INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TACPAN (TACPAN)

Composition:

Active substance: tacrolimus;

1 capsule contains tacrolimus (as tacrolimus monohydrate) 0.5 mg or 1 mg or 5 mg;

Excipients: hypromellose E-5, hypromellose E-15, anhydrous lactose, sodium croscarmellose, magnesium stearate, gelatin, titanium dioxide (E 171), iron oxide yellow (E 172) (0.5 mg capsules), iron oxide red (E 172) (5.0 mg capsules).

Pharmaceutical form. Hard capsules.

Main physicochemical properties:

0.5 mg: light-yellow hard gelatin capsules size "5" containing white or almost white granular powder;

1 mg: white hard gelatin capsules size "5" containing white or almost white granular powder;

5 mg: pink hard gelatin capsules size "4" containing white or almost white granular powder.

Pharmacotherapeutic group. Antineoplastic and immunomodulating medicinal products. Immunosuppressants. Calcineurin inhibitors. ATC code L04AD02.

Pharmacological properties.

Pharmacodynamics.

At the molecular level, the effects of tacrolimus are mediated by binding to a cytosolic protein (FKBP12), which facilitates 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 specific group of lymphokine genes.

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

Pharmacokinetics.

Absorption. Tacrolimus is absorbed from the gastrointestinal tract.

Peak blood concentrations (Cmax) are reached approximately 1–3 hours after administration. In some patients, the drug is continuously absorbed over a prolonged period, achieving a relatively flat absorption profile.

The oral bioavailability of tacrolimus averages 20–25%.

After oral administration of the medicinal product Takpan (0.3 mg/kg/day) to liver transplant patients, steady-state drug concentrations were generally achieved within 3 days.

The rate and extent of tacrolimus absorption are higher when the drug is taken on an empty stomach. Concurrent intake with food reduces both the rate and extent of tacrolimus absorption, most markedly after a high-fat meal. The effect of a high-carbohydrate meal is less pronounced.

In stable liver transplant patients, the bioavailability of Takpan was reduced when administered orally after a meal with moderate fat content. A decrease in the area under the pharmacokinetic curve (AUC) by 27%, maximum concentration (Cmax) by 50%, and an increase in tmax by 173% were observed in whole blood. Concomitant administration with food reduced both the rate and extent of drug absorption.

In a study of stable kidney transplant patients, oral administration of the drug immediately after a standard light breakfast resulted in a less pronounced effect on oral bioavailability. A reduction in AUC (2–12%), Cmax (15–38%), and an increase in tmax (38–80%) were observed in whole blood.

Bile secretion does not affect the absorption of Takpan.

A strong correlation exists between AUC and trough drug levels in whole blood at steady state. Therefore, monitoring of trough drug levels in whole blood may assist in adequately assessing systemic drug exposure.

Distribution

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

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

Tacrolimus is widely distributed throughout the body. The steady-state volume of distribution based on plasma concentrations is approximately 1300 L (in healthy volunteers). The corresponding value based on whole blood averages 47.6 L.

Tacrolimus is a drug with low clearance. In healthy volunteers, the mean total clearance, estimated from whole blood concentrations, is 2.25 L/h. In adult liver and kidney transplant patients, the values were 4.1 L/h, 6.7 L/h, and 3.9 L/h, respectively. In pediatric liver transplant patients, total clearance is approximately twice that observed in adult liver transplant patients.

Factors leading to increased clearance should be considered: low hematocrit and protein levels (leading to increased unbound fraction of tacrolimus) or enhanced metabolism due to corticosteroid therapy.

The elimination half-life of tacrolimus is prolonged and variable. In healthy volunteers, the mean half-life from whole 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. In transplant patients, increased drug clearance leads to a reduced elimination half-life.

Metabolism

Tacrolimus is metabolized in the liver, primarily by cytochrome P450 3A4 (CYP3A4). Tacrolimus is also extensively metabolized in the intestine.

Several metabolites have been identified. In vitro models have shown that only one metabolite exhibits significant immunosuppressive activity. Other metabolites have weak or negligible activity. Only one metabolite is present in systemic circulation, and at low concentrations. Thus, metabolites do not contribute significantly to the pharmacological activity of tacrolimus.

