Prograf

Prograf The active ingredient of the drug (Tacrolimus) binds to cytosolic protein (FKBP12), responsible for the intracellular accumulation of the drug. Designed for the prevention and treatment of allograft liver, kidneys and heart rejection reactions, including those resistant to standard immunosuppressive therapy regimes.

Product dosage: 0.5mg
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Product dosage: 1mg
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Synonyms Protopic

Prograf (tacrolimus) is a cornerstone calcineurin inhibitor immunosuppressant medication, critically indicated for the prophylaxis of organ rejection in patients receiving allogeneic liver, kidney, or heart transplants. It is a macrolide lactone antibiotic that exerts its potent immunosuppressive effects by selectively inhibiting T-lymphocyte activation, a pivotal step in the immune response against foreign tissue. This guide provides a comprehensive, expert-level overview of its pharmacology, clinical application, and essential safety information for healthcare professionals managing post-transplant care.

Features

• Active Ingredient: Tacrolimus (a macrolide lactone immunosuppressant).
• Mechanism of Action: Binds to the FKBP-12 protein, forming a complex that inhibits calcineurin phosphatase. This blockade prevents the dephosphorylation and nuclear translocation of NFAT (Nuclear Factor of Activated T-cells), thereby inhibiting T-lymphocyte activation and the subsequent interleukin synthesis.
• Available Formulations: Immediate-release capsules (0.5 mg, 1 mg, 5 mg) and a prolonged-release formulation for once-daily administration.
• Bioavailability: Exhibits variable and incomplete oral bioavailability (approximately 17-22% in adult liver transplant patients), highly dependent on food intake and other factors.
• Metabolism: Extensively metabolized hepatically primarily by the CYP3A4 isoenzyme system.
• Half-life: Mean elimination half-life is approximately 35 hours in healthy subjects and can be significantly longer in patients with hepatic impairment.
• Therapeutic Drug Monitoring (TDM) Required: Therapy MUST be monitored by frequent quantitative assessment of whole blood tacrolimus concentrations due to its narrow therapeutic index and significant inter- and intra-patient variability in pharmacokinetics.

Benefits

• Superior Efficacy in Rejection Prophylaxis: Demonstrated high efficacy in preventing acute rejection episodes in solid organ transplant recipients, with some studies showing superior outcomes compared to older calcineurin inhibitors.
• Corticosteroid-Sparing Effect: Allows for significant reduction or eventual elimination of corticosteroid use in maintenance immunosuppression protocols, thereby mitigating long-term steroid-related adverse effects.
• Flexible Dosing Protocols: Available in both immediate and prolonged-release formulations, allowing for tailored regimens that can improve adherence and potentially stabilize trough levels.
• Established Safety Profile: Decades of clinical use have resulted in a well-characterized and manageable side effect profile, allowing clinicians to proactively monitor and mitigate risks.
• Foundation of Combination Therapy: Serves as the primary immunosuppressive agent in most modern multi-drug regimens, effectively synergizing with antimetabolites (e.g., mycophenolate mofetil) and mTOR inhibitors.

Common use

Prograf is exclusively indicated for the prophylaxis of organ rejection in patients receiving allogeneic transplants. Its primary uses include:

• Liver Transplantation: Prophylaxis of rejection in adult and pediatric patients.
• Kidney Transplantation: Prophylaxis of rejection in adult and pediatric patients. It is often used in conjunction with other immunosuppressants.
• Heart Transplantation: Prophylaxis of rejection in adult patients. In some cases, it may be used off-label for the prevention of rejection in other solid organ transplants (e.g., lung, pancreas) or for the treatment of certain autoimmune conditions under highly specialized care, though this is not its approved indication.

Dosage and direction

Administration is highly individualized and MUST be under the direct supervision of a transplant specialist.

• Initial Dosing: For adult liver transplant patients, oral initial dosing is typically 0.10-0.15 mg/kg/day in two divided doses (every 12 hours). For kidney and heart transplant patients, it is typically 0.15-0.20 mg/kg/day in two divided doses. Pediatric patients often require higher doses per body weight.
• Administration: Must be taken consistently either 1 hour before or 2 hours after a meal, as food significantly decreases bioavailability. The prolonged-release formulation should be taken once daily in the morning, consistently with or without food.
• Therapeutic Drug Monitoring (TDM): Dosing is strictly adjusted based on frequent monitoring of 12-hour trough whole blood concentrations (Cmin). Target trough levels are higher immediately post-transplant and are gradually reduced during maintenance therapy. Typical target ranges (vary by institution and organ):
  • Early Post-Transplant: 10-15 ng/mL
  • Months 2-3: 8-12 ng/mL
  • Maintenance (after 3-6 months): 5-10 ng/mL
• Do not switch between immediate-release and prolonged-release formulations without medical supervision, as they are not bioequivalent.

