Tacrolimus (5 brand names, 6 dosage forms, 3 routes)
Available dosage forms: CAPSULE, INJECTABLE, CAPSULE, EXTENDED RELEASE, OINTMENT, TABLET, EXTENDED RELEASE, FOR SUSPENSION.
Routes of administration: ORAL, INJECTION, TOPICAL.
Brand Names
- ASTAGRAF XL
- ENVARSUS XR
- PROGRAF
- PROTOPIC
- TACROLIMUS
Boxed Warning
Increased risk for developing serious infections and malignancies with tacrolimus or other immunosuppressants that may lead to hospitalization or death. (5.1, 5.2)
Contraindications
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)].
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 PROGRAF 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)]
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 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).
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 [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.