Tacrolimus: uses, appearance and warnings

Tacrolimus capsules are a calcineurin-inhibitor immunosuppressant 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 or Heart Transplant Tacrolimus capsules are indicated for the prophylaxis of organ rejection, in adult and pediatric patients receiving allogeneic kidney transplant [see Clinical Studies ( 14.1 )] , liver transplant [see Clinical Studies ( 14.2 )] , or heart transplant [see Clinical Studies ( 14.3 )] in combination with other immunosuppressants. Additional information pertaining to use in adult and pediatric populations for lung transplantation is approved for Astellas Pharma US, Inc.'s Prograf® products. However, due to Astellas Pharma US, Inc.'s marketing exclusivity rights (ODE-360), this drug product is not labeled with that information.

Tacrolimus capsules USP, are hard gelatin capsules for oral administration containing anhydrous tacrolimus, USP as follows: Tacrolimus capsules USP, 0.5mg: Opaque light yellow color, size "4" hard gelatin capsules imprinted with "C5" "0.5mg" on cap with black ink, containing white to off white granular powder. Tacrolimus capsules USP, 1mg: Opaque white color, size "4" hard gelatin capsules imprinted with "C6" "1 mg" on cap with black ink, containing white to off white granular powder. Tacrolimus capsules USP, 5mg: Opaque grayish red color, size "4" hard gelatin capsules imprinted with "C7'' "5mg" on cap with black ink, containing white to off white granular powder. Capsules: 0.5 mg, 1 mg and 5 mg ( 3 )

16.1 Tacrolimus Capsules, USP Strength 0.5 mg (containing the equivalent of 0.5 mg anhydrous tacrolimus USP) 1 mg (containing the equivalent of 1 mg anhydrous tacrolimus USP) 5 mg (containing the equivalent of 5 mg anhydrous tacrolimus USP) Shape capsule capsule capsule Color Cap light yellow white grayish red Body light yellow white grayish red Imprint Cap "C5" "0.5mg" "C6" "1mg" "C7" "5mg" Body Not Available Not Available Not Available 30 count bottle NDC 85972-101-30 NDC 85972-102-30 NDC 85972-103-30 100 count bottle NDC 85972-101-01 NDC 85972-102-01 NDC 85972-103-01 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 (68°F to 77°F); excursions permitted 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. Wearing disposable gloves is recommended during dilution of the injection in the hospital and when wiping any spills. 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 .

Hypersensitivity to tacrolimus or HCO-60 (polyoxyl 60 hydrogenated castor oil). ( 4 ) Tacrolimus capsules 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) ] .

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. ( 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. ( 5.15 ) Thrombotic Microangiopathy, Including Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura: May occur, especially in patients with infections and certain concomitant medications. ( 5.16 ) 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 . 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 changes; exposure 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: Polyomavirus-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 for 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 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 or 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 due to Tacrolimus and Drug Interactions Tacrolimus, like other calcineurin inhibitors, can cause acute or chronic nephrotoxicity in transplant patients due to its vasoconstrictive effect on renal vasculature, toxic tubulopathy and tubular-interstitial effects. Nephrotoxicity was reported in clinical trials [see Adverse Reactions ( 6.1 )]. Acute renal impairment associated with tacrolimus toxicity can result in high serum creatinine, hyperkalemia, decreased secretion of urea and hyperuricemia, and is usually reversible. In patients with elevated serum creatinine and tacrolimus whole blood trough concentrations greater than the recommended range, consider dosage reduction or temporary interruption of tacrolimus administration. 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). When tacrolimus is used concurrently with other known nephrotoxic drugs, monitor renal function and tacrolimus blood concentrations, and adjust doses of both tacrolimus and/or concomitant medications during concurrent use [see Drug Interactions ( 7.2 )]. 5.6 Neurotoxicity Tacrolimus may cause a spectrum of neurotoxicities. …

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 Concord Biotech Limited at Telephone: 1-855-407-0586 or FDA at 1-800-FDA-1088 or www.fda.g ov/medwatch. …

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 ). …