Elimination

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

Clinical characteristics.

Indications.

Prevention of allograft rejection in liver, kidney, or heart transplantation.

Treatment of allograft rejection resistant to therapy with other immunosuppressive medicinal products.

Contraindications.

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

Interaction with other medicinal products and other forms of interaction.

Metabolic interactions

Systemically available tacrolimus is metabolized in the liver by CYP3A4. There is also evidence of gastrointestinal CYP3A4 metabolism in the intestinal wall. Concomitant administration of medicinal products, including herbal products, with established inhibitory or inductive effects on CYP3A4 may affect tacrolimus metabolism and thereby increase or decrease blood concentrations of tacrolimus.

When using substances that potentially may alter CYP3A4 metabolism, strict monitoring of blood tacrolimus levels, QT interval prolongation (ECG), renal function, and other adverse effects is strongly recommended. Dose adjustment or interruption of tacrolimus may be necessary to maintain equivalent tacrolimus exposure (see sections "Method of administration and dosage" and "Special precautions for use").

Inhibitors of metabolism

For the substances listed below, an increase in blood tacrolimus levels has been clinically demonstrated. Strong interactions have been observed with antifungal agents such as ketoconazole, fluconazole, itraconazole, voriconazole, and isavuconazole; the macrolide antibiotic erythromycin; HIV protease inhibitors (e.g., ritonavir, nelfinavir, saquinavir); hepatitis C virus protease inhibitors (e.g., telaprevir, boceprevir, and the combination of ombitasvir and paritaprevir with ritonavir with or without dasabuvir); the antiviral agent letermovir for treatment of cytomegalovirus infection; the pharmacokinetic booster cobicistat; and tyrosine kinase inhibitors nilotinib and imatinib.

Concomitant use of these substances may necessitate dose reduction of tacrolimus in almost all patients.

Weaker interactions have been observed with clotrimazole, clarithromycin, josamycin, nifedipine, nicardipine, diltiazem, verapamil, amiodarone, danazol, ethinylestradiol, omeprazole, nefazodone, and medicinal products containing extract of Schisandra sphenanthera.

In vitro studies have identified the following substances as potential inhibitors of tacrolimus metabolism: bromocriptine, cortisone, dapsone, ergotamine, gestodene, lidocaine, mephenytoin, miconazole, midazolam, nilvadipine, norethisterone, quinidine, tamoxifen, and troleandomycin.

Cannabidiol (an inhibitor of P-glycoprotein). Reports indicate increased blood tacrolimus levels when tacrolimus is used concomitantly with cannabidiol. This may be related to inhibition of intestinal P-glycoprotein, leading to increased bioavailability of tacrolimus. Therefore, concomitant use of tacrolimus and cannabidiol should be approached with caution, with monitoring of minimum blood tacrolimus concentrations and, if necessary, dose adjustment of the medicinal product Takpan (see sections "Method of administration and dosage" and "Special precautions for use").

Grapefruit juice may increase blood tacrolimus levels; therefore, its use should be avoided.

Lansoprazole and cyclosporine may inhibit CYP3A4-mediated metabolism of tacrolimus and thereby increase blood concentrations of tacrolimus.

Other interactions potentially increasing blood tacrolimus levels

Tacrolimus is highly bound to plasma proteins. Interactions may occur with other active substances that have high affinity for plasma proteins (e.g., nonsteroidal anti-inflammatory drugs (NSAIDs), oral anticoagulants, or oral antidiabetic agents).

Other potential interactions that may increase systemic exposure to tacrolimus include interactions with the prokinetic agent metoclopramide, cimetidine, and magnesium-aluminum hydroxide.

Inducers of metabolism

Based on clinical experience, the following drugs may reduce blood tacrolimus concentrations:

Strong interactions have been observed with rifampicin, phenytoin, and St. John's wort-containing products; in such cases, dose increase of tacrolimus may be necessary in almost all patients. Clinically significant interactions have also been observed with phenobarbital. Maintenance doses of corticosteroids reduce blood tacrolimus concentrations.

