Prograf (tacrolimus) is a cornerstone calcineurin inhibitor immunosuppressant, essential for the prevention of organ rejection in transplant recipients. It functions by selectively inhibiting T-lymphocyte activation, a critical pathway in the cellular immune response. This precise mechanism allows for potent and effective management of the immune system, providing a solid foundation for long-term graft survival. Its use is integral in heart, kidney, and liver transplantation protocols worldwide.

Features

• Active Pharmaceutical Ingredient: Tacrolimus
• Available formulations: Immediate-release capsules, prolonged-release capsules, and injection for intravenous infusion
• Mechanism of Action: Calcineruin inhibitor; binds to FKBP-12 to form a complex that inhibits calcineurin phosphatase
• Bioavailability: Exhibits variable oral bioavailability (approximately 17-22% for immediate-release), significantly influenced by food intake
• Metabolism: Primarily hepatic, via the CYP3A4 enzyme system
• Half-life: Mean elimination half-life is approximately 35 hours in stable adult liver transplant patients
• Excretion: Primarily fecal

Benefits

• Potent and selective suppression of T-cell activation, directly targeting a primary pathway of allograft rejection.
• Provides a critical therapeutic option for patients who are refractory to or intolerant of cyclosporine-based regimens.
• Contributes to significantly improved long-term graft and patient survival rates in major organ transplants.
• Offers formulation flexibility (immediate-release, prolonged-release) to tailor therapy to individual patient needs and adherence profiles.
• Supported by decades of extensive clinical data and real-world experience, establishing a well-understood efficacy and safety profile.
• Forms the backbone of many modern multi-drug immunosuppressive protocols, allowing for potential steroid-sparing regimens.

Common use

Prograf is indicated for the prophylaxis of organ rejection in patients receiving allogeneic liver, kidney, or heart transplants. It is used concomitantly with other immunosuppressive agents, most commonly corticosteroids and, in many cases, an antiproliferative agent like mycophenolate mofetil. Therapy is typically initiated immediately post-transplant and is intended for long-term maintenance immunosuppression. Its use may also be considered in rescue therapy for patients experiencing rejection episodes on other immunosuppressive regimens.

Dosage and direction

Dosing is highly individualized and must be managed under the close supervision of a transplant specialist. Dosing is based on ideal body weight and targeted to achieve specific whole blood trough concentrations.

• Initial Oral Dose (Adults):
  • Liver transplantation: 0.10 - 0.15 mg/kg/day in two divided doses (every 12 hours).
  • Kidney transplantation: 0.2 mg/kg/day in two divided doses (every 12 hours).
  • Heart transplantation: 0.075 mg/kg/day in two divided doses (every 12 hours).
• Administration: Must be taken consistently either with food or without food, as food decreases bioavailability. The chosen method (fasting vs. with food) must remain constant. Capsules should be swallowed whole with water and not crushed, chewed, or opened.
• Therapeutic Drug Monitoring (TDM): Crucial for safe and effective use. Dosage adjustments are guided by frequent monitoring of 12-hour trough blood concentrations (Cmin), target ranges for which are transplant-type and time-post-transplant specific (e.g., typically 5-15 ng/mL early post-transplant, lower for maintenance).
• IV Administration: Reserved for patients unable to take oral medication. Dosed as a continuous infusion at 0.03-0.05 mg/kg/day. Patients should be switched to oral therapy as soon as clinically feasible.

Precautions

• Nephrotoxicity: Prograf can cause dose-dependent and concentration-dependent renal impairment. Renal function (serum creatinine, BUN) must be monitored closely. The risk is increased with other nephrotoxic drugs.
• Neurotoxicity: Patients may experience severe neurotoxic events, including tremor, headache, altered mental status, seizures, and coma. Risk factors include high trough concentrations, hepatic impairment, and concomitant use of other neurotoxic agents.
• Hyperkalemia: May occur; serum potassium levels should be monitored. Concomitant use of potassium-sparing diuretics or potassium supplements should be undertaken with caution.
• Hypertension: Common side effect that often requires management with antihypertensive therapy.
• Hyperglycemia: Can post-transplant diabetes mellitus (PTDM); blood glucose should be monitored regularly.
• Malignancy and Serious Infections: Immunosuppression increases susceptibility to infections and the risk of developing lymphoma and other malignancies, particularly of the skin. Patients should be advised to limit UV exposure and use protective clothing and sunscreen.
• Pregnancy (Category C): Should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Contraindications

Prograf is contraindicated in patients with a hypersensitivity to tacrolimus or any other component of the formulation. The injection is additionally contraindicated in patients with a hypersensitivity to castor oil (a component of the injectable formulation).

