Dailiport

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT DAILIPORT (DAILIPORT)

Composition:

Active substance: tacrolimus:

1 capsule contains 0.5 mg, 1 mg, 3 mg, or 5 mg of tacrolimus in the form of tacrolimus monohydrate (corresponding to 0.511 mg, 1.022 mg, 3.067 mg, and 5.112 mg of tacrolimus monohydrate, respectively);

Excipients:

ethylcellulose (nominal viscosity: 10 mPa·s), hypromellose type 2910 (nominal viscosity: 3 mPa·s), lactose monohydrate;

Capsule fillers: lactose monohydrate, magnesium stearate;

Capsule body: sunset yellow FCF, ponceau 4R, brilliant blue FCF, titanium dioxide, gelatin;

Capsule cap for 0.5 mg: tartrazine, titanium dioxide, gelatin;

Capsule cap for 1 mg: titanium dioxide, gelatin;

Capsule cap for 3 mg: brilliant blue FCF, sunset yellow FCF, titanium dioxide, gelatin;

Capsule cap for 5 mg: erythrosine, titanium dioxide, gelatin;

Printing ink: shellac glaze in ethanol, n-butyl alcohol, aluminum lake of ponceau 4R, aluminum lake of brilliant blue FCF, isopropyl alcohol, aluminum lake of sunset yellow FCF, propylene glycol, lecithin (soy), simethicone.

Pharmaceutical form. Prolonged-release capsules.

Main physicochemical properties:

Capsules 0.5 mg: light brown body and light yellow cap with black print "0.5 mg". Contents of capsules — powder or compacted powder ranging from white to yellowish;

Capsules 1 mg: light brown body and white cap with black print "1 mg". Contents of capsules — powder or compacted powder ranging from white to yellowish;

Capsules 3 mg: light brown body and light orange cap with black print "3 mg". Contents of capsules — powder or compacted powder ranging from white to yellowish;

Capsules 5 mg: light brown body and pink cap with black print "5 mg". Contents of capsules — powder or compacted powder ranging from white to yellowish.

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

Pharmacological properties.

Pharmacodynamics

At the molecular level, the effects and intracellular accumulation of tacrolimus are mediated by binding to a cytosolic protein (FKBP 12). The "FKBP 12 — tacrolimus" complex specifically and competitively inhibits calcineurin, resulting in calcium-dependent blockade of T-cell signal transduction pathways and prevention of transcription of a discrete set of lymphokine genes.

Tacrolimus is a highly potent immunosuppressant. In both in vitro and in vivo experiments, tacrolimus clearly reduced the formation of cytotoxic lymphocytes, which play a key role in transplant rejection. Tacrolimus suppresses the production of lymphokines (interleukin-2, -3, γ-interferon), T-cell activation, expression of the interleukin-2 receptor, as well as T-helper-dependent B-cell proliferation.

Pharmacokinetics

Absorption

It has been established that tacrolimus is rapidly absorbed in the human gastrointestinal tract. Deilypor\ (prolonged-release capsules) — tacrolimus in a dosage form providing sustained absorption of the drug in the gastrointestinal tract. The mean time to reach Cmax is approximately 2 hours. Absorption of tacrolimus is variable; the bioavailability of tacrolimus after oral administration in immediate-release capsules averages 20–25% (variability in adult patients ranges from 6 to 43%). Bioavailability, as well as the rate and extent of absorption of tacrolimus, are reduced when the drug is taken with food. The pattern of bile secretion does not affect the absorption of tacrolimus; therefore, treatment with the drug can be initiated orally. After reaching steady-state concentrations of tacrolimus with administration of Deilypor, there is a high correlation between AUC and trough (C0) blood levels of tacrolimus. Thus, monitoring trough (C0) concentrations of tacrolimus in blood allows for estimation of systemic drug exposure.

Distribution and elimination

Distribution of tacrolimus in the human body after intravenous administration is biphasic. In systemic circulation, tacrolimus is highly bound to erythrocytes.
The ratio of tacrolimus concentrations in whole blood to plasma is ~20:1. A significant portion of plasma tacrolimus (>98.8%) is bound to plasma proteins (serum albumin, 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), and based on whole blood concentrations, averages 47.6 L.