High doses of prednisolone or methylprednisolone used to treat acute rejection may increase or decrease blood tacrolimus levels.

Carbamazepine, metamizole, and isoniazid may reduce blood tacrolimus concentrations.

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 previously treated with cyclosporine (see sections "Method of administration and dosage" and "Special precautions for use").

Tacrolimus has been shown to increase blood levels of phenytoin.

Since tacrolimus may reduce the therapeutic range of hormonal contraceptives, usually resulting in increased hormonal exposure, particular attention and caution should be exercised when deciding on 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 reduce the clearance and increase the elimination half-life of pentobarbital and phenazone.

Mycophenolic acid

Caution should be exercised when switching patients receiving combination therapy with cyclosporine (which affects 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 efficacy of mycophenolic acid.

Therapeutic monitoring of mycophenolic acid may be advisable when switching from cyclosporine to tacrolimus or vice versa.

Other interactions leading to clinically harmful outcomes

Concomitant administration of tacrolimus with medicinal products having nephrotoxic or neurotoxic effects may increase these effects (e.g., aminoglycosides, topoisomerase II inhibitors, vancomycin, co-trimoxazole, sulfamethoxazole-trimethoprim, NSAIDs, ganciclovir, or acyclovir). Increased nephrotoxicity has been reported after administration of amphotericin B and ibuprofen in combination with tacrolimus.

Since treatment with tacrolimus may be associated with hyperkalemia or may exacerbate existing hyperkalemia, excessive potassium intake or use of potassium-sparing diuretics (e.g., amiloride, triamterene, or spironolactone) should be avoided (see section "Special precautions for use").

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

Special precautions for use

Errors have been reported during the use of the medicinal product, including accidental, unintentional, or uncontrolled use of inappropriate formulations of tacrolimus, such as immediate-release or prolonged-release forms. This may lead to serious adverse reactions, including transplant rejection or other adverse effects resulting from either insufficient or excessive tacrolimus exposure. Patients should remain on the same tacrolimus formulation with an appropriate daily dosing regimen; changes in formulations or regimens should occur only under close supervision by a transplant specialist (see sections "Dosage and administration" and "Adverse reactions").

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

When co-administering medicinal products with potential interactions, especially CYP3A4 inhibitors (such as telaprevir, boceprevir, ritonavir, ketoconazole, voriconazole, itraconazole, telithromycin, or clarithromycin) or CYP3A4 inducers (such as rifampicin, rifabutin), blood levels of tacrolimus should be monitored to maintain appropriate tacrolimus exposure.

P-glycoprotein

Concomitant use of the medicinal product Takpan with P-glycoprotein inhibitors should be administered with caution, as this may increase blood levels of tacrolimus. Close monitoring of tacrolimus blood levels and the patient's clinical status is necessary. Dose adjustment of tacrolimus may be required (see section "Interaction with other medicinal products and other forms of interaction").

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

Concomitant use of cyclosporine and tacrolimus should be avoided. Tacrolimus should be used with caution in patients who have previously received cyclosporine (see sections "Dosage and administration" and "Interaction with other medicinal products and other forms of interaction").

Supplements or 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").

The risk of nephrotoxic and neurotoxic reactions may increase when tacrolimus is used concomitantly with medicinal products known to have nephrotoxic or neurotoxic effects (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.

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.

Tacrolimus blood levels may vary significantly during episodes of diarrhea; additional careful monitoring of tacrolimus blood concentrations is required if diarrhea occurs.

Cardiac disorders

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

Tacrolimus may prolong the QT interval and cause torsades de pointes. Caution should be exercised 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 receiving medicinal products that prolong the QT interval, including those with electrolyte imbalances or known increased tacrolimus exposure (see section "Interaction with other medicinal products and other forms of interaction").

Lymphoproliferative disorders and malignancies

Post-transplant lymphoproliferative disorders (PTLD) associated with Epstein-Barr virus (EBV) may occur in patients treated with Takpan (see section "Adverse effects"). Patients switched to treatment with Takpan should not receive concomitant antilymphocyte therapy. EBV-seronegative children under 2 years of age have shown an increased risk of developing lymphoproliferative disorders. Therefore, serological testing for EBV capsid antigen should be performed in patients of this group before initiating treatment with Takpan. During treatment, careful monitoring of Epstein-Barr virus polymerase chain reaction (PCR) should be conducted. Positive EBV PCR may persist for months and is not necessarily indicative of lymphoproliferative disorder or lymphoma.

