Prograf

I N S T R U C T I O N for medical use of the medicinal product PROGRAF® (PROGRAF®)

Composition:

Active substance: tacrolimus;

1 ml of solution contains 5 mg of tacrolimus;

Excipients: polyoxyl 40 hydrogenated castor oil; anhydrous ethanol.

Pharmaceutical form. Concentrate for solution for intravenous administration.

Main physicochemical properties: clear, colorless solution.

Pharmacotherapeutic group. Immunosuppressant. Calcineurin inhibitor. ATC code L04AD02.

Pharmacological properties.

Pharmacodynamics.

At the molecular level, the effects of tacrolimus are mediated by binding to a cytosolic protein (FKBP12), which is responsible for intracellular accumulation of the drug. The FKBP12-tacrolimus complex specifically and competitively binds to calcineurin and inhibits it, resulting in calcium-dependent inhibition of T-cell signal transduction pathways, thereby preventing transcription of a discrete group of lymphokine genes.

Tacrolimus is a highly potent immunosuppressive agent that suppresses the formation of cytotoxic lymphocytes, which are primarily responsible for transplant rejection, reduces T-cell activation, T-helper-dependent B-cell proliferation, as well as production of lymphokines (such as interleukins-2, -3, and γ-interferon) and expression of the interleukin-2 receptor.

Pharmacokinetics.

Distribution

The distribution pattern of tacrolimus after intravenous administration can be described as biphasic.

In systemic circulation, tacrolimus is extensively bound to erythrocytes. The blood-to-plasma concentration ratio in undiluted blood is approximately 20:1. In plasma, the drug is highly bound (>98.8%) to proteins, primarily serum albumin and α-1-acid glycoprotein.

Tacrolimus is widely distributed throughout the body. The volume of distribution at steady state, based on plasma concentrations, is approximately 1,300 L (in healthy volunteers). The corresponding value based on undiluted blood averages 47.6 L.

Tacrolimus is a drug with low clearance. In healthy volunteers, the mean value of total clearance, estimated based on drug concentrations in undiluted blood, is 2.25 L/hour. In adult patients with liver and kidney transplants, the values are 4.1 L/hour and 6.7 L/hour, respectively. Total clearance in adults with liver transplants is approximately twice as high as in healthy volunteers.

The elimination half-life of tacrolimus is prolonged. In healthy volunteers, the mean half-life based on concentrations in undiluted blood is approximately 43 hours. In adult and pediatric liver transplant patients, the half-life averages 11.7 and 12.4 hours, respectively, compared to 15.6 hours in adult kidney transplant patients.

Metabolism

In vitro studies have identified eight metabolites, of which only one exhibits significant immunosuppressive activity.

Tacrolimus is extensively metabolized by hepatic microsomal cytochrome P450 3A4 (CYP3A4) and cytochrome P450 3A5 (CYP3A5).

Elimination

After administration of radiolabeled (14C) tacrolimus, the majority of radioactivity was excreted in feces. Approximately 2% is excreted in urine. Less than 1% of unchanged tacrolimus was found in urine and feces, indicating that tacrolimus is almost completely metabolized prior to elimination. The primary route of elimination is biliary.

Clinical characteristics.

Indications.

Prophylaxis and treatment of allogeneic liver, kidney, and heart transplant rejection.

Treatment of allogeneic transplant rejection resistant to other immunosuppressive therapy regimens.

Contraindications.

Hypersensitivity to tacrolimus, other macrolides, or to any of the excipients.

Known hypersensitivity to castor oil, polyoxylated hydrogenated, or structurally related components.

Special precautions.

Due to the immunosuppressive effect of tacrolimus, inhalation or direct contact with skin or mucous membranes of the injectable formulation or powder contained in the drug packaging should be avoided. If such contact occurs, the skin and affected eye(s) should be thoroughly rinsed with water.

Interaction with other medicinal products and other types of interactions.

Metabolic interactions

Systemically available tacrolimus is metabolized in the liver by CYP3A4. There is also evidence of CYP3A4 intestinal metabolism in the gut wall. Concomitant administration of medicinal products, including herbal products, with known inhibitory or inductive effects on CYP3A4 may affect tacrolimus metabolism and thereby increase or decrease blood concentrations of tacrolimus. Similarly, discontinuation of such medicinal products or herbal remedies may affect the rate of tacrolimus metabolism and thus influence blood levels of tacrolimus.

Pharmacokinetic studies have shown that increased blood levels of tacrolimus when co-administered with CYP3A4 inhibitors are primarily due to increased oral bioavailability of tacrolimus resulting from inhibition of gastrointestinal metabolism. The effect on hepatic clearance is less pronounced.

When using substances that potentially alter CYP3A4 metabolism concomitantly, close monitoring under the supervision of a transplant specialist is strongly recommended, including monitoring of blood tacrolimus levels, QT interval prolongation (ECG), renal function, and other adverse effects such as neurotoxicity. If necessary, appropriate dose adjustments or interruptions of tacrolimus therapy should be made to maintain equivalent exposure (see sections "Dosage and administration", "Special instructions").