Tacrolimus is a substance with low clearance. In healthy volunteers, the mean total clearance, calculated based on whole blood concentrations, is 2.25 L/h. In adult patients after liver, kidney, and heart transplantation, clearance values were 4.1 L/h, 6.7 L/h, and 3.9 L/h, respectively. Low hematocrit and hypoproteinemia increase the unbound fraction of tacrolimus, thereby accelerating its clearance. Corticosteroids used in transplantation may also enhance the rate of metabolism and accelerate tacrolimus clearance.

The elimination half-life of tacrolimus is prolonged and variable. In healthy volunteers, the mean elimination half-life in whole blood is nearly 43 hours.

Metabolism and biotransformation

Tacrolimus is actively metabolized in the liver, primarily by cytochrome P450-3A4 (CYP3A4) and cytochrome P450-3A5 (CYP3A5). Metabolism of tacrolimus occurs extensively in the intestinal wall. Several metabolites of tacrolimus have been identified. In vitro studies have shown that only one of the metabolites exhibits immunosuppressive activity comparable to that of tacrolimus. Other metabolites demonstrated weak or no immunosuppressive activity. Only one metabolite of tacrolimus has been detected in systemic circulation, at low concentrations. Therefore, the pharmacological activity of the drug is practically independent of its metabolites.

Excretion

Following intravenous and oral administration of 14C-labeled tacrolimus, the majority of radioactivity was recovered in feces. Approximately 2% of radioactivity was found in urine. About 1% of tacrolimus was excreted unchanged in both urine and feces. Thus, tacrolimus is almost completely metabolized prior to elimination; the primary route of elimination is via bile.

Clinical characteristics.

Indications.

For the prevention and treatment of allogeneic liver and kidney transplant rejection in adult patients.

For the treatment of allogeneic transplant rejection resistant to standard immunosuppressive regimens in adult patients.

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

Interaction with other medicinal products and other forms of interactions.

Metabolic interactions

Systemically available tacrolimus is metabolized in the liver by CYP3A4. There is also evidence of CYP3A4-mediated intestinal metabolism in the gut wall. Concomitant administration of medicinal products or herbal preparations with established inhibitory or inductive effects on CYP3A4 may increase or decrease, respectively, tacrolimus blood concentrations. Similarly, discontinuation of such medicinal products or herbal medicines may affect the metabolism rate of tacrolimus and consequently influence tacrolimus blood levels.

Pharmacokinetic studies have shown that increased tacrolimus blood levels during concomitant use 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.

Tacrolimus blood levels should be closely monitored under the supervision of a transplantation specialist, graft function should be carefully assessed, QT interval (ECG) should be monitored, and renal function and other adverse effects—particularly neurotoxicity—should be controlled during concomitant use of substances with the potential to affect CYP3A4. If necessary, tacrolimus administration should be interrupted or the dose adjusted to maintain equivalent tacrolimus exposure (see sections "Method of administration and dosage," "Special precautions").

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

Medicinal products affecting the efficacy of tacrolimus are listed in the table below. Examples of interactions are not exhaustive or comprehensive; therefore, the product 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.

Medicinal products affecting the efficacy of tacrolimus

Concomitant use of tacrolimus with a mammalian target of rapamycin (mTOR) inhibitor (e.g., sirolimus, everolimus) increases the risk of thrombotic microangiopathy (including hemolytic uremic syndrome and thrombotic thrombocytopenic purpura) (see section "Special precautions").

Since treatment with tacrolimus may cause hyperkalemia or exacerbate existing hyperkalemia, large intakes of potassium and use of potassium-sparing diuretics (e.g., amiloride, triamterene, or spironolactone) should be avoided (see section "Special precautions"). Caution is advised when using tacrolimus concomitantly with other agents that increase serum potassium levels, such as trimethoprim and co-trimoxazole (trimethoprim/sulfamethoxazole), as trimethoprim is known to act as an amiloride-like potassium-sparing diuretic. 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 use 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 is possible. 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").

Tacrolimus may cause an increase in blood levels of phenytoin.