Precautions

• Nephrotoxicity: Prograf can cause dose-dependent and concentration-dependent renal dysfunction. Monitor serum creatinine and BUN closely. The risk is increased with concurrent use of other nephrotoxic drugs.
• Neurotoxicity: Monitor for tremors, headache, altered mental status, seizures, and posterior reversible encephalopathy syndrome (PRES). Risk factors include hepatic impairment, high trough concentrations, and concomitant use with other neurotoxic agents.
• Hyperglycemia / Diabetes Mellitus: May cause insulin-dependent post-transplant diabetes mellitus (PTDM), which may be reversible upon discontinuation. Monitor blood glucose regularly.
• Hypertension: Commonly occurs and usually requires management with antihypertensive agents.
• Hyperkalemia: May occur; monitor serum potassium levels. Avoid potassium-sparing diuretics.
• Malignancy and Infections: Immunosuppression increases susceptibility to infections (viral, bacterial, fungal, protozoal) and the risk of developing lymphoma and other malignancies, particularly skin cancer. Regular skin examinations are crucial.
• 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 known hypersensitivity to tacrolimus or any component of the formulation, including castor oil (derivative) found in the injection.
• Concomitant use with cyclosporine, as both are nephrotoxic and their combined use is not recommended.
• Concomitant use with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin) unless the benefit outweighs the risk and with close monitoring, as this can lead to severely elevated tacrolimus levels.

Possible side effect

Adverse reactions are common and often related to trough concentrations.

• Very Common (>10%): Tremor, headache, diarrhea, nausea, hypertension, renal impairment, hyperglycemia, insomnia.
• Common (1-10%): Anemia, leukocytosis, hypomagnesemia, hyperkalemia, hypokalemia, hyperuricemia, abdominal pain, vomiting, rash, pruritus, asthenia, fever, pain, peripheral edema.
• Less Common: Seizures, confusion, encephalopathy, psychosis, anxiety, depression, hearing loss, tinnitus, arrhythmias, heart failure, pancreatitis, hepatitis, leukopenia, thrombocytopenia, hemolytic uremic syndrome, allergic reactions, alopecia, photosensitivity.

Drug interaction

Prograf is a major substrate of CYP3A4 and P-glycoprotein (P-gp), making it highly susceptible to interactions.

• Increase Tacrolimus Levels (Risk of Toxicity):
  • Strong CYP3A4 Inhibitors: Ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin.
  • Moderate CYP3A4 Inhibitors: Fluconazole, erythromycin, diltiazem, verapamil, nicardipine, cimetidine, chloramphenicol.
  • Other: Grapefruit juice, nefazodone, boceprevir, telaprevir, HIV protease inhibitors (e.g., ritonavir), cannabidiol (Epidiolex®).
• Decrease Tacrolimus Levels (Risk of Rejection):
  • Strong CYP3A4 Inducers: Rifampin, rifabutin, St. John’s Wort, phenytoin, carbamazepine, phenobarbital.
• Additive Nephrotoxicity: Concomitant use with other nephrotoxic agents (e.g., aminoglycosides, amphotericin B, cisplatin, ganciclovir, NSAIDs, cyclosporine).
• Additive Neurotoxicity: Concomitant use with other neurotoxic compounds.
• Vaccines: Live vaccines should be avoided. The immune response to inactivated vaccines may be diminished.

Missed dose

• If a dose is missed, it should be taken as soon as possible on the same day.
• If it is closer to the time of the next dose, the missed dose should be skipped. The patient 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, as it may necessitate additional therapeutic drug monitoring.

Overdose

• Symptoms: Overdose is expected to produce exaggerated adverse effects, particularly severe nephrotoxicity, neurotoxicity (tremor, headache, mental status changes, seizures), hyperglycemia, and gastrointestinal symptoms.
• Management: There is no specific antidote. Management consists of immediate general supportive measures and symptomatic treatment. Consider drug discontinuation and frequent monitoring of tacrolimus levels. Due to its high molecular weight and extensive binding to erythrocytes and plasma proteins, tacrolimus is not dialyzable. Charcoal hemoperfusion may be considered in severe cases.

Storage

• Store at room temperature between 20°C to 25°C (68°F to 77°F). Excursions are permitted between 15°C and 30°C (59°F and 86°F).
• Keep in the original container and protect from light and moisture.
• Keep out of reach of children and pets.

Disclaimer

This information is for educational and professional medical reference purposes only and is not a substitute for the professional judgment of a healthcare provider in diagnosing and treating patients. The content does not cover all possible uses, directions, precautions, interactions, or adverse effects. The author is not liable for any errors, omissions, or for any outcomes resulting from the use of this information. The prescribing physician remains the ultimate authority regarding a patient’s specific therapeutic regimen. Always consult the official FDA-approved prescribing information before administering any medication.

Reviews

• “As a transplant nephrologist for over 20 years, tacrolimus remains the gold standard in our immunosuppressive armamentarium. Its efficacy is undeniable, but it demands immense respect for its narrow therapeutic window. Meticulous TDM and patient education are non-negotiable for successful long-term outcomes.” – Transplant Nephrologist, Major Academic Center
• “The introduction of the once-daily formulation has been a game-changer for adherence in our pediatric heart transplant population. Stabilizing levels has become somewhat more predictable, though the fundamental challenges of inter-patient variability remain.” – Pediatric Transplant Pharmacist
• “Managing the side effect profile, particularly the metabolic complications like PTDM and nephrotoxicity, is the daily challenge. It’s a powerful but unforgiving drug that requires a vigilant, multidisciplinary team approach for each patient.” – Transplant Coordinator
• “From a patient perspective, the side effects (tremors, headaches) were significant initially but became manageable as my levels stabilized. The trade-off for a functioning kidney is one I accept, but it requires constant blood tests and strict routine.” – Kidney Transplant Recipient (5 years post-op)