Prograf (tacrolimus) is a cornerstone calcineurin inhibitor immunosuppressant, essential for the prevention of organ rejection in transplant recipients. Its potent mechanism of action selectively inhibits T-lymphocyte activation, providing a critical foundation for post-transplant maintenance therapy. Available in capsule and injection formulations, it is a mainstay protocol medication for kidney, liver, heart, and other solid organ transplants, requiring meticulous therapeutic drug monitoring to ensure optimal efficacy and safety.

Features

• Active Pharmaceutical Ingredient: Tacrolimus
• Available Formulations: Immediate-release capsules (0.5 mg, 1 mg, 5 mg), prolonged-release capsules, and injection for intravenous infusion
• Mechanism of Action: Potent calcineurin inhibitor that suppresses T-cell activation and proliferation by inhibiting calcineurin phosphatase
• Bioavailability: Exhibits variable oral bioavailability (approximately 17-22% for immediate-release), significantly influenced by food intake and other factors
• Metabolism: Primarily hepatically metabolized via the CYP3A4 isoenzyme system
• Half-life: Mean elimination half-life is approximately 35 hours in healthy subjects, with a wide range observed in patients
• Excretion: Primarily fecal

Benefits

• Provides highly effective prophylaxis against acute allograft rejection in solid organ transplant recipients.
• Offers a critical therapeutic option for patients refractory to other immunosuppressive regimens.
• Facilitates long-term graft survival when maintained within the narrow therapeutic window.
• Allows for personalized dosing regimens based on frequent therapeutic drug monitoring (TDM) of trough blood concentrations.
• Available in multiple formulations to accommodate different clinical scenarios and patient needs post-transplantation.

Common use

Prograf is indicated for the prophylaxis of organ rejection in patients receiving allogeneic kidney, liver, or heart transplants. It is used concomitantly with other immunosuppressive agents, typically corticosteroids and, in many protocols, an antiproliferative agent (e.g., mycophenolate mofetil). Therapy should be initiated under the supervision of a physician experienced in immunosuppressive therapy and the management of transplant patients. Its use is also established in certain cases of refractory rejection.

Dosage and direction

Dosing is highly individualized and must be titrated based on therapeutic drug monitoring to achieve target trough blood concentrations, which vary by organ transplanted, time since transplant, and institutional protocol.

• Oral Administration (Adults):
  • Kidney Transplant: Initial dose is typically 0.2 mg/kg/day, administered in two divided doses (every 12 hours). Dosing is adjusted to target trough concentrations.
  • Liver Transplant: Initial dose is typically 0.10 - 0.15 mg/kg/day, administered in two divided doses (every 12 hours).
  • Heart Transplant: Initial dose is typically 0.075 mg/kg/day, administered in two divided doses (every 12 hours).
• Administration: Must be taken consistently either with food or without food, as food decreases bioavailability. Capsules should be swallowed whole with water and not crushed, chewed, or opened.
• IV Administration: Reserved for patients unable to take oral medication. Dosed as a continuous infusion. The IV dose is typically 1/5th of the oral dose and should be switched to oral therapy as soon as clinically feasible.

Precautions

• Nephrotoxicity: Prograf can cause dose-dependent nephrotoxicity, which may be acute or chronic. Renal function must be monitored closely.
• Neurotoxicity: Adverse neurologic events, including tremor, headache, altered mental status, seizures, and posterior reversible encephalopathy syndrome (PRES), have been reported.
• Hyperglycemia: May cause insulin-dependent post-transplant diabetes mellitus (PTDM); blood glucose should be monitored regularly.
• Hypertension: Commonly occurs and requires management with antihypertensive therapy.
• Hyperkalemia: May occur; serum potassium levels should be monitored, particularly in patients with renal impairment.
• Malignancy and Infection: Immunosuppression increases susceptibility to infections and the risk of developing lymphoma and other malignancies.
• Pregnancy (Category C): Use only if the potential benefit justifies the potential risk to the fetus. Tacrolimus crosses the placenta.