As with other immunosuppressive medicinal products, due to the risk of skin malignancies, exposure to sunlight and ultraviolet radiation should be limited. Protective clothing and sunscreen with a high protection factor should be used.

The risk of secondary malignancy with immunosuppressive medicinal products is unknown (see section "Adverse reactions").

Reversible posterior encephalopathy syndrome

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 blood pressure control should be ensured. Most patients recover completely after appropriate management.

Visual disturbances

Visual disturbances, 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 any changes in visual acuity, color perception, blurred vision, or visual field defects and should undergo immediate ophthalmological evaluation if necessary.

Infections, including opportunistic infections

Patients receiving immunosuppressants, including Takpan, are at increased risk of opportunistic infections (bacterial, fungal, viral, and protozoal), particularly 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. Clinicians should consider these possibilities when performing differential diagnosis in immunocompromised patients with worsening liver or kidney function or neurological symptoms. Prophylaxis and treatment should follow clinical guidelines.

Cases of pure red cell aplasia

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

Excipients

The medicinal product Takpan contains lactose and therefore should not be administered to patients with rare hereditary conditions of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding

Pregnancy

The drug can cross the placenta.

Some data from organ transplant recipients suggest no evidence of increased risk of adverse effects on pregnancy outcomes with tacrolimus compared to other immunosuppressive agents. However, cases of spontaneous abortion have been reported. Other epidemiological data are currently lacking. Treatment with tacrolimus in pregnant women is possible only when no safer alternative exists and when 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 (particularly renal function). There is a risk of preterm delivery (at 37 weeks) and a risk of transient neonatal hyperkalemia, which resolves spontaneously.

In animal studies, tacrolimus caused embryofetal toxicity at doses causing maternal toxicity.

Breastfeeding period

Tacrolimus passes into breast milk. Since a harmful effect on the newborn cannot be excluded, women taking Takpan should discontinue breastfeeding.

Fertility

In animal studies, tacrolimus showed a negative effect on male fertility: reduced sperm count and motility.

Ability to affect reaction speed when driving or operating machinery

Tacrolimus may cause visual and neurological disturbances. These effects may be intensified by concomitant alcohol use.

Method of Administration and Dosage

Treatment with the medicinal product Takpan requires careful monitoring by qualified personnel with access to appropriate equipment. Only physicians experienced in immunosuppressive therapy in organ transplant recipients may prescribe this medicinal product and make changes to the immunosuppressive regimen.

Accidental, unintentional, or uncontrolled substitution between immediate- or extended-release formulations of tacrolimus is dangerous. This may lead to transplant rejection and increases the risk of adverse reactions, including inadequate or excessive immunosuppression, due to clinically significant differences in systemic exposure to tacrolimus. Patients must receive only one formulation of tacrolimus with an appropriate dosing schedule; changing the formulation or mode of administration must occur only under close supervision by a transplantation specialist (see sections "Special Warnings and Precautions for Use", "Adverse Effects"). After switching to any alternative formulation, blood concentrations of tacrolimus must be monitored and the dose adjusted to maintain adequate systemic exposure to tacrolimus.

General Information

The dosage of Takpan should be determined primarily based on clinical assessment of rejection risk, individual drug tolerance, and blood levels of tacrolimus (see below recommendations regarding measurement of trough blood concentrations). If clinical signs of rejection occur, adjustment of the immunosuppressive regimen should be considered.

Tacrolimus may be administered intravenously and orally. If necessary, the contents of the capsules may be dissolved in water and administered via a nasogastric tube.

During the early postoperative period, Takpan is usually administered concomitantly with other immunosuppressive medicinal products. The dose may be adjusted depending on the chosen immunosuppressive regimen.

