Tacrolimus

1 INDICATIONS AND USAGE Tacrolimus Capsules USP is a calcineurin-inhibitor immuno-suppressant indicated for the prophylaxis of organ rejection in adult and pediatric patients receiving allogeneic liver, kidney, heart or lung transplants, in combination with other immunosuppressants. ( 1.1 ) 1.1 Prophylaxis of Organ Rejection in Kidney, Liver, Heart or Lung Transplant Tacrolimus Capsules USP is indicated for the prophylaxis of organ rejection, in adult and pediatric patients receiving allogeneic kidney transplant [see Clinical Studies ( 14.1 )], liver transplants [see Clinical Studies ( 14.2 )], heart transplant [see Clinical Studies ( 14.3 )], or lung transplant [see Clinical Studies ( 14.4 )] in combination with other immunosuppressants.

2 DOSAGE AND ADMINISTRATION 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 dosage adjustments for African-American patients ( 2.2 ), hepatic and renal impaired. ( 2.4 , 2.5 ) For complete dosing information see the Full Prescribing Information ADULT Patient Population Initial Oral Dosage (formulation) Whole Blood Trough Concentration Range 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 Lung Transplant With azathioprine or MMF 0.075 mg/kg/day 1 capsules, divided in two doses, every 12 hours Month 1-3: 10-20 ng/mL Month 4-12: 8-12 ng/mL MMF= Mycophenolate mofetil 1. Patients with cystic fibrosis may require higher doses due to lower bioavailability. 2. Dose at 0.1 mg/kg/day if antibody induction treatment is administered . PEDIATRIC Patient Population Initial Oral Dosage (formulation) Whole Blood Trough Concentration Range 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 divided in two doses, every 12 hours Month 1-12: 5-20 ng/mL Heart Transplant 0.3 mg/kg/day 2 capsules divided in two doses, every 12 hours Month 1-12: 5-20 ng/mL Lung Transplant 0.3 mg/kg/day 1, 2 capsules divided in two doses, every 12 hours Weeks 1-2: 10-20 ng/mL Week 2 to Month 12: 10-15 ng/mL 2.1 Important Administration Instructions Tacrolimus Capsules USP should not be used without supervision by a physician with experience in immunosuppressive therapy. Tacrolimus Capsules USP 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 USP may be taken with or without food. However, since the presence of food affects the bioavailability of Tacrolimus Capsules USP, 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 USP [see Drug Interactions ( 7.2 )] Tacrolimus Capsules USP should not be used simultaneously with cyclosporine. Tacrolimus Capsules USP or cyclosporine should be discontinued at least 24 hours before initiating the other. In the presence of elevated Tacrolimus Capsules USP or cyclosporine concentrations, dosing with the other drug usually should be further delayed. Therapeutic drug …

3 DOSAGE FORMS AND STRENGTHS 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 )

4 CONTRAINDICATIONS Tacrolimus Capsules USP are contraindicated in patients with a hypersensitivity to tacrolimus. Tacrolimus injection is contraindicated in patients with a hypersensitivity to HCO-60 (polyoxyl 60 hydrogenated castor oil). Hypersensitivity symptoms reported include dyspnea, rash, pruritus, and acute respiratory distress syndrome [see Adverse Reactions (6) ]. Hypersensitivity to tacrolimus or HCO-60 (polyoxyl 60 hydrogenated castor oil). ( 4 )