Since tacrolimus may alter the therapeutic range of hormonal contraceptives, typically leading to increased hormonal exposure, contraceptive methods should be chosen with particular caution.

Currently, there is insufficient information on the interaction between tacrolimus and statins. Clinical data suggest that the pharmacokinetics of statins are not significantly altered when co-administered with tacrolimus.

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

Mycofenolic acid

Caution should be exercised when switching patients receiving combination therapy with cyclosporine (which affects the enterohepatic recirculation of mycophenolic acid) to tacrolimus, which does not have this effect, as this may lead to altered exposure to mycophenolic acid. Medicinal products affecting the enterohepatic circulation of mycophenolic acid may reduce plasma levels and efficacy of mycophenolic acid. Monitoring of the therapeutic effect of mycophenolic acid may be advisable when switching from cyclosporine to tacrolimus or vice versa.

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").

Special precautions for use.

Errors have been reported with the use of the medicinal product, particularly in cases of accidental, unintentional, or uncontrolled changes in the formulation of immediate-release or extended-release tacrolimus. This may lead to serious adverse reactions, including transplant rejection, or other adverse reactions resulting from either insufficient or excessive tacrolimus exposure. Patients should receive only one tacrolimus formulation with a corresponding daily dosing regimen; changes in formulations or regimens should occur only under strict supervision by a transplant specialist (see sections "Dosage and administration" and "Adverse reactions").

Deylport is not recommended for use in children due to lack of safety and/or efficacy data in this patient population.

For adult patients, there are no clinical data on the use of Deylport for the treatment of rejection refractory to other immunosuppressants.

Currently, there are no clinical data on the use of Deylport for the prevention of transplant rejection in heart transplantation.

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

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, which may result in serious adverse reactions, including 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 and lead 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 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 adjust the tacrolimus dose as needed and maintain stable tacrolimus exposure. Renal function, ECG (including QT interval), and the patient's clinical status should also be closely monitored.

Dose adjustment should be based on the individual clinical situation of the patient. Immediate dose reduction may be required at the start 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, leading to subtherapeutic blood levels of tacrolimus; therefore, such a situation requires careful monitoring and supervision by a transplant specialist.

CYP3A4 inducers

Concomitant use with CYP3A4 inducers may reduce blood levels of tacrolimus, increasing the risk of transplant rejection. It is recommended to avoid concomitant use of strong CYP3A4 inducers (such as rifampicin, phenytoin, carbamazepine) and tacrolimus. If co-administration cannot be avoided, tacrolimus blood levels should be monitored frequently, starting from the first few days of concomitant use, under the supervision of a transplant specialist, to adjust the tacrolimus dose as needed and maintain stable tacrolimus exposure. The function of the transplant 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, 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 using tacrolimus concomitantly with agents that inhibit P-glycoprotein, as increased tacrolimus levels may occur. Tacrolimus blood levels and the patient's clinical status should be closely monitored. Dose adjustment of tacrolimus may be necessary (see section "Interaction with other medicinal products and other forms of interaction").

Herbal products

During treatment with Deylport, herbal products 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.

Other interactions

Concomitant use of cyclosporine and tacrolimus should be avoided; caution is advised when using tacrolimus in patients previously treated with cyclosporine (see sections "Dosage and administration" and "Interaction with other medicinal products and other forms of interaction").

Avoid intake of potassium-rich products or potassium-sparing diuretics (see section "Interaction with other medicinal products and other forms of interaction").

The concomitant use of tacrolimus with medicinal products having nephrotoxic or neurotoxic effects increases 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. Use of live attenuated vaccines should be avoided.

Nephrotoxicity

In transplant patients, tacrolimus may cause impaired kidney function. Acute renal failure, if not actively managed, may progress to chronic kidney disease. Patients with impaired renal function should be closely observed, as dose reduction of tacrolimus may be required. The risk of nephrotoxicity is increased 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 concomitant use cannot be avoided, tacrolimus blood levels 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 conditions. Adequate treatment should be initiated immediately if suspicious symptoms occur.

During diarrhea, blood levels of tacrolimus may fluctuate significantly; careful monitoring of tacrolimus blood concentration is required if diarrhea occurs.

