: Blindness, optic neuropathy, optic atrophy, photophobia Gastrointestinal.

Disorders: Gastrointestinal hemorrhage, gastrointestinal perforation, pancreatitis, peritonitis, stomach ulcer, intestinal obstruction, ascites, colitis, ileus, impaired gastric emptying, dysphagia Hepatobiliary.

Disorders: Hepatic failure, hepatic necrosis, cirrhosis, cholangitis, venoocclusive liver disease, bile duct stenosis, hepatic steatosis, jaundice Hypersensitivity Reactions: Hypersensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria Immune System.

Disorders: Graft versus host disease (acute and chronic).

Investigations: Increased international normalized ratio Metabolism and Nutrition.

Disorders: Hypoproteinemia Musculoskeletal and Connective Tissue.

Disorders: Rhabdomyolysis, myalgia, polyarthritis, pain in extremity including Calcineurin-Inhibitor Induced Pain Syndrome (CIPS) Neoplasms: Lymphoma including EBV-associated lymphoproliferative disorder, hepatosplenic T-cell lymphoma, PTLD, leukemia, melanoma Nervous System.

Disorders: Cerebral infarction, progressive multifocal leukoencephalopathy (PML) sometimes fatal, posterior reversible encephalopathy syndrome (PRES) , coma, status epilepticus, quadriplegia, flaccid paralysis, hemiparesis, aphasia, syncope, carpal tunnel syndrome, nerve compression, mutism, dysarthria, somnolence Psychiatric.

Disorders: Mental status changes Renal and Urinary.

Disorders: Hemorrhagic cystitis, hematuria, urinary retention, urinary incontinence Respiratory, Thoracic and Mediastinal.

Disorders: Interstitial lung disease, pulmonary hypertension, lung infiltration, rhinitis allergic, hiccups Skin and Subcutaneous Tissue.

Disorders: Hyperpigmentation, photosensitivity Vascular.

Postmarketing cases of overdose with tacrolimus have been reported.

Overdosage adverse reactions included: nervous system disorders (tremor, headache, confusional state, balance disorders, encephalopathy, lethargy and somnolence) gastrointestinal disturbances (nausea, vomiting, and diarrhea) abnormal renal function (increased blood urea nitrogen and elevated serum creatinine) urticaria hypertension peripheral edema, and infections [one fatal postmarketing case of bilateral pneumopathy and CMV infection was attributed to tacrolimus (extended-release) overdose.

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.

Tacrolimus extended-release capsules is contraindicated in patients with known hypersensitivity to tacrolimus.

Known hypersensitivity to tacrolimus.

Capsules must be taken whole.

Take consistently every morning at the same time on an empty stomach at least 1 hour before a meal or at least 2 hours after a meal.

Avoid eating grapefruit or drinking grapefruit juice or alcohol.

African-American patients and patients with severe hepatic impairment may require dosing adjustments.

Frequent monitoring of trough concentrations is recommended.

For complete dosing information, see Full Prescribing Information.

MMF = Mycophenolate mofetil Recommended Tacrolimus Extended-Release Capsules Initial Dosage Patient Population Initial Oral Dosage Whole Blood Trough Concentration Range ADULT With basiliximab, MMF and steroids 0.15 mg/kg to 0.2 mg/kg once daily prior to reperfusion or within 48 hours of completion of transplant Month 1: 7 ng/mL to 15 ng/mL Month to Month 6: 5 ng/mL to 15 ng/mL More than 6 Months: 5 ng/mL to 10 ng/mL With MMF and steroids, without basiliximab induction First dose (pre-operative): 0.1 mg/kg, within 12 hours prior to reperfusion Subsequent doses (post-operative): 0.2 mg/kg once daily at least 4 hours after pre-operative dose and within 12 hours after reperfusion Month 1: 10 ng/mL to 15 ng/mL Month to Month 6: 5 ng/mL to 15 ng/mL More than 6 Months: 5 ng/mL to 10 ng/mL 2.1 Important Administration Instructions Tacrolimus extended-release capsules should not be used without the supervision by a physician with experience in immunosuppressive therapy.

