Tacrolimus Monohydrate

Approved Indications:

• Organ Transplantation:
• Prophylaxis of organ rejection in patients receiving allogeneic liver, kidney, or heart transplants.
• Use in combination with other immunosuppressants such as corticosteroids and azathioprine or mycophenolate mofetil.
• Topical Use (Non-transplant):
• Atopic Dermatitis (Eczema): Moderate to severe cases in adults and children (≥2 years) unresponsive to conventional therapies.

Important Off-Label / Clinically Accepted Uses:

• Myasthenia Gravis
• Lupus Nephritis
• Uveitis (non-infectious)
• Autoimmune Hepatitis
• Ulcerative Colitis (refractory)
• Psoriasis (severe or resistant)
• Nephrotic Syndrome (steroid-resistant)

Tacrolimus is a calcineurin inhibitor that suppresses immune responses by binding to an intracellular protein, FK506-binding protein (FKBP-12). This complex inhibits the phosphatase activity of calcineurin, a crucial step for the activation of T-lymphocytes through nuclear factor of activated T-cells (NF-AT). This suppression prevents transcription of interleukin-2 (IL-2) and other cytokines, thereby inhibiting T-cell proliferation and immune response against transplanted organs or inflammatory skin conditions.

• Absorption: Oral bioavailability is approximately 20–25%; affected by food (especially high-fat meals).
• Time to Peak Plasma Concentration: 1–3 hours post oral dose.
• Distribution: Extensively distributed; protein binding ~99% (mostly to albumin and alpha-1-acid glycoprotein).
• Metabolism: Extensively metabolized in the liver by CYP3A4 and CYP3A5 enzymes.
• Active Metabolites: Inactive or less active than parent compound.
• Half-life: ~12 hours (may vary by patient condition and ethnicity).
• Excretion: Primarily via bile in feces (>90%); <1% excreted unchanged in urine.
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• Pregnancy: Tacrolimus is classified as Pregnancy Category C. Animal studies have shown adverse fetal effects, but human data are limited. Use only if potential benefits outweigh risks.
• Lactation: Tacrolimus is excreted in human milk. Breastfeeding is not recommended due to potential immunosuppressive effects in the infant.

• Primary Class: Immunosuppressant
• Subclass: Calcineurin Inhibitor (Macrolide Lactone Immunosuppressant)

• Known hypersensitivity to tacrolimus or any component of the formulation
• Concomitant use with cyclosporine (increased nephrotoxicity)
• History of severe adverse effects with calcineurin inhibitors
• Uncontrolled infections

• Nephrotoxicity: Common and dose-dependent; monitor renal function regularly.
• Neurotoxicity: May cause tremors, seizures, or confusion.
• Hypertension & Hyperkalemia: Monitor blood pressure and electrolytes.
• Infections & Malignancies: Increased risk of opportunistic infections and lymphoma; monitor WBC and signs of infection.
• Diabetes Mellitus: Risk of post-transplant diabetes, especially in liver recipients.
• Monitoring Required: Blood trough levels, renal and liver function, BP, blood glucose.
• Topical Use: Avoid long-term or continuous use due to theoretical risk of skin cancer and lymphoma (black box warning in some countries).

Common (Systemic Use):

• Nephrotoxicity
• Hypertension
• Headache
• Tremor
• Hyperglycemia
• Nausea, diarrhea
• Insomnia

Serious:

• Post-transplant lymphoproliferative disorder (PTLD)
• Severe infections (viral, fungal, bacterial)
• Seizures, encephalopathy
• Cardiac arrhythmias
• Anaphylaxis (IV form)

Topical Use:

• Burning or stinging at application site
• Pruritus
• Erythema
• Skin infection (rare)

• CYP3A4 Inhibitors (↑ Tacrolimus levels):
• Ketoconazole, erythromycin, clarithromycin, ritonavir, grapefruit juice
• CYP3A4 Inducers (↓ Tacrolimus levels):
• Rifampin, phenytoin, carbamazepine, St. John’s Wort
• Additive Nephrotoxicity:
• NSAIDs, aminoglycosides, amphotericin B
• Drugs Increasing QT Prolongation Risk:
• Caution with fluoroquinolones, macrolides
• Live Vaccines:
• Avoid during and after therapy due to immunosuppression

• Updated TDM Ranges: Some guidelines (e.g., KDIGO) now recommend more individualized trough levels for long-term maintenance therapy.
• Topical Use Cautions: Renewed emphasis on limiting chronic use in children due to cancer risk concerns; alternative intermittent regimens recommended.
• Biosimilar Forms Available: Some regulatory bodies have approved tacrolimus biosimilars with demonstrated equivalence.

• Oral Capsules:
• Store below 25°C, protected from moisture.
• Keep in original packaging; avoid direct light.
• Topical Ointment:
• Store at 15–25°C.
• Do not refrigerate or freeze.
• IV Injection (if used):
• Store vials at 2–8°C.
• Use immediately after reconstitution; discard unused portion.