Cardiac disorders

Cases of ventricular hypertrophy or septal hypertrophy, reported as cardiomyopathy, have been rarely observed but have occurred in patients treated with immediate-release tacrolimus, and thus are possible with Deylport. Myocardial hypertrophy was mostly reversible and occurred at 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. Patients at high risk 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, dose reduction of Deylport or switching to another immunosuppressant should be considered.

Tacrolimus may prolong the QT interval and cause torsades de pointes. It should be used with caution in patients with risk factors for QT prolongation, particularly those with personal or family history of QT prolongation, congestive heart failure, bradyarrhythmia, or electrolyte imbalances. Caution is also advised in patients with diagnosed or suspected congenital long QT syndrome or acquired prolonged QT interval, and in patients receiving concomitant medications that prolong the QT interval, alter electrolyte levels, or increase tacrolimus levels (see section "Interaction with other medicinal products and other forms of interaction").

Lymphoproliferative disorders and malignancies

Post-transplant lymphoproliferative disorders (PTLD) and other malignancies, including skin cancer and Kaposi’s sarcoma associated with Epstein-Barr virus (EBV), may occur in patients treated with tacrolimus (see section "Adverse reactions"). The concomitant use of immunosuppressants with anti-lymphocyte antibodies (such as basiliximab, daclizumab) increases the risk of EBV-associated PTLD. There are also reports of increased risk of lymphoproliferative disorders in patients negative for EBV-VCA (viral capsid antigen). Therefore, serological testing for EBV-VCA should be performed before initiating Deylport in this patient group. During treatment, careful monitoring for EBV using polymerase chain reaction (PCR) is recommended. Positive EBV-PCR may persist for several months and by itself does not indicate PTLD or lymphoma.

As with other potent immunosuppressive agents, the risk of secondary malignancies is unknown (see section "Adverse reactions").

Cases of Kaposi’s sarcoma, including aggressive forms with fatal outcomes, have been reported in patients receiving tacrolimus. In some cases, regression of Kaposi’s sarcoma was observed after reduction in immunosuppression intensity.

During treatment with tacrolimus, as with other immunosuppressive agents, exposure to sunlight and ultraviolet radiation should be limited, protective clothing should be worn, and high-protection sunscreen should be used to reduce the risk of skin malignancies.

Infections, including opportunistic infections

Patients receiving immunosuppressants, including Deylport, have an increased risk of opportunistic infections (bacterial, fungal, viral, and protozoal), particularly cytomegalovirus (CMV) infection, BK virus-associated nephropathy, and JC virus-associated progressive multifocal leukoencephalopathy. Patients also have an increased risk of viral hepatitis infections (e.g., reactivation of hepatitis B and C and/or new infection, as well as 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 immunocompromised patients with worsening liver or kidney function or neurological symptoms. Prophylaxis and treatment should follow current clinical guidelines.

Thrombotic microangiopathy (including hemolytic-uremic syndrome and thrombotic thrombocytopenic purpura)

Thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS), sometimes leading 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. The physician should also consider discontinuing tacrolimus.

Concomitant use of tacrolimus with mammalian target of rapamycin (mTOR) inhibitors (e.g., sirolimus, everolimus) increases the risk of thrombotic microangiopathy (including HUS and TTP).

Posterior reversible encephalopathy syndrome

Posterior reversible encephalopathy syndrome (PRES) has been reported in patients receiving tacrolimus. If patients receiving tacrolimus present with symptoms of PRES, such as headache, mental status changes, seizures, or visual disturbances, appropriate diagnostic procedures (e.g., MRI) should be performed. If PRES is diagnosed, systemic tacrolimus therapy should be discontinued immediately, and blood pressure and seizures should be adequately managed. Most patients fully recover after appropriate treatment.

Visual disturbances

Visual disturbances, sometimes progressing to vision loss, have occurred in patients receiving tacrolimus. In some cases, switching to alternative immunosuppressive therapy was considered. Patients should be advised to report changes in visual acuity, color perception, blurred vision, or visual field defects; immediate ophthalmological evaluation is recommended if such symptoms occur.

Cases of pure red cell aplasia

Cases of pure red cell aplasia (PRCA) have occurred 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.