Tacrolimus extended-release capsules is not interchangeable or substitutable for tacrolimus extended-release tablets, tacrolimus immediate-release capsules or tacrolimus for oral suspension.

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.

Advise patients to swallow tacrolimus extended-release capsules whole with liquid; patients must not chew, divide, or crush the capsules.

Tacrolimus extended-release capsules should be taken consistently every morning at the same time to ensure consistent and maximum possible drug exposure, on an empty stomach at least 1 hour before a meal, or at least 2 hours after a meal.

If a dose is missed, the dose may be taken up to 14 hours after the scheduled time (i.e., for a missed 8:00 AM dose, a dose may be taken by 10:00 PM).

Beyond the 14-hour time frame, the patient should wait until the usual scheduled time the following morning to take the next regular daily dose.

Instruct the patient not to double the next dose.

Advise patients to avoid eating grapefruit or drinking grapefruit juice or alcoholic beverages while taking tacrolimus extended-release capsules.

Therapeutic drug monitoring is recommended for all patients receiving tacrolimus extended-release capsules. 2.2 Dosage Recommendations for Kidney Transplant Patients Table 1 includes the recommended starting tacrolimus extended-release capsules dosages and whole blood trough concentration ranges; the observed trough concentrations are shown in another section of the Full Prescribing Information.

Titrate the tacrolimus extended-release capsules dosage based on clinical assessments of rejection and tolerability, and to achieve target trough concentration ranges.

Table 1: Recommended Starting Daily Dosage Regimen of Tacrolimus Extended-Release Capsules MMF = mycophenolate mofetil Recommended Tacrolimus Extended-Release Capsules Initial Dosage* Patient Population Initial Oral Dosage Whole Blood Trough Concentration Range ADULT With basiliximab, MMF and steroids 0.15 mg/kg to 0.2 mg/kg once daily prior to reperfusion or within 48 hours of completion of transplant.

• Month 1: 7 ng/mL to 15 ng/mL.

• Month to Month 6: 5 ng/mL to 15 ng/mL.

• More than 6 Months: 5 ng/mL to 10 ng/mL With MMF and steroids, without basiliximab induction.

• First dose (pre-operative): 0.1 mg/kg, within 12 hours prior to reperfusion.

• Subsequent doses (post-operative): 0.2 mg/kg once daily at least 4 hours after pre-operative dose and within 12 hours after reperfusion.

• Month 1: 10 ng/mL to 15 ng/mL.

• More than 6 Months: 5 ng/mL to 10 ng/mL Pediatric use information is approved for Astellas Pharma US, Inc.'s ASTAGRAF XL (tacrolimus extended-release capsules).

However, due to Astellas Pharma US, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information. 2.3 Dosage Modifications for African-American Patients, Patients with Hepatic Impairment, and Drug Interactions African-American patients, compared to Caucasian patients, may need to be titrated to higher tacrolimus extended-release capsules dosages to attain comparable trough concentrations.

Patients with severe hepatic impairment (Child-Pugh ≥ 10) may require a lower starting dosage of tacrolimus extended-release capsules, due to the reduced clearance and prolonged half-life.

Dose adjustments of tacrolimus extended-release capsules may be necessary when administered concomitantly with CYP3A inducers or CYP3A inhibitors or cannabidiol. 2.4 Therapeutic Drug Monitoring Measure tacrolimus whole blood trough concentrations at least two times on separate days during the first week after initiation of dosing and after a change in dosage, after a change in co-administration of CYP3A4 inducers and/or inhibitors or cannabidiol, or after a change in renal or hepatic function.

When interpreting measured concentrations, consider that the time to achieve tacrolimus steady state is approximately 7 days after initiating or changing the tacrolimus extended-release capsules dose.

Monitor tacrolimus whole blood trough concentrations using a validated assay [e.g., immunoassays or high performance liquid chromatography with tandem mass spectrometric detection (HPLC/MS/MS).

The immunosuppressive activity of tacrolimus is mainly due to the parent drug rather than to its metabolites.

Immunoassays may react with metabolites as well as the parent drug.

Therefore, whole blood tacrolimus trough concentrations obtained with immunoassays may be numerically higher than concentrations obtained with an assay using HPLC/MS/MS.