Similarly, careful monitoring of patients is required when tacrolimus is used concomitantly with multiple agents affecting CYP3A4, since the effect of tacrolimus may be enhanced or diminished.

Medicinal products affecting the efficacy of tacrolimus are listed in the table below. Examples of interactions between medicinal products and individual substances are not exhaustive or comprehensive; therefore, the prescribing information for each medicinal product used concomitantly with tacrolimus should be consulted to obtain information on metabolic pathways, potential interactions, possible risks, and specific measures to be taken when considering concomitant use.

Medicinal products affecting the efficacy of tacrolimus

Concomitant use of tacrolimus with a mammalian target of rapamycin (mTOR) inhibitor, such as sirolimus or everolimus, may increase the risk of thrombotic microangiopathy, including hemolytic uremic syndrome and thrombotic thrombocytopenic purpura (see section "Special precautions for use").

Since treatment with tacrolimus may be associated with hyperkalemia or may exacerbate existing hyperkalemia, potassium supplements or potassium-sparing diuretics such as amiloride, triamterene, or spironolactone should be avoided (see section "Special precautions for use"). Caution is advised when tacrolimus is used concomitantly with other agents that increase serum potassium levels, such as trimethoprim and co-trimoxazole (trimethoprim/sulfamethoxazole), as trimethoprim is known to act as a potassium-sparing diuretic similar to amiloride. Careful monitoring of serum potassium levels is recommended.

Effect of tacrolimus on the metabolism of other medicinal products

Tacrolimus is a known inhibitor of CYP3A4; therefore, concomitant administration of tacrolimus with medicinal products metabolized by CYP3A4 may affect the metabolism of such medicinal products.

The elimination half-life of cyclosporine is prolonged when administered concomitantly with tacrolimus. In addition, a synergistic effect/additive nephrotoxic effect may occur. For these reasons, combined administration of cyclosporine and tacrolimus is not recommended, and physicians should exercise caution when prescribing tacrolimus to patients who have previously received cyclosporine (see sections "Dosage and administration" and "Special precautions for use").

It has been demonstrated that tacrolimus may cause an increase in phenytoin blood levels.

Since tacrolimus may reduce the therapeutic window of hormonal contraceptives, usually resulting in increased hormonal exposure, particular attention and caution should be exercised when selecting contraceptive methods.

Currently, there is insufficient knowledge regarding the interaction between tacrolimus and statins. Clinical data suggest that the pharmacokinetics of statins are not significantly altered when administered concomitantly with tacrolimus.

Animal studies have shown that tacrolimus may potentially reduce the clearance and prolong the half-life of pentobarbital and phenazone.

Mycophenolic acid

Caution should be exercised when switching patients receiving combination therapy with cyclosporine (which affects the enterohepatic recirculation of mycophenolic acid) to tacrolimus (which lacks this effect), as this may alter the impact of mycophenolic acid. Medicinal products affecting the enterohepatic cycle of mycophenolic acid may reduce plasma levels and the efficacy of mycophenolic acid.

When switching from cyclosporine to tacrolimus or vice versa, therapeutic monitoring of mycophenolic acid may be advisable.

Immunosuppressants may affect the response to vaccination; therefore, vaccination during treatment with tacrolimus may be less effective. The use of live attenuated vaccines should be avoided (see section "Special precautions for use").

Special precautions for use.

During the initial post-transplant period, periodic monitoring of the following parameters is recommended: arterial blood pressure, ECG, neurological status and visual function, fasting blood glucose, electrolyte concentrations (especially potassium), liver and kidney function tests, hematological parameters, coagulation profile, and serum protein levels. If clinically significant changes occur, adjustment of immunosuppressive therapy is required.

Substances with potential for interaction

Inhibitors or inducers of CYP3A4 should be used concomitantly with tacrolimus only after consultation with a transplant specialist due to the potential for drug interactions that may lead to serious adverse reactions, including transplant rejection or toxicity (see section "Interaction with other medicinal products and other forms of interaction").

CYP3A4 inhibitors

Concomitant use with CYP3A4 inhibitors may increase blood levels of tacrolimus, potentially leading to serious adverse reactions, including nephrotoxicity, neurotoxicity, and QT interval prolongation. It is recommended to avoid concomitant use of strong CYP3A4 inhibitors (such as ritonavir, cobicistat, ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin, clarithromycin, or josamycin) with tacrolimus. If such co-administration cannot be avoided, blood levels of tacrolimus should be monitored starting from the first few days of concomitant use under the supervision of a transplant specialist to maintain required tacrolimus exposure. Renal function, ECG (including QT interval), and the patient's clinical status should also be closely monitored.

Dose adjustments should be based on the individual clinical condition of each patient. An immediate dose reduction may be necessary at the beginning of treatment (see section "Interaction with other medicinal products and other forms of interaction").

Similarly, discontinuation of CYP3A4 inhibitors may affect the metabolism rate of tacrolimus, potentially leading to subtherapeutic blood levels of tacrolimus; therefore, such situations require careful monitoring and supervision by a transplant specialist.

