Tacrolimus is a calcineurin-inhibitor immunosuppressant indicated for the prophylaxis of organ rejection in adult and pediatric patients receiving allogeneic liver, kidney, heart, or lung transplants, in combination with other immunosuppressive agents.

Tacrolimus binds to the intracellular protein FKBP-12. A complex is then formed with tacrolimus–FKBP-12, calcium, calmodulin, and calcineurin (a ubiquitous intracellular enzyme). This complex inhibits the phosphatase activity of calcineurin. As a result, dephosphorylation and nuclear translocation of key transcription factors such as nuclear factor of activated T-cells (NF-AT) and nuclear factor kappa-light-chain enhancer of activated B-cells (NF-κB) are blocked.

Tacrolimus suppresses the expression and/or production of multiple cytokines, including IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, interferon-γ, tumor necrosis factor-α, and granulocyte-macrophage colony-stimulating factor (GM-CSF). It also reduces IL-2 receptor expression and nitric oxide production, induces apoptosis, and increases transforming growth factor-β production, contributing to immunosuppressive effects. Overall, it inhibits T-lymphocyte activation and proliferation as well as T-helper cell–dependent B-cell responses, resulting in immunosuppression.

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, heart, or lung 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.

Initial Oral Tacrolimus Capsules Dosage Recommendations and Whole Blood Trough Concentration Range in Adults:

Note: In lung transplantation, cystic fibrosis patients may have a reduced bioavailability of orally administered tacrolimus resulting in the need for higher doses to achieve target tacrolimus trough concentrations. Monitor tacrolimus trough concentrations and adjust the dose accordingly.

Initial Oral Tacrolimus Capsules Dosage Recommendations and Whole Blood Trough Concentration Range in Children:

Note: In lung transplantation, cystic fibrosis patients may have a reduced bioavailability of orally administered tacrolimus resulting in the need for higher doses to achieve target tacrolimus trough concentrations. Monitor tacrolimus trough concentrations and adjust the dose accordingly.

• Mycophenolic acid products: May increase MPA exposure after switching from cyclosporine to tacrolimus; monitor for toxicity and adjust dose if needed.
• Nelfinavir and grapefruit juice: Increase tacrolimus levels via CYP3A inhibition; avoid concurrent use.
• CYP3A inhibitors: Increase tacrolimus concentrations; monitor levels and adjust dose accordingly.
• CYP3A4 inducers: Decrease tacrolimus concentrations; dose adjustment and monitoring required.
• Cannabidiol: May require therapeutic drug monitoring and dose reduction when used together.

Hypersensitivity to tacrolimus or HCO-60 (polyoxyl 60 hydrogenated castor oil).

Common adverse effects (≥15%) include 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 hyperlipidemia.

Pregnancy: May cause fetal harm. Patients should be informed of potential risks.

Not interchangeable with extended-release tacrolimus products: risk of medication errors; patients/caregivers should be instructed to identify capsule appearance correctly.

New-onset diabetes after transplantation: monitor blood glucose regularly.

Nephrotoxicity (acute or chronic): may require dose reduction; use caution with other nephrotoxic drugs.

Neurotoxicity: including Posterior Reversible Encephalopathy Syndrome (PRES); monitor neurological symptoms and reduce or discontinue if needed.

Hyperkalemia: monitor serum potassium; caution when used with other potassium-increasing agents.

Hypertension: may require antihypertensive therapy; monitor for drug interactions.

Anaphylactic reactions (IV form): observe closely for signs of hypersensitivity during injection use.

Not recommended with sirolimus: especially in liver and heart transplant due to increased risk of serious adverse effects.

Myocardial hypertrophy: dose reduction or discontinuation may be required.

Immunizations: avoid live vaccines during therapy.

Pure red cell aplasia: consider discontinuation if occurs.

Thrombotic microangiopathy (including HUS and TTP): may occur, especially in patients with infections or concomitant risk medications.

Acute overdoses (up to 30-fold) may cause tremor, renal dysfunction, hypertension, and edema. Activated charcoal has been used in some cases, but evidence is limited. Management is mainly supportive and symptomatic.

Drugs affecting the immune response

Store below 30°C in a dry place, protected from light and moisture. Keep out of reach of children.