Special populations

Clinical experience with the use of the drug in non-Caucasian patients and in patients with increased risk of immunological disorders (e.g., retransplantation, presence of panel-reactive antibodies) is limited.

Patients with severe hepatic impairment may require dose reduction (see section "Dosage and administration").

Excipients

0.5 mg capsules

Capsules contain lactose and azo dyes containing sodium.

The medicinal product should not be used in patients with rare hereditary disorders associated with galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

This medicinal product contains the azo dyes sunset yellow FCF (E 110), ponceau 4R (E 129), and tartrazine (E 102), which may cause allergic reactions.

This medicinal product contains less than 1 mmol sodium (23 mg) per capsule, i.e., essentially "sodium-free".

1 mg, 3 mg, and 5 mg capsules

Capsules contain lactose and azo dyes containing sodium.

The medicinal product should not be used in patients with rare hereditary disorders associated with galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

This medicinal product contains the azo dyes sunset yellow FCF (E 110) and ponceau 4R (E 129), which may cause allergic reactions.

This medicinal product contains less than 1 mmol sodium (23 mg) per capsule, i.e., essentially "sodium-free".

The printing ink used to mark Deylport capsules contains soy lecithin. For patients with hypersensitivity to peanuts or soy products, the benefit of using Deylport should be weighed against the potential risk and severity of hypersensitivity reactions.

Use during pregnancy or breastfeeding.

Pregnancy

Human data show that tacrolimus crosses the placenta in women. Limited data from organ transplant recipients do not indicate an increased risk of adverse effects of tacrolimus on pregnancy outcomes compared to other immunosuppressive medicinal products. However, cases of spontaneous abortion have been reported. Currently, no other relevant epidemiological data are available. Treatment with tacrolimus in pregnant women should only be considered when no safer alternative exists and when the potential benefit to the mother outweighs the potential risk to the fetus. Monitoring of newborns whose mothers received tacrolimus during pregnancy is recommended to detect potential adverse effects (particularly renal function). There is a risk of preterm delivery (< 37 weeks) (frequency 66/123 births, i.e., 53.7%), although most newborns had normal birth weight for gestational age. There is also a risk of neonatal hyperkalemia (frequency 8 out of 111 newborns, i.e., 7.2%), although potassium levels normalized spontaneously.

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

Fertility

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

Breastfeeding period

Tacrolimus passes into breast milk. Since adverse effects on the newborn cannot be excluded, women taking Deylport should discontinue breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

Tacrolimus may cause visual and neurological disturbances. Concomitant alcohol consumption may enhance this effect.

Studies on the effect of tacrolimus on the ability to drive or operate machinery have not been conducted.

Method of Administration and Dosage

Deyllyport is an oral formulation of tacrolimus administered once daily. Treatment with Deyllyport requires careful monitoring by qualified personnel equipped with appropriate facilities. Only physicians experienced in immunosuppressive therapy in organ transplant recipients may prescribe this medicinal product and make adjustments to the ongoing immunosuppressive regimen.

Different oral formulations of tacrolimus should not be substituted without clinical supervision.
Accidental, unintentional, or uncontrolled substitution of different oral formulations of the drug with varying release profiles is dangerous. This may lead to transplant rejection or increased incidence of adverse reactions, including inadequate or excessive immunosuppression, due to clinically significant differences in systemic exposure to tacrolimus. Patients should adhere to the regimen of one specific formulation of tacrolimus with a corresponding daily dosing schedule; any change in formulation or dosing regimen should occur only under close supervision by a transplantation specialist (see sections "Special Warnings and Precautions for Use," "Adverse Effects"). After switching to any other formulation, blood concentration of tacrolimus should be monitored and the dose adjusted to maintain adequate systemic exposure to tacrolimus.

Dosage

The recommended initial doses listed below are intended as guidelines.

In the early postoperative period, Deyllyport is usually administered concomitantly with other immunosuppressive medicinal products. The dose may be adjusted depending on the chosen immunosuppressive regimen. The dosage of Deyllyport should be determined primarily based on clinical assessment of rejection risk and individual drug tolerance, as well as therapeutic drug monitoring data (see subsection "Therapeutic Drug Monitoring" below). If clinical symptoms of rejection occur, adjustment of the immunosuppressive regimen should be considered.