Possible side effect

A wide range of adverse reactions has been reported, many of which are dose/concentration-dependent.

• Very Common (>10%): Tremor, headache, diarrhea, nausea, hypertension, renal dysfunction, hyperglycemia, insomnia.
• Common (1-10%): Abdominal pain, vomiting, constipation, anemia, leukocytosis, hypomagnesemia, hyperkalemia, hypokalemia, hyperuricemia, rash, pruritus, back pain, fever, asthenia, paresthesia.
• Serious: Nephrotoxicity, neurotoxicity (including posterior reversible encephalopathy syndrome - PRES), severe infections (bacterial, viral, fungal, protozoal), cardiac arrhythmias, QT prolongation, pure red cell aplasia, hepatic dysfunction, anaphylaxis.

Drug interaction

Prograf is a substrate of CYP3A4 and P-glycoprotein (P-gp). Concomitant use with agents that affect these pathways can dramatically alter its blood concentrations.

• Strong Inhibitors of CYP3A4 (Increase Tacrolimus Levels): Ketoconazole, itraconazole, voriconazole, clarithromycin, erythromycin, diltiazem, verapamil, grapefruit juice. Concomitant use requires significant tacrolimus dose reduction and frequent TDM.
• Strong Inducers of CYP3A4 (Decrease Tacrolimus Levels): Rifampin, rifabutin, phenytoin, St. John’s Wort, carbamazepine. Concomitant use will likely require an increase in tacrolimus dose and frequent TDM.
• Nephrotoxic Agents (Additive Risk): Aminoglycosides, amphotericin B, NSAIDs, ganciclovir. Combined use increases the risk of renal damage.
• Other Interactions: Potassium-sparing diuretics (risk of hyperkalemia), live vaccines (diminished efficacy and risk of infection), other immunosuppressants (additive immunosuppressive effect).

Missed dose

If a dose is missed, it should be taken as soon as it is remembered on the same day. If it is almost time for the next dose, the missed dose should be skipped. Patients should never take a double dose to make up for a missed one. The managing physician or transplant coordinator should be informed of the missed dose, especially if it occurs frequently, as it may impact trough level monitoring.

Overdose

Overdose would be expected to amplify the drug’s known adverse effects, particularly renal impairment, neurological symptoms (tremor, headache, altered mental status), hyperkalemia, and QT prolongation. There is no specific antidote. Management is supportive and includes continuous monitoring of vital signs and ECG, frequent assessment of tacrolimus blood levels, and treatment of specific symptoms. Hemodialysis is not effective in clearance due to high protein binding and extensive distribution in red blood cells. Charcoal hemoperfusion may be considered in severe cases.

Storage

• Store capsules at room temperature (20°C to 25°C or 68°F to 77°F), with excursions permitted between 15°C and 30°C (59°F to 86°F).
• Protect from light and moisture. Keep in the original container.
• Do not freeze.
• Keep out of reach of children and pets.

Disclaimer

This information is for educational and informational purposes only and does not constitute medical advice. It is not a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician, transplant specialist, 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 administration must be strictly directed by a qualified healthcare professional familiar with your individual medical history.

Reviews

“Prograf has been the bedrock of my immunosuppressive regimen for over a decade post-kidney transplant. While managing the side effects (tremors, initially) and the constant blood draws for levels was challenging, the trade-off for a functioning graft is undeniable. Its efficacy is proven, and my team has deep experience titrating it.” - M.C., Kidney Transplant Recipient (12 years)

“As a transplant pharmacist, Prograf is a drug I manage daily. Its narrow therapeutic index and extensive interaction profile make it demanding, but also highly controllable. The ability to monitor levels and make precise adjustments is powerful. It remains a gold-standard agent for a reason, though it demands immense respect and vigilance from both the clinical team and the patient.” - Dr. A. Sharma, Clinical Transplant Pharmacist

“The initial period on Prograf was difficult with significant tremors and headaches, but these subsided as my dose was lowered to a maintenance level. The constant vigilance regarding infections and sun exposure is a lifelong commitment. However, the alternative is unthinkable. It’s a powerful drug that gives me my life back, but it is not without its significant demands.” - J.L., Liver Transplant Recipient (5 years)