CYP3A4 inducers

Concomitant use with CYP3A4 inducers may reduce blood levels of tacrolimus, potentially increasing the risk of transplant rejection. It is recommended to avoid concomitant use of strong CYP3A4 inducers (such as rifampicin, phenytoin, carbamazepine) with tacrolimus. If such co-administration cannot be avoided, frequent monitoring of tacrolimus blood levels should be initiated from the first few days of concomitant use under the supervision of a transplant specialist, to adjust the tacrolimus dose if necessary and maintain consistent exposure. The function of the transplanted organ should also be closely monitored (see section "Interaction with other medicinal products and other forms of interaction").

Similarly, discontinuation of CYP3A4 inducers may affect the metabolism rate of tacrolimus, potentially leading to supratherapeutic blood levels of tacrolimus, and therefore requires careful monitoring and supervision by a transplant specialist.

P-glycoprotein

Caution should be exercised when administering tacrolimus concomitantly with agents that inhibit P-glycoprotein, as increased tacrolimus levels may occur. Blood levels of tacrolimus in whole blood and the patient's clinical status should be closely monitored. Dose adjustment of tacrolimus may be required (see section "Interaction with other medicinal products and other forms of interaction").

Herbal products

When using Prograf**®**, herbal preparations containing St. John’s wort (Hypericum perforatum) should be avoided due to the risk of interactions leading to reduced blood levels of tacrolimus and diminished therapeutic effect of tacrolimus (see section "Interaction with other medicinal products and other forms of interaction").

Other interactions

Concomitant use of cyclosporine and tacrolimus should be avoided; caution is advised when using tacrolimus in patients who have previously received cyclosporine (see sections "Method of administration and dosage" and "Interaction with other medicinal products and other forms of interaction").
Intake of medications/food products containing high amounts of potassium or potassium-sparing diuretics should be avoided (see section "Interaction with other medicinal products and other forms of interaction").

Concomitant use of tacrolimus with medicinal products known to have nephrotoxic or neurotoxic effects may increase the risk of nephrotoxic and neurotoxic reactions (see section "Interaction with other medicinal products and other forms of interaction").

Vaccination

Immunosuppressants may affect the response to vaccination; vaccination may be less effective during treatment with tacrolimus. Live attenuated vaccines should be avoided.

Nephrotoxicity

In post-transplant patients, tacrolimus may cause renal function impairment. Acute renal failure, if left untreated, may progress to chronic kidney disease. Patients with impaired renal function should be closely observed, as dose reduction of tacrolimus may be necessary. The risk of nephrotoxicity may increase when tacrolimus is used concomitantly with nephrotoxic agents (see section "Interaction with other medicinal products and other forms of interaction"). Concomitant use of tacrolimus with nephrotoxic drugs should be avoided. If such concomitant use cannot be avoided, blood levels of tacrolimus and renal function should be closely monitored, and dose reduction should be considered in case of nephrotoxicity.

Gastrointestinal disorders

Gastrointestinal perforations have been reported in patients receiving tacrolimus. Gastrointestinal tract perforation is a medically significant complication that may lead to life-threatening or serious conditions. Appropriate treatment should be initiated immediately upon suspicion or onset of symptoms.

Blood levels of tacrolimus may fluctuate significantly during diarrhea; additional careful monitoring of tacrolimus blood concentrations is required if diarrhea occurs.

Cardiac disorders

Cases of ventricular hypertrophy or septal hypertrophy, reported as cardiomyopathy, have been observed rarely. In most cases, myocardial hypertrophy was reversible and occurred predominantly in children with blood concentrations of tacrolimus exceeding the maximum recommended levels. Other risk factors for this adverse event include pre-existing heart disease, corticosteroid use, arterial hypertension, renal and hepatic dysfunction, infections, hypervolemia, and edema. Therefore, patients at high risk, especially young children and patients receiving intensive immunosuppressive therapy, should undergo echocardiographic and ECG monitoring before and after transplantation (at 3 months and then at 9–12 months). If abnormalities are detected, consideration should be given to reducing the dose of Prograf**®** or switching to another immunosuppressant.

Tacrolimus may prolong the QT interval and cause Torsades de pointes. Caution is advised in patients with risk factors for QT prolongation, including those with personal or familial history of prolonged QT interval, patients with congestive heart failure, bradyarrhythmias, or electrolyte imbalances. Caution is also advised in patients diagnosed or suspected of congenital long QT syndrome or acquired prolonged QT interval, or in patients concurrently using medicinal products that prolong the QT interval, including those causing electrolyte imbalances or known increased tacrolimus exposure (see section "Interaction with other medicinal products and other forms of interaction").

Lymphoproliferative disorders and malignancies

Lymphoproliferative disorders (PTLD) associated with Epstein-Barr virus (EBV) may develop in patients treated with Prograf**®** (see section "Side effects"). Patients switched to Prograf**®** therapy should not receive anti-lymphocyte therapy simultaneously. In children under 2 years of age who are EBV-VCA seronegative, an increased risk of lymphoproliferative disorders has been reported. Therefore, in patients in this group, serological testing for EBV-VCA should be performed before initiating treatment with Prograf**®**. During treatment, careful monitoring of Epstein-Barr virus (EBV) by polymerase chain reaction (PCR) is recommended. Positive EBV PCR may persist for months and is not indicative of lymphoproliferative disorder or lymphoma.

As with other immunosuppressive medicinal products, due to the potential risk of skin malignancies, exposure to sunlight and ultraviolet radiation should be limited; protective clothing should be worn and high-protection sunscreen should be used.

As with other immunosuppressive medicinal products, the risk of secondary cancers is unknown (see section "Adverse reactions").

Reversible posterior encephalopathy syndrome (RPES)

Reversible posterior encephalopathy syndrome (RPES) has been reported in patients receiving tacrolimus. If patients taking tacrolimus develop symptoms of RPES such as headache, altered mental status, seizures, or visual disturbances, appropriate diagnostic procedures (e.g., MRI) should be performed. Upon diagnosis of RPES, systemic tacrolimus therapy should be discontinued immediately, and adequate control of blood pressure and seizures should be initiated. Most patients recover completely after appropriate treatment.

Visual disturbances

Ocular disorders, sometimes progressing to vision loss, have been observed in patients receiving tacrolimus. In some cases, switching to alternative immunosuppressive therapy was required. Patients should be advised to report changes in visual acuity, color vision disturbances, blurred vision, or visual field defects; in such cases, immediate evaluation and referral to an ophthalmologist, if necessary, are recommended.

Infections, including opportunistic infections

Patients receiving immunosuppressants, including Prograf**®**, are at increased risk of opportunistic infections (bacterial, fungal, viral, and protozoal), particularly cytomegalovirus (CMV) infection, BK virus-associated nephropathy, and progressive multifocal leukoencephalopathy (PML) caused by JC virus. There is also an increased risk of infectious viral hepatitis (e.g., reactivation of hepatitis B or C, new infection, or hepatitis E, which may become chronic). These infections are often associated with high overall immunosuppressive burden and may lead to serious or fatal outcomes, including transplant rejection. This should be considered by physicians when performing differential diagnosis in patients with worsening liver or kidney function or neurological symptoms. Prophylaxis and treatment should follow clinical guidelines.

Thrombotic microangiopathy (TMA) (including hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP))

TMA, including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS), which may sometimes lead to renal failure or death, should be considered in patients presenting with hemolytic anemia, thrombocytopenia, fatigue, fluctuating neurological symptoms, renal dysfunction, and fever. If TMA is diagnosed, immediate treatment is required, and discontinuation of tacrolimus should be considered at the physician’s discretion.

Concomitant use of tacrolimus with mammalian target of rapamycin (mTOR) inhibitors, such as sirolimus or everolimus, may increase the risk of thrombotic microangiopathy (including hemolytic uremic syndrome and thrombotic thrombocytopenic purpura) in mammals.

Cases of pure red cell aplasia (PRCA)

Cases of pure red cell aplasia (PRCA) have been reported in patients receiving tacrolimus. All patients had risk factors for PRCA, such as parvovirus B19 infection, underlying disease, or concomitant use of PRCA-associated drugs.

Excipients

The medicinal product contains polyoxyl 35 castor oil, which may cause anaphylactic reactions. Caution is advised in patients previously exposed to medicinal products containing polyoxyl 35 castor oil or its derivatives, and in patients with a predisposition to allergic reactions. The risk of allergic reactions may be reduced by decreasing the infusion rate of the diluted concentrate of Prograf**®** or by pre-treatment with an antihistamine. Patients should be closely monitored for 30 minutes during infusion due to the potential for allergic reactions.

This medicinal product contains 638 mg of alcohol (ethanol) per 5 mg/mL solution for intravenous infusion, equivalent to 16 mL of beer or 7 mL of wine. The small amount of ethanol in this product does not produce a noticeable effect.

In case of accidental arterial or perivascular administration of the reconstituted Prograf**®** concentrate for infusion solution, 5 mg/mL, irritation at the injection site may occur.

Use during pregnancy or breastfeeding.

Pregnancy

Data from human use show that tacrolimus crosses the human placenta. Limited data from organ transplant recipients show no evidence of increased risk of adverse effects on pregnancy course or outcome with tacrolimus compared to other immunosuppressive agents. However, cases of spontaneous abortion have been reported. Currently, no other relevant epidemiological data are available. Treatment with tacrolimus during pregnancy should only be permitted if no safer alternative exists and if the potential benefit to the mother outweighs the potential risk to the fetus. To detect potential adverse effects of tacrolimus, newborns of mothers who received tacrolimus during pregnancy should be monitored (especially renal function). There is a risk of preterm delivery (<37 weeks), and there is also a risk of neonatal hyperkalemia, which, however, normalizes spontaneously.

In studies in rats and rabbits, tacrolimus caused signs of embryofetal toxicity at doses associated with maternal toxicity.

Fertility

In rats, tacrolimus showed negative effects on male fertility, including reduced sperm count and motility.

Breastfeeding period

Tacrolimus passes into breast milk. Since a potentially adverse effect of tacrolimus on the newborn cannot be excluded, women taking Prograf**®** should discontinue breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

Tacrolimus may cause visual and neurological disturbances. These effects may be enhanced if Prograf**®** is used concomitantly with alcohol.

Administration and Dosage

Treatment with Prograf**®** requires careful monitoring performed by highly qualified personnel using appropriate equipment. This medicinal product can be prescribed and changes to immunosuppressive therapy can be made only by physicians experienced in immunosuppressive therapy in organ transplant recipients.

The drug is administered parenterally when the patient's condition does not allow oral intake of capsules. As soon as the patient's clinical condition improves, they should be switched to oral administration of the drug in the form of Prograf**®** capsules.

The duration of intravenous therapy should not exceed 7 days.

After switching a patient from parenteral to oral administration of tacrolimus in capsule form, it should be noted that medication errors with tacrolimus have been observed in practice. Accidental, unintentional, or uncontrolled switching of a patient from one oral formulation of tacrolimus (immediate-release or extended-release) to another is dangerous. This may lead to transplant rejection or increased incidence of adverse effects, including cases of insufficient or excessive immunosuppression due to corresponding clinical differences in systemic exposure to tacrolimus. A patient should be prescribed tacrolimus as a single medicinal form with an appropriate daily dosing regimen; changes in the medicinal form or regimen may occur only under careful supervision by a transplant specialist. For subsequent switching to any alternative medicinal forms, therapeutic drug monitoring and dose adjustment are required to maintain systemic exposure to tacrolimus.

General Information

Recommended initial doses are provided below as guidance. Dosing of the medicinal product Prograf**®** should be primarily based on clinical assessment of rejection risk and individual patient tolerance to the drug, as well as on monitoring data of tacrolimus blood concentration (see information in section "Special Instructions": Recommendations for achieving the required drug concentration in whole blood).

If clinical signs of rejection occur, adjustment of the immunosuppressive therapy regimen should be considered.

Prograf**®** should be administered intravenously or orally. In general, dosing can be initiated orally, if necessary, by administering the capsule contents dissolved in water through a nasogastric tube.

Prograf**®** is generally used in combination with other immunosuppressive agents during the initial postoperative period. The dosage of Prograf**®** may vary depending on the chosen immunosuppressive regimen.

Prograf**®** concentrate for solution for intravenous infusion should be used only intravenously. Do not administer the undiluted drug. Before administration, it must be diluted with 5% glucose solution or 0.9% sodium chloride solution in glass, polyethylene, or polypropylene containers. Only clear, colorless solutions should be used.

Bolus injection of the drug is not recommended.

The concentration of the infusion solution should range between 0.004–0.1 mg/mL. The total volume of infusion over 24 hours should range between 20–500 mL.

Unused infusion concentrate in an opened ampoule or unused reconstituted solution must be immediately discarded to avoid contamination.

Liver Transplantation

Prevention of graft rejection – adults.

Drug administration should begin approximately 12 hours after completion of surgery.

If the patient's condition does not allow oral administration (Prograf**®** capsules), intravenous therapy should be initiated at a dose of 0.01–0.05 mg/kg/day administered as a continuous intravenous infusion over 24 hours.

Prevention of graft rejection – children.

If the patient's condition does not allow oral administration (Prograf**®** capsules), intravenous therapy should be initiated at a dose of 0.05 mg/kg/day administered as a continuous intravenous infusion over 24 hours.

Maintenance therapy – adults and children.

During maintenance therapy, the dose of Prograf**®** is generally reduced. In some cases, concomitant immunosuppressive drugs may be discontinued, using Prograf**®** as monotherapy. Improvement in the patient's condition after transplantation may alter the pharmacokinetics of tacrolimus, necessitating dose adjustment.

Treatment of rejection – adults and children.

Treatment of rejection episodes requires higher doses of Prograf**®** in combination with additional corticosteroid therapy and short courses of monoclonal/polyclonal antibodies. If signs of toxicity occur, dose reduction of Prograf**®** may be necessary.

When switching patients to Prograf**®** therapy, the same initial doses as those used for immunosuppression prophylaxis are recommended. For switching patients from cyclosporine therapy to Prograf**®**, see information in section "Special Instructions": Dose adjustment in special patient populations. Transition from cyclosporine therapy.

Kidney Transplantation

Prevention of graft rejection – adults.

Therapy with the drug should be initiated within 24 hours after completion of surgery.

If the patient's condition does not allow oral administration (Prograf**®** capsules), intravenous therapy should be initiated at a dose of 0.05–0.1 mg/kg/day administered as a continuous intravenous infusion over 24 hours.

Prevention of graft rejection – children.

If the patient's condition does not allow oral administration (Prograf**®** capsules), intravenous therapy should be initiated at a dose of 0.075–0.1 mg/kg/day administered as a continuous intravenous infusion over 24 hours.

Maintenance therapy – adults and children.

During maintenance therapy, doses of Prograf**®** should be reduced. In some cases, concomitant immunosuppressive drugs may be discontinued, leaving Prograf**®** as the base component of dual therapy. Improvement in the patient's condition after transplantation may alter the pharmacokinetics of tacrolimus, necessitating dose adjustment.

Treatment of rejection episodes – adults and children.

Treatment of rejection episodes requires higher doses of Prograf**®** in combination with additional corticosteroid therapy and short courses of monoclonal/polyclonal antibodies. If signs of toxicity occur, dose reduction of Prograf**®** may be necessary.

When switching patients to Prograf**®** therapy, the same initial doses as those used for immunosuppression prophylaxis are recommended. For switching patients from cyclosporine therapy to Prograf**®**, see information in section "Special Instructions": Dose adjustment in special patient populations. Transition from cyclosporine therapy.

Heart Transplantation

Prevention of graft rejection – adults.

Prograf**®** should be used in combination with antibody induction (with delayed initiation of Prograf**®** therapy). After antibody induction, drug administration should begin within 5 days after surgery, once the patient's clinical condition has stabilized. If the patient's condition does not allow oral administration (Prograf**®** capsules), intravenous therapy should be initiated at a dose of 0.01–0.02 mg/kg/day administered as a continuous intravenous infusion over 24 hours.

Prevention of graft rejection – children.

After heart transplantation in children, primary immunosuppression with Prograf**®** can be performed either in combination with antibody induction or as monotherapy.

In cases where antibody induction is not performed, Prograf**®** should be administered intravenously at an initial dose of 0.03–0.05 mg/kg/day as a continuous intravenous infusion over 24 hours until tacrolimus concentration in whole blood reaches 15–25 ng/mL. As soon as clinically feasible, the patient should be switched to oral administration (Prograf**®** capsules) at an initial dose of 0.30 mg/kg/day, administered 8–12 hours after completion of intravenous infusion.

Maintenance therapy – adults and children.

During maintenance therapy, Prograf**®** doses are reduced. Improvement in the patient's condition after transplantation may alter the pharmacokinetics of tacrolimus, necessitating dose adjustment.

Treatment of rejection – adults and children.

Treatment of rejection episodes requires higher doses of Prograf**®** in combination with additional corticosteroid therapy and short courses of monoclonal/polyclonal antibodies.

When switching adult patients to oral Prograf**®** therapy (capsules), the initial dose of 0.15 mg/kg/day should be divided into two doses (e.g., morning and evening).

When switching children to oral Prograf**®** therapy (capsules), the initial dose of 0.2–0.3 mg/kg/day should be divided into two doses (e.g., morning and evening).

Information on switching patients from cyclosporine to Prograf**®** is provided in section "Special Instructions": Dose adjustment in special patient populations. Transition from cyclosporine therapy.

Special Populations

Hepatic Impairment

In patients with severe hepatic dysfunction, dose reduction of tacrolimus may be required to maintain minimum blood levels of tacrolimus within the recommended therapeutic range.

Renal Impairment

Since renal function does not affect the pharmacokinetics of tacrolimus, dose adjustment is not necessary. However, due to the nephrotoxic potential of tacrolimus, careful monitoring of renal function is recommended (including serum creatinine levels, creatinine clearance calculation, and urine output monitoring).

Elderly Patients

There is no evidence that elderly patients require special dosing.

Conversion (switching) from cyclosporine to tacrolimus

Caution should be exercised when switching patients from baseline cyclosporine therapy to tacrolimus-based therapy (see sections "Special Instructions" and "Interaction with other medicinal products and other forms of interaction"). Therapy with Prograf**®** should be initiated after determining cyclosporine plasma concentration and assessing the patient's clinical condition. Conversion should be delayed if elevated cyclosporine blood levels are present. In practice, Prograf**®** therapy is usually initiated 12–24 hours after discontinuation of cyclosporine. After switching, cyclosporine blood levels should be monitored, as there may be an effect on cyclosporine clearance.

Recommendations for achieving the required drug concentration in whole blood.

Drug dosage selection should be based on clinical assessment of rejection process and individual patient tolerance.

To optimize drug dosing, tacrolimus concentration in whole blood is determined using immunoassay methods, including semi-automated microparticle enzyme immunoassay (MEIA). Comparison of published scientific data on tacrolimus blood concentration with individual clinical parameters should be done cautiously, taking into account the assay method used. In current medical practice, immunoassay methods are used to determine tacrolimus concentration in whole blood.

In the early postoperative period, minimum tacrolimus levels in whole blood should be monitored. With oral administration, minimum tacrolimus levels in whole blood should be monitored every 12 hours immediately before the next dose. The frequency of drug level monitoring should depend on clinical needs. Since Prograf**®** is a drug with low clearance, dose regimen adjustments may take several days before changes in blood drug levels become apparent. Minimum drug levels in blood should be monitored approximately twice weekly during the early post-transplant period and then periodically during maintenance therapy. Minimum tacrolimus blood levels should also be monitored after dose changes, changes in immunosuppressive regimen, or concomitant use with drugs that may affect tacrolimus concentration in whole blood (see section "Interaction with other medicinal products and other forms of interaction").

Results of clinical trials suggest that most patients can be successfully treated if minimum tacrolimus blood levels are maintained below 20 ng/mL. When interpreting data on drug concentration in whole blood, it is important to assess the patient's clinical condition.

In clinical practice, during the early period after transplantation, minimum drug levels in whole blood generally ranged between 5–20 ng/mL after liver transplantation and 10–20 ng/mL after kidney and heart transplantation. Later, during maintenance therapy after liver, kidney, and heart transplantation, blood drug concentrations ranged from 5 to 15 ng/mL.

Children. Generally, children require doses 1.5–2 times higher than adults to achieve similar blood drug levels.

Overdose.

Information on overdose is limited. Several episodes of accidental overdoses have been reported in patients taking tacrolimus. Symptoms included tremor, headache, nausea, vomiting, infections, urticaria, lethargic state, elevated blood urea nitrogen, serum creatinine, and alanine aminotransferase.

There is currently no specific antidote for Prograf**®**. In case of overdose, standard supportive measures and symptomatic treatment should be implemented.

Due to the high molecular weight of tacrolimus, poor water solubility, and extensive binding to erythrocytes and plasma proteins, dialysis is ineffective. In individual patients with very high tacrolimus blood concentrations, hemofiltration or diafiltration may be effective. In cases of oral overdose, gastric lavage and/or use of adsorbents (e.g., activated charcoal) may be effective if initiated immediately after drug intake.

Side effects

Due to the nature of the underlying disease and the large number of medications administered simultaneously after transplantation, the exact side effect profile of immunosuppressants is difficult to establish.

Most of the adverse reactions described below are reversible and/or resolve with dose reduction.

Oral administration is associated with a lower incidence of adverse reactions compared to intravenous administration.

The frequency of adverse reactions is defined as follows: very common (≥ 1/10); common (≥ 1/100 to <1/10); uncommon (≥ 1/1000 to <1/100); rare (≥ 1/10000 to <1/1000); very rare (<1/10000), frequency not known (cannot be estimated due to insufficient data). Within each frequency group, adverse effects are listed in order of decreasing severity.

Infections and infestations

During therapy with tacrolimus, as with other potent immunosuppressants, patients are at increased risk of developing infections (viral, bacterial, fungal, protozoal). Pre-existing infections may worsen. Manifestations of both localized and generalized infections may occur.

In patients receiving immunosuppressive therapy, including the medicinal product Prograf**®**, cases of CMV infection, BK virus-associated nephropathy, and progressive multifocal leukoencephalopathy (PML) associated with JC virus have been reported.

Benign, malignant and unspecified neoplasms (including cysts and polyps)

Patients receiving immunosuppressive therapy have an increased risk of developing malignant neoplasms. With the use of tacrolimus, both benign and malignant neoplasms have been reported, including Epstein-Barr virus (EBV)-associated lymphoproliferative disorders and skin malignancies.

Blood and lymphatic system disorders

Common: anemia, leukopenia, thrombocytopenia, leukocytosis, erythrocyte parameter abnormalities.
Uncommon: coagulopathies, coagulation parameter changes and bleeding, pancytopenia, neutropenia, thrombotic microangiopathy.
Rare: thrombotic thrombocytopenic purpura, hypoprothrombinemia.
Frequency not known: pure red cell aplasia, agranulocytosis, hemolytic anemia, febrile neutropenia.

Immune system disorders

Allergic and anaphylactoid reactions have been observed in patients receiving tacrolimus (see section "Special precautions").

Endocrine system disorders

Rare: hirsutism.

Metabolism and nutrition disorders

Very common: hyperglycemic states, diabetes mellitus, hyperkalemia.
Common: hypomagnesemia, hypophosphatemia, hypokalemia, hypocalcemia, hyponatremia, fluid retention, hyperuricemia, decreased appetite, anorexia, metabolic acidosis, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, other electrolyte disturbances.
Uncommon: dehydration, hypoproteinemia, hyperphosphatemia, hypoglycemia.

Psychiatric disorders

Very common: insomnia.
Common: anxiety symptoms, confusion and disorientation, depression, depressed mood, mood disorders and disturbances, nightmares, hallucinations, psychiatric disorders.
Uncommon: psychotic disorder.

Nervous system disorders

Very common: tremor, headache.
Common: seizures, consciousness disturbances, paresthesia and dysesthesia, peripheral neuropathies, dizziness, writing disturbances, nervous system disorders.
Uncommon: coma, hemorrhage in the central nervous system and cerebral circulation disorders, paralysis and paresis, encephalopathy, speech and articulation disorders, amnesia.
Rare: hypertension.
Very rare: myasthenia.
Frequency not known: reversible posterior leukoencephalopathy syndrome (RPLS).

Eye disorders

Common: blurred vision, photophobia, eye disorders.
Uncommon: cataract.
Rare: blindness.
Frequency not known: optic neuropathy.

Ear and labyrinth disorders

Common: tinnitus.
Uncommon: hearing loss.
Rare: sensorineural deafness.
Very rare: hearing disorders.

Cardiac disorders

Common: ischemic coronary disorders, tachycardia.
Uncommon: ventricular arrhythmias and cardiac arrest, heart failure, cardiomyopathies, ventricular hypertrophy, supraventricular arrhythmias, palpitations, pathological ECG findings, rhythm and pulse disorders.
Rare: pericarditis.
Very rare: pathological echocardiography findings, QT interval prolongation on electrocardiogram, torsades de pointes arrhythmia.

Vascular disorders

Very common: arterial hypertension.
Common: bleeding, thromboembolic and ischemic complications, peripheral vascular disorders, vascular hypotensive disorders.
Uncommon: infarction, deep vein thrombosis of extremities, shock.

Respiratory, thoracic and mediastinal disorders

Common: dyspnea, pulmonary parenchymal disorders, pleural effusion, pharyngitis, cough, nasal congestion and rhinitis.
Uncommon: respiratory failure, respiratory tract disorders, bronchial asthma.
Rare: acute respiratory distress syndrome.

Gastrointestinal disorders

Very common: diarrhea, nausea.
Common: gastrointestinal inflammatory disorders, gastrointestinal ulcers and perforations, gastrointestinal hemorrhages, stomatitis and ulcers, ascites, vomiting, gastrointestinal and abdominal pain, dyspeptic symptoms and manifestations, constipation, flatulence, bloating and abdominal distension, loose stools, gastrointestinal manifestations and symptoms.
Uncommon: paralytic ileus, peritonitis, acute and chronic pancreatitis, elevated blood amylase levels, gastroesophageal reflux disease, impaired gastric evacuation function.
Rare: partial intestinal obstruction (subileus), pancreatic pseudocysts.

Hepatobiliary disorders

Very common: liver function test abnormalities.
Common: cholestasis and jaundice, hepatocellular injury and hepatitis, cholangitis.
Rare: hepatic artery thrombosis, veno-occlusive liver disease.
Very rare: liver failure, bile duct stricture.

Skin and subcutaneous tissue disorders

Common: pruritus, rash, alopecia, acne, hyperhidrosis.
Uncommon: dermatitis, photosensitivity.
Rare: toxic epidermal necrolysis (Lyell's syndrome).
Very rare: Stevens-Johnson syndrome.

Musculoskeletal and connective tissue disorders

Common: arthralgia, muscle cramps, limb pain, back pain.
Uncommon: joint disorders.
Rare: decreased mobility.

Renal and urinary disorders

Very common: renal failure.
Common: renal failure, acute renal failure, oliguria, tubular necrosis, toxic nephropathy, urine test abnormalities, bladder and urethra disorders.
Uncommon: anuria, hemolytic uremic syndrome.
Very rare: nephropathy, hemorrhagic cystitis.

Reproductive system and breast disorders

Uncommon: dysmenorrhea and uterine bleeding.

General disorders and administration site conditions

Common: asthenic conditions, pyrexia, edema, pain and discomfort, increased blood alkaline phosphatase levels, weight gain, thermoregulation disorders.
Uncommon: multiple organ failure, influenza-like syndrome, altered perception of ambient temperature, chest tightness, anxiety sensation, malaise, increased blood lactate dehydrogenase levels, weight loss.
Rare: thirst, falls, crushing chest pain, ulcers, decreased mobility, wounds.
Very rare: increase in fat tissue mass.

Injury, poisoning and procedural complications

Common: primary graft dysfunction.

Treatment errors have been reported, including accidental, unintentional or uncontrolled substitution between immediate-release and prolonged-release tacrolimus formulations. Cases of graft rejection have been reported (frequency cannot be estimated from available data).

Description of selected adverse reactions

Limb pain has been described in several published case reports as part of calcineurin inhibitor-induced pain syndrome (CIPS). This pain is typically bilateral, symmetric, severe, ascending in the lower limbs, may be associated with high therapeutic levels of tacrolimus, and may respond to dose reduction. In some cases, switching to alternative immunosuppression was required.

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients or their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions. Store in a light-protected place at a temperature not exceeding 25 °C. Keep out of reach of children.

After dilution, the solution should be stored at 2–8 °C for 24 hours in glass, polyethylene, or polypropylene containers.

Incompatibilities. Tacrolimus is absorbed by polyvinyl chloride plastic. Tubing, syringes, and other equipment used for the preparation and administration of Prograf**®** concentrate for solution for intravenous infusion containing 5 mg/mL must not contain polyvinyl chloride.

Packaging. 1 mL in a 2 mL nominal capacity ampoule made of colorless transparent glass (USP type 1) with a ring and dot. 10 ampoules in a plastic blister pack. One pack in a cardboard box.

Prescription status. Prescription only.

Manufacturer. Astellas Ireland Co., Ltd, Ireland.

Manufacturer's address.
Astellas Ireland Co., Ltd: Killorglin, Co. Kerry, V93 FC86, Ireland.

Marketing Authorization Holder. Astellas Pharma Europe B.V., the Netherlands.

Address of Marketing Authorization Holder. Sylviusweg, 62, 2333 BE Leiden, the Netherlands.