In de novo kidney and liver transplant recipients who received Deyllyport, the AUC_0–24 of tacrolimus on Day 1 was 30% and 50% lower, respectively, compared to AUC_0–24 when the same dose of tacrolimus in immediate-release capsule formulation was administered. By Day 4, systemic exposure to tacrolimus (measured as trough plasma levels) was equivalent between the two aforementioned formulations in kidney and liver transplant recipients. To ensure adequate tacrolimus exposure during the first 2 weeks after transplantation, careful monitoring of the minimum blood concentration of tacrolimus is recommended. Since tacrolimus is a drug with low clearance, several days may be required to reach steady-state concentrations after dose adjustment of Deyllyport.

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

Prevention of Kidney Allograft Rejection

Oral therapy with Deyllyport should be initiated at a daily dose of 0.20–0.30 mg/kg/day administered as a single morning dose. Initiate treatment within 24 hours after transplantation.

The dose of Deyllyport is generally reduced during the post-transplant period. In some cases, concomitant immunosuppressive therapy may be discontinued, allowing monotherapy with Deyllyport. The post-transplant condition of the patient may alter the pharmacokinetics of tacrolimus and require further dose adjustments of Deyllyport.

Prevention of Liver Allograft Rejection

Oral therapy with Deyllyport should be initiated at a dose of 0.10–0.20 mg/kg once daily in the morning. Initiate treatment 12–18 hours after transplantation.

The dose of Deyllyport is generally reduced during the post-transplant period. In some cases, concomitant immunosuppressive therapy may be discontinued, allowing monotherapy with Deyllyport. The post-transplant condition of the patient may alter the pharmacokinetics of tacrolimus and require further dose adjustments of Deyllyport.

Conversion from Immediate-Release Capsules to Deyllyport

When converting patients after allograft transplantation from maintenance therapy with immediate-release capsules administered twice daily to Deyllyport once daily, the daily dose ratio during transition should be 1:1 (mg:mg). Deyllyport should be administered in the morning.

In stable patients converted from immediate-release capsules (twice daily) to Deyllyport (once daily) at a 1:1 (mg:mg) total daily dose ratio, systemic exposure to tacrolimus (AUC_0–24) with Deyllyport was approximately 10% lower than with immediate-release capsules. The relationship between trough concentration (C₂₄) and systemic exposure (AUC_0–24) with Deyllyport is comparable to that with immediate-release capsules. When switching from immediate-release capsules to Deyllyport capsules, the minimum drug concentration in plasma should be measured before and for two weeks after the switch. After conversion, the trough level of tacrolimus in plasma should be monitored and the dose adjusted, if necessary, to maintain equivalent systemic exposure.

Transition from Cyclosporine to Tacrolimus

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"). Concomitant administration of cyclosporine and tacrolimus is not recommended. Therapy with Deyllyport should be initiated after determining cyclosporine plasma concentration and evaluating the patient's clinical status. The transition should be delayed if cyclosporine blood levels are elevated. In practice, tacrolimus 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.

Treatment of Allograft Rejection

Recommended approaches to manage allograft rejection include increasing the tacrolimus dose, intensifying corticosteroid therapy, or short courses of monoclonal/polyclonal antibody therapy. If signs of tacrolimus toxicity occur (e.g., severe adverse reactions — see section "Adverse Reactions"), dose reduction of Deyllyport may be required.

Treatment of Kidney or Liver Allograft Rejection

When switching from other immunosuppressants to Deyllyport once daily, treatment should be initiated at the recommended initial oral doses for prevention of kidney or liver allograft rejection, respectively.

Treatment of Heart Allograft Rejection

For adult patients converted to Deyllyport, the initial oral dose is 0.15 mg/kg/day in the morning.

Treatment of Allograft Rejection after Other Organ Transplantations
There is no clinical experience with Deyllyport in patients after lung, pancreas, or intestinal transplantation. Deyllyport should be prescribed for treatment of lung transplant recipients at an initial oral dose of 0.10–0.15 mg/kg/day, for pancreas transplant recipients at an initial oral dose of 0.2 mg/kg/day, and for intestinal transplant recipients at an initial oral dose of 0.3 mg/kg/day.