6 ADVERSE REACTIONS The following serious and otherwise important adverse drug reactions are discussed in greater detail in other sections of labeling: Lymphoma and Other Malignancies [see Warnings and Precautions ( 5.1 )] Serious Infections [see Warnings and Precautions ( 5.2 )] New Onset Diabetes After Transplant [see Warnings and Precautions ( 5.4 )] Nephrotoxicity [see Warnings and Precautions ( 5.5 )] Neurotoxicity [see Warnings and Precautions ( 5.6 )] Hyperkalemia [see Warnings and Precautions ( 5.7 )] Hypertension [see Warnings and Precautions ( 5.8 )] Anaphylactic Reactions with Tacrolimus Injection [see Warnings and Precautions ( 5.9 )] Myocardial Hypertrophy [see Warnings and Precautions ( 5.13 )] Pure Red Cell Aplasia [see Warnings and Precautions ( 5.15 )] Thrombotic Microangiopathy, Including Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura [ see Warnings and Precautions ( 5.16 )] The most common adverse reactions (≥15%) were abnormal renal function, hypertension, diabetes mellitus, fever, CMV infection, tremor, hyperglycemia, leukopenia, infection, anemia, bronchitis, pericardial effusion, urinary tract infection, constipation, diarrhea, headache, abdominal pain, insomnia, paresthesia, peripheral edema, nausea, hyperkalemia, hypomagnesemia, and hyperlipemia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Panacea Biotec Pharma Ltd. at 1-877-687-4130 or FDA at 1-800-FDA-1088 or www.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 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% …

7 DRUG INTERACTIONS 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 ) Therapeutic drug monitoring and dose reduction for tacrolimus should be considered when tacrolimus is co-administered with cannabidiol ( 5.17 , 7.3 ). 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 with MPA, 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 Tacrolimus1 Drug/Substance Class or Name Drug Interaction Effect Recommendations Grapefruit or grapefruit juice2 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 Inducers3: 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 Inhibitors3: Protease inhibitors (e.g, nelfinavir, telaprevir, boceprevir, ritonavir), azole antifungals (e.g., voriconazole, posaconazole, itraconazole, ketoconazole), antibiotics (e.g., clarithromycin, troleandomycin, chloramphenicol), nefazodone, letermovir, schisandra sphenanthera extracts May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation). A rapid sharp rise in tacrolimus levels may occur early, despite an immediate reduction of tacrolimus dose [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) ]. Early and frequent monitoring of tacrolimus whole blood trough levels should start within 1-3 days and continue monitoring as necessary. [see Warnings and Precautions (5.11) ] 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 and Administration (2.2 , 2.6 ) and Clinical Pharmacology (12.3) ]. Other drugs, such as: Magnesium and aluminum hydroxide antacids Metoclopramide May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., …

8 USE IN SPECIFIC POPULATIONS Pregnancy: Can cause fetal harm. Advise pregnant women of the potential risk to the fetus. ( 8.1 , 8.3 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy registry that monitors pregnancy outcomes in women exposed to Tacrolimus Capsules USP during pregnancy. The Transplantation Pregnancy Registry 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 https://www.transplantpregnancyregistry.org/ . Risk Summary 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 [see Human Data ]. 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 to 6.9 times the recommended clinical dose range [0.2 to 0.075 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 to 6.9 times the recommended clinical dose range, 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 to 6.9 times the recommended clinical dose range, on a mg/m 2 basis). Interventricular septal defects, hydronephrosis, craniofacial malformations and skeletal effects were observed in offspring that died [see Animal Data ] 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 may increase hyperglycemia in pregnant women with diabetes (including gestational diabetes). Monitor maternal blood glucose levels regularly [see Warnings and Precautions ( 5.4 )] Tacrolimus may exacerbate hypertension in pregnant women and increase pre-eclampsia. Monitor and control blood pressure [see Warnings and Precautions ( 5.7 , 5.8 )] 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. Labor or Delivery There is an increased risk for premature delivery ( 10) compared to healthy volunteers with normal hepat …

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).

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

10 OVERDOSAGE Limited overdosage experience is available. Acute overdosages of up to 30 times the intended dose have been reported. Almost all cases have been asymptomatic and all patients recovered with no sequelae. Acute overdosage was sometimes followed by adverse reactions consistent with those reported with the use of Tacrolimus Capsules USP [See Adverse Reactions ( 6.1 , 6.2 )] 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.

16 HOW SUPPLIED/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 43817- 421 -01 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 43817- 422 -01 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 43817- 423 -01 Bottle of 100 Note: Tacrolimus Capsules USP are not filled to maximum capsule capacity. Capsule contains labeled amount. Store and Dispense Store at 20°C to 25°C (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 USP should not be opened or crushed. Avoid inhalation or direct contact with skin or mucous membranes of the powder contained in Tacrolimus Capsules USP. 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 .