Method of Administration

It is recommended to divide the daily oral dose into two administrations (e.g., morning and evening). Capsules should be taken immediately after removal from the blister pack. Capsules must be swallowed whole with liquid (preferably water).

To achieve maximum absorption, the drug should be taken on an empty stomach (fasting) or at least 1 hour before or 2–3 hours after food intake.

Immunosuppression must be maintained continuously to prevent transplant rejection; therefore, the duration of therapy is not limited.

Liver Transplantation

Prevention of transplant rejection in adults

Oral therapy with Takpan should be initiated at a daily dose of 0.1–0.2 mg/kg, divided into two doses (morning and evening). Drug administration should begin 12 hours after surgery.

If the patient's condition does not allow oral administration, tacrolimus in another formulation should be administered intravenously by continuous infusion over 24 hours at a dose of 0.01–0.05 mg/kg/day.

Prevention of transplant rejection in children

The initial oral dose should be 0.3 mg/kg/day, divided into two doses (e.g., morning and evening). If the patient's clinical condition does not allow oral administration, tacrolimus in another formulation should be administered intravenously by continuous infusion over 24 hours at a dose of 0.05 mg/kg/day.

Maintenance therapy in adults and children

During maintenance therapy, the dose of Takpan is usually reduced. In some cases, concomitant immunosuppressive agents may be discontinued, allowing Takpan to be used as monotherapy. Improvement in the patient's condition after transplantation may alter tacrolimus pharmacokinetics, necessitating dose adjustments.

Treatment of rejection in adults and children

Treatment of rejection episodes requires higher doses of Takpan in combination with additional corticosteroid therapy and short courses of monoclonal/polyclonal antibodies. If signs of toxicity occur (see section "Adverse Effects"), dose reduction may be necessary.

When switching patients to Takpan therapy, the same initial doses as for primary immunosuppression are recommended.

For conversion from cyclosporine to Takpan, see the sections "Special Populations" and "Conversion from Cyclosporine to Tacrolimus" below.

Kidney Transplantation

Prevention of transplant rejection in adults

Oral therapy should be initiated at a dose of 0.2–0.3 mg/kg/day, divided into two doses (e.g., morning and evening). Treatment should begin within 24 hours after completion of surgery.

Prevention of transplant rejection in children

Oral therapy should be initiated at a dose of 0.3 mg/kg/day, divided into two doses (e.g., morning and evening). If the patient's condition does not allow oral administration, tacrolimus in another formulation should be administered intravenously by continuous infusion over 24 hours at a dose of 0.075–0.1 mg/kg/day.

Maintenance therapy in adults and children

During maintenance therapy, the dose of Takpan should be reduced. In some cases, concomitant immunosuppressive agents may be discontinued, allowing Takpan to be used as the base component of dual therapy. Improvement in the patient's condition after transplantation may alter tacrolimus pharmacokinetics, necessitating dose adjustments.

Treatment of rejection episodes in adults and children

Treatment of rejection episodes requires higher doses of the medicinal product in combination with additional corticosteroid therapy and short courses of monoclonal/polyclonal antibodies. If signs of toxicity occur (see section "Adverse Effects"), dose reduction may be necessary.

When switching patients to Takpan therapy, the same initial doses as for primary immunosuppression are recommended.

For conversion from cyclosporine to Takpan, see the sections "Special Populations" and "Conversion from Cyclosporine to Tacrolimus" below.

Heart Transplantation

Prevention of transplant rejection in adult patients

The medicinal product may be used with or without antibody induction therapy (considering delayed initiation of Takpan therapy) in clinically stable patients.

After antibody induction, oral therapy should be initiated at a dose of 0.075 mg/kg/day, divided into two doses (e.g., morning and evening). 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, tacrolimus in another formulation should be administered intravenously by continuous infusion over 24 hours at a dose of 0.01–0.02 mg/kg/day.

An alternative approach has been published, in which oral tacrolimus is initiated within 12 hours after transplantation. This approach is used in patients without signs of organ dysfunction (e.g., kidney). In this case, tacrolimus at an initial dose of 2–4 mg/day should be combined with mycophenolate mofetil and corticosteroids or with sirolimus and corticosteroids.