Therapeutic Drug Monitoring

Dose selection should be based on clinical assessment of individual rejection risk and drug tolerance, as well as on monitoring data of therapeutic trough levels of tacrolimus in blood.

Several methods for determining tacrolimus concentration in whole blood should be used to select the optimal dose. When comparing monitoring results published in scientific literature with those from a specific clinic, the method used to determine tacrolimus blood concentration must be considered. In current clinical practice, blood levels of tacrolimus are predominantly monitored using immunoassay methods. The correlation between trough concentration (C₂₄) and systemic exposure (AUC_0–24) of tacrolimus is practically identical when using immediate-release and prolonged-release capsules.

Trough levels of tacrolimus in blood should be monitored during the post-transplant period. The trough concentration should be measured approximately 24 hours after administration of Deyllyport, just before the next dose. More frequent monitoring of trough levels is recommended during the first 2 weeks after transplantation, followed by periodic monitoring during maintenance therapy. Therapeutic trough levels of tacrolimus in blood should be particularly closely monitored after switching from immediate-release capsules to Deyllyport, after dose adjustments, changes in immunosuppressive regimen, or concomitant use of medicinal products that may alter tacrolimus blood concentration (see section "Interaction with Other Medicinal Products and Other Forms of Interaction"). Monitoring frequency should be determined based on clinical necessity. Since tacrolimus is a low-clearance drug, several days may be required to achieve steady-state blood concentrations after dose adjustment of Deyllyport.

According to clinical trial data, most patients achieve successful outcomes when therapeutic trough blood levels of tacrolimus do not exceed 20 ng/mL. Interpretation of therapeutic trough concentration data should take into account the patient's clinical condition. Available data indicate that during the early post-transplant period, the therapeutic blood level range for liver transplant recipients is 5–20 ng/mL, and for kidney or heart transplant recipients, 10–20 ng/mL. During maintenance immunosuppressive therapy, blood concentrations typically range between 5–15 ng/mL in liver, kidney, or heart transplant recipients.

Special Populations

Hepatic Impairment

Patients with severe hepatic dysfunction may require dose reduction of Deyllyport to maintain trough 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 monitoring of serum creatinine levels, creatinine clearance calculation, and urine output).

Race
Non-Caucasian patients may require higher doses of tacrolimus than Caucasian patients to achieve similar trough plasma concentrations.

Gender
There is no evidence that male and female patients require different doses to achieve similar trough plasma concentrations.

Elderly Patients

There is no evidence that elderly patients require special dosing.

Method of Administration

The recommended daily oral dose of Deyllyport should be taken once daily in the morning.

Prolonged-release capsules should be taken immediately after removal from the blister pack. Patients should be warned about the presence of a desiccant (silica gel packet) in the packaging, which is not intended for ingestion. Capsules should be swallowed whole with liquid (preferably water). To achieve maximum absorption, capsules should be taken on an empty stomach: 1 hour before or 2–3 hours after a meal. If a dose is missed, it should be taken as soon as possible, preferably on the same day; a double dose should not be taken the next morning.

For patients unable to take oral medicinal products immediately after organ transplantation, therapy may be initiated with intravenous administration of tacrolimus at a dose approximately ⅕ of the recommended oral dose for the respective indication.

Children

The safety and efficacy of Deyllyport in children have not been established. Limited data are available, but they are insufficient to provide dosage recommendations.

Overdose.

Information on overdose is limited. Several episodes of accidental overdose 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 levels.

There is currently no specific antidote for tacrolimus. 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. Hemofiltration or diafiltration may be effective in selected 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.

Side effects

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

The most common side effects (reported in >10% of patients) include tremor, renal failure, hyperglycemic conditions, diabetes mellitus, hyperkalemia, infections, arterial hypertension, and insomnia.

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 (≥1/10,000 to <1/1000); very rare (<1/10,000); frequency not known (cannot be estimated due to insufficient data). Within each frequency category, adverse effects are listed in order of decreasing severity.

Infections