Comparison of the whole blood tacrolimus trough concentrations of patients to those described in the prescribing information and other published literature must be made with knowledge of the assay method(s) employed.

Tacrolimus extended-release capsules are supplied as listed in Table 19.

Table 19: Strengths of Tacrolimus Extended-Release Capsules 0.5 mg Oblong capsule with opaque yellowish pink cap and opaque light orange body.

Capsule is branded with dull red “SD-TC” on capsule body and dull red “0.5 mg” on the capsule cap.

Blister carton packed with an aluminum foil bag containing 5 blister cards of 10 capsules on each card. (NDC 71432-2001-1). 1 mg Oblong capsule with opaque light yellow cap and opaque light orange body.

Capsule is branded with dull red “SD-TC” on capsule body and dull red “1 mg” on the capsule cap.

Blister carton packed with an aluminum foil bag containing 5 blister cards of 10 capsules on each card. (NDC 71432-2002-1) 5 mg Oblong capsule with an opaque red-orange cap and opaque orange body.

Capsule is branded with dull red “SD-TC” on capsule body and dull red “5 mg” on the capsule cap.

Blister carton packed with an aluminum foil bag containing 5 blister cards of 10 capsules on each card. (NDC 71432-2003-1) Store and Dispense Store at 25°C (77°F); excursions permitted from 15° to 30°C (59° to 86°F) .

There is a pregnancy registry that monitors pregnancy outcomes in women exposed to tacrolimus extended-release capsules during pregnancy.

International (TPRI) is a voluntary pregnancy exposure registry that monitors outcomes of pregnancy in female transplant recipients and those fathered by male transplant recipients exposed to immunosuppressants including tacrolimus.

Healthcare providers are encouraged to advise their patients to register by contacting the Transplantation Pregnancy Registry International at 1-877-955-6877 or.

Tacrolimus can cause fetal harm when administered to a pregnant woman.

Data from postmarketing surveillance and

TPRI suggest that infants exposed to tacrolimus in utero are at a risk of prematurity, birth defects/congenital anomalies, low birth weight, and fetal distress.

Advise pregnant women of the potential risk to the fetus.