Contraindications

Prograf is contraindicated in patients with a hypersensitivity to tacrolimus or any component of the formulation. Concomitant use with cyclosporine is contraindicated due to additive nephrotoxicity; Prograf dosing should begin at least 24 hours after discontinuing cyclosporine.

Possible side effect

A wide spectrum of adverse reactions is possible due to the drug’s potent immunosuppressive and pharmacological effects. Very common (>10%) and common (1-10%) side effects include:

• Infections: Increased risk of bacterial, viral (including CMV, BK virus), fungal, and parasitic infections.
• Renal: Impaired renal function, elevated blood urea nitrogen (BUN) and creatinine.
• Metabolic: Hyperglycemia, diabetes mellitus, hyperkalemia, hypomagnesemia, hyperuricemia.
• Cardiovascular: Hypertension, edema.
• Neurological: Tremor, headache, insomnia, paresthesia, dizziness, seizures.
• Gastrointestinal: Diarrhea, nausea, vomiting, abdominal pain, constipation.
• Hematologic: Anemia, leukocytosis, thrombocytopenia.
• Other: Alopecia, pruritus, rash, asthenia, fever, pain.

Drug interaction

Tacrolimus is a substrate of CYP3A4 and P-glycoprotein, making it susceptible to numerous clinically significant interactions.

• Strong Inhibitors of CYP3A4: (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, ritonavir) can significantly increase tacrolimus blood levels, increasing the risk of toxicity. Dose reduction and close monitoring are mandatory.
• Strong Inducers of CYP3A4: (e.g., rifampin, rifabutin, phenytoin, St. John’s Wort) can significantly decrease tacrolimus blood levels, increasing the risk of rejection. Dose increase and close monitoring are required.
• Nephrotoxic Drugs: Concomitant use with other nephrotoxic agents (e.g., aminoglycosides, amphotericin B, NSAIDs) may potentiate renal dysfunction.
• Potassium-Sparing Agents: Concomitant use with potassium-sparing diuretics, ACE inhibitors, or angiotensin II receptor antagonists may exacerbate hyperkalemia.
• Vaccines: Immunosuppressants may diminish the therapeutic effect of vaccines; live vaccines are contraindicated.

Missed dose

If a dose is missed, it should be taken as soon as possible on the same day. However, if it is close to the time for the next scheduled dose, the missed dose should be skipped. Patients should never double the next dose to make up for a missed one. The managing physician or transplant coordinator should be informed of the missed dose for further guidance, as it may necessitate additional drug level monitoring.

Overdose

Overdose is expected to produce exaggerated adverse effects, particularly nephrotoxicity, neurotoxicity (including tremors, headache, and altered mental status), hyperglycemia, and gastrointestinal disturbances. There is no specific antidote. Management involves general supportive measures and symptomatic treatment. Given its high molecular weight and extensive protein binding, tacrolimus is not dialyzable. All suspected overdoses require immediate medical attention.

Storage

• Store capsules at room temperature, between 20°C to 25°C (68°F to 77°F), in the original container.
• Protect from light and moisture.
• Keep out of reach of children and pets.
• Do not use after the expiration date printed on the packaging.

Disclaimer

This information is for educational purposes only and is not a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician, transplant team, or other qualified health provider with any questions you may have regarding a medical condition or medication. Never disregard professional medical advice or delay in seeking it because of something you have read here. Dosing and management must be directed by a qualified healthcare professional experienced in transplant medicine.

Reviews

“Prograf has been the bedrock of my immunosuppressive regimen since my liver transplant seven years ago. While the side effects, particularly the tremors initially, were challenging, meticulous level monitoring by my team has kept them manageable. The trade-off for a functioning graft is unequivocal.” - J.M., Transplant Recipient

“As a transplant nephrologist, tacrolimus remains the gold standard for maintenance immunosuppression. Its efficacy is unparalleled, but it demands immense respect. It is not a ‘set-and-forget’ drug; it requires a dedicated partnership between the patient and the healthcare team for lifelong success, focusing on vigilant therapeutic drug monitoring and management of metabolic complications.” - Dr. A. Sharma, MD