Prevention of transplant rejection in children

After pediatric heart transplantation, primary immunosuppression with Takpan may be performed with or without antibody induction.

In cases where antibody induction is not performed, tacrolimus in another formulation should be administered intravenously by continuous infusion over 24 hours at a dose of 0.03–0.05 mg/kg/day until tacrolimus whole blood concentrations reach 15–25 ng/mL. As soon as clinically feasible, patients should be switched to oral administration at an initial dose of 0.3 mg/kg/day, administered 8–12 hours after completion of intravenous infusion.

After antibody induction, oral therapy should be initiated at a dose of 0.1–0.3 mg/kg/day, divided into two doses (e.g., morning and evening).

Maintenance therapy in adults and children

During maintenance therapy, doses of Takpan should be reduced. Improvement in the patient's condition after transplantation may alter tacrolimus pharmacokinetics, necessitating dose adjustments.

Treatment of rejection in adults and children

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

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

When switching children to Takpan therapy, the initial dose of 0.2–0.3 mg/kg/day should be divided into two doses (e.g., morning and evening). Information on conversion from cyclosporine to Takpan is provided in the section "Special Warnings and Precautions for Use".

Treatment of rejection after transplantation of other organs

Treatment of lung transplant patients with Takpan should be initiated at a dose of 0.1–0.15 mg/kg/day, pancreas transplant patients at 0.2 mg/kg/day, and intestinal transplant patients at 0.3 mg/kg/day.

Special Populations

Hepatic Impairment

Patients with severe hepatic impairment may require dose reduction of tacrolimus to maintain trough blood concentrations within the recommended therapeutic range.

Renal Impairment

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

Elderly Patients

There is no evidence that elderly patients require special dosage adjustments.

Conversion from Cyclosporine to Tacrolimus

Extreme caution should be exercised when converting patients from cyclosporine-based to tacrolimus-based therapy (see sections "Special Warnings and Precautions for Use" and "Interaction with Other Medicinal Products and Other Forms of Interaction"). Therapy with Takpan should be initiated after measuring cyclosporine plasma concentrations and assessing the patient's clinical status. Conversion should be delayed if elevated cyclosporine blood levels are present. In practice, Takpan therapy is usually initiated 12–24 hours after discontinuation of cyclosporine. After conversion, cyclosporine blood levels should be monitored, as there may be an effect on cyclosporine clearance.

Recommendations for Achieving Target Drug Concentrations in Whole Blood

The drug dose should be individualized based on clinical assessment of rejection risk and patient tolerance.

To optimize dosing, tacrolimus concentrations in whole blood should be measured using immunoassays, including semi-automated microparticle enzyme immunoassay. Comparison of published tacrolimus blood concentration data with individual clinical findings should be performed cautiously, based on knowledge and understanding of the assay method used. Immunoassays are currently used in clinical practice to determine tacrolimus concentrations in whole blood.

During the early postoperative period, trough levels of tacrolimus in whole blood should be monitored. For oral administration, trough levels should be measured every 12 hours, immediately before the next dose. Monitoring frequency depends on clinical needs. Since Takpan is a low-clearance drug, dose adjustments may take several days before changes in blood levels become apparent. Trough drug levels should be measured approximately twice weekly during the early post-transplant period and periodically during maintenance therapy. Trough levels of tacrolimus in blood should also be monitored after dose changes, changes in immunosuppressive regimen, or concomitant use of drugs that may affect tacrolimus concentrations in whole blood (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Clinical study data suggest that most patients can be successfully treated if trough blood concentrations of tacrolimus are maintained below 20 ng/mL. When interpreting blood concentration data, the patient's clinical status must be carefully evaluated.

In clinical practice, during the early period after transplantation, trough blood concentrations typically range from 5–20 ng/mL after liver transplantation and 10–20 ng/mL after kidney and heart transplantation. During subsequent maintenance therapy after liver, kidney, and heart transplantation, blood concentrations usually range from 5 to 15 ng/mL.

Children

Children generally require doses 1.5–2 times higher than adults to achieve target blood concentrations.

Overdose

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

There is currently no specific antidote for Takpan. In case of overdose, standard supportive measures and symptomatic treatment should be administered.

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

Adverse Reactions

Due to the nature of the underlying disease and the large number of medications administered simultaneously following transplantation, it is difficult to precisely define the adverse effect profile of immunosuppressants.

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

Oral administration is associated with fewer 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 category, adverse effects are listed in decreasing order of severity.

Infections and infestations

Due to 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. Both localized and generalized infection manifestations may occur.

In patients receiving immunosuppressants, including the medicinal product Takpan, cases of BK virus-associated nephropathy and progressive multifocal leukoencephalopathy (PML) associated with JC virus have been reported.

Neoplasms (benign, malignant and unspecified)

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 lymphoproliferative disorders and Epstein–Barr virus (EBV)-associated skin malignancies.

Blood and lymphatic system disorders

Common: anemia, leukopenia, thrombocytopenia, leukocytosis, abnormalities in erythrocyte parameters.

Uncommon: coagulopathies, coagulation abnormalities and bleeding, pancytopenia, neutropenia.

Rare: thrombotic thrombocytopenic purpura, hypoprothrombinemia, thrombotic microangiopathy.

Frequency not known: pure red cell aplasia, agranulocytosis, hemolytic anemia.

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, paresthesias and dysesthesias, peripheral neuropathies, dizziness, writing disturbances, nervous system disorders.

Uncommon: coma, hemorrhage in the central nervous system (CNS) and cerebrovascular disorders, paralysis and paresis, encephalopathy, speech and articulation disorders, amnesia.

Rare: hypertension.

Very rare: myasthenia.

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 impairment.

Cardiac disorders

Common: ischemic coronary disorders, tachycardia.

Uncommon: ventricular arrhythmias and cardiac arrest, heart failure, cardiomyopathies, ventricular hypertrophy, supraventricular arrhythmias, palpitations, pathological ECG findings, disturbances in heart rate, rhythm, and pulse.

Rare: pericarditis.

Very rare: pathological echocardiography findings, QT interval prolongation on electrocardiogram, torsades de pointes arrhythmia.

Vascular disorders

Very common: arterial hypertension.

Common: hemorrhage, thromboembolic and ischemic complications, peripheral vascular disorders, vasohypotensive 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: inflammatory gastrointestinal 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 symptoms and manifestations.

Uncommon: paralytic ileus, peritonitis, acute and chronic pancreatitis, elevated blood amylase levels, gastroesophageal reflux disease, impaired gastric emptying.

Rare: partial intestinal obstruction (subileus), pancreatic pseudocysts.

Hepatobiliary disorders

Common: liver function and liver enzyme abnormalities, cholestasis and jaundice, hepatocellular injury and hepatitis, cholangitis.

Rare: hepatic artery thrombosis, veno-occlusive liver disease.

Very rare: liver failure, biliary duct stenosis.

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, renal function impairment.

Common: renal failure, acute renal failure, oliguria, tubular necrosis, toxic nephropathy, urinary abnormalities, bladder and urethral 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 states, pyrexia, edema, pain and discomfort, elevated blood alkaline phosphatase levels, weight gain, thermoregulation disorders.

Uncommon: multiorgan failure, influenza-like syndrome, impaired perception of ambient temperature, chest tightness, anxiety sensation, malaise, elevated blood lactate dehydrogenase levels, weight loss.

Rare: thirst, falls, constricting chest pain, decreased mobility, ulcers.

Very rare: increase in fat tissue mass.

Frequency not known: febrile neutropenia.

Injury, poisoning and procedural complications

Common: primary graft dysfunction.

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

Limb pain has been described in several published case reports as part of calcineurin inhibitor-induced pain syndrome. 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 of tacrolimus. In some cases, switching to an alternative immunosuppressive regimen was required.

Shelf life. 2 years.

Storage conditions. Store in the original packaging, out of reach of children, at a temperature not exceeding 25 °C.

Packaging. 10 hard capsules per blister, 5 blisters or 6 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer. Panacea Biotec Pharma Ltd.

Manufacturer's address.

Malpur, Baddi, Tehsil Nalagarh, District Solan, Himachal Pradesh, 173 205, India.