Administration of oral tacrolimus to pregnant rabbits and rats throughout the period of organogenesis was associated with maternal toxicity/lethality, and an increased incidence of abortion, malformation and embryofetal death at clinically relevant doses [0.5 the maximum recommended clinical dose (0.2 mg/kg/day), on a mg/m 2 basis. Administration of oral tacrolimus to pregnant rats after organogenesis and throughout lactation produced maternal toxicity, effects on parturition, reduced pup viability and reduced pup weight at clinically relevant doses (0.8 the maximum recommended clinical dose, on a mg/m 2 basis). Administration of oral tacrolimus to rats prior to mating, and throughout gestation and lactation produced maternal toxicity/lethality, marked effects on parturition, embryofetal loss, malformations, and reduced pup viability at clinically relevant doses (0.8 times the maximum recommended clinical dose, on a mg/m 2 basis). Interventricular septal defects, hydronephrosis, craniofacial malformations and skeletal effects were observed in offspring that died. The background risk of major birth defects and miscarriage in the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo-Fetal Risk Risks during pregnancy are increased in organ transplant recipients. The risk of premature delivery following transplantation is increased. Pre-existing hypertension and diabetes confer additional risk to the pregnancy of an organ transplant recipient. Pre-gestational and gestational diabetes are associated with birth defects/congenital anomalies, hypertension, low birth weight and fetal death. Cholestasis of pregnancy (COP) was reported in 7% of liver or liver-kidney (LK) transplant recipients, compared with approximately 1% of pregnancies in the general population. However, COP symptoms resolved postpartum and no long-term effects on the offspring were reported. Maternal Adverse Reactions Tacrolimus extended-release capsules may increase hyperglycemia in pregnant women with diabetes (including gestational diabetes). Monitor maternal blood glucose levels regularly. Tacrolimus extended-release capsules may exacerbate hypertension in pregnant women and increase pre-eclampsia. Monitor and control blood pressure. Fetal/Neonatal Adverse Reactions Renal dysfunction, transient neonatal hyperkalemia and low birth weight have been reported at the time of delivery in infants of mothers taking tacrolimus extended-release capsules. Labor or Delivery There is an increased risk for premature delivery (less than 37 weeks) following transplantation and maternal exposure to tacrolimus extended-release capsules. Data Human Data There are no adequate and well-controlled studies on the effects of tacrolimus in human pregnancy. Safety data from the TPRI and postmarketing surveillance suggest infants exposed to tacrolimus in utero have an increased risk for miscarriage, pre-term delivery (less than 37 weeks), low birth weight (less than 2,500 gram), birth defects/congenital anomalies and fetal distress. TPRI reported and 241 total pregnancies in kidney and liver transplant recipients exposed to tacrolimus, respectively. The TPRI pregnancy outcomes are summarized in Table 6. In the table below, the number of recipients exposed to tacrolimus concomitantly with mycophenolic acid (MPA) products during the preconception and first trimester periods is high (27% and 29% for kidney and liver transplant recipients, respectively). Because MPA products may also cause birth defects, the birth defect rate may be confounded and this should be taken into consideration when reviewing the data, particularly for birth defects. Birth defects observed include cardiac malformations, craniofacial malformations, renal/urogenital disorders, skeletal abnormalities, neurological abnormalities and multiple malformations. Table 6: TPRI-Reported Pregnancy Outcomes in Transplant Recipients with Exposure to Tacrolimus Kidney Liver Pregnancy Outcomes Includes multiple births and terminations. 462 253 Miscarriage 24.5% 25% Live births 331 180 Pre-term delivery (less than 37 weeks) 49% 42% Low birth weight (less than 2,500 gram) 42% 30% Birth defects 8% Birth defect rate confounded by concomitant MPA products exposure in over half of offspring with birth defects. 5% Additional information reported by TPRI in pregnant transplant patients receiving tacrolimus included diabetes during pregnancy in 9% of kidney recipients and 13% of liver recipients and hypertension during pregnancy in 53% of kidney recipients and 16.2% of liver recipients. Animal Data Administration of oral tacrolimus to pregnant rabbits throughout organogenesis produced maternal toxicity and abortion at 0.32 mg/kg (0.5 times the maximum recommended clinical dose [0.2 mg/kg/day], on a mg/m 2 basis).

At 1 mg/kg (1.6 times the maximum recommended clinical dose), embryofetal lethality and fetal malformations (ventricular hypoplasia, interventricular septal defect, bulbous aortic arch, stenosis of ductus arteriosus, omphalocele, gallbladder agenesis, skeletal anomalies) were observed.

Administration of 3.2 mg/kg oral tacrolimus (2.6 times the maximum recommended clinical dose) to pregnant rats throughout organogenesis produced maternal toxicity/lethality, embryofetal lethality and decreased fetal body weight in the offspring of C-sectioned dams; and decreased pup viability and interventricular septal defect in offspring of dams that delivered.

In a peri-/postnatal development study, oral administration of tacrolimus to pregnant rats during late gestation (after organogenesis) and throughout lactation produced maternal toxicity, effects on parturition, and reduced pup viability at 3.2 mg/kg (2.6 times the maximum recommended clinical dose); among these pups that died early, an increased incidence of kidney hydronephrosis was observed.

Reduced pup weight was observed at 1 mg/kg (0.8 times the maximum recommended clinical dose).

Administration of oral tacrolimus to rats prior to mating, and throughout gestation and lactation produced maternal toxicity/lethality, embryofetal loss and reduced pup viability at 3.2 mg/kg (2.6 times the maximum recommended clinical dose range).

Interventricular septal defects, hydronephrosis, craniofacial malformations and skeletal effects were observed in offspring that died.

Effects on parturition (incomplete delivery of nonviable pups) were observed at 1 mg/kg (0.8 times the maximum recommended clinical dose) .

information is approved for Astellas Pharma US, Inc.’s ASTAGRAF XL (tacrolimus extended-release capsules).

However, due to Astellas Pharma US, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

Clinical studies of tacrolimus extended-release capsules did not include sufficient numbers of patients aged and over to determine whether they respond differently from younger patients.

In Studies and 2, 29 patients were 65 years of age and older, and 3 patients were 75 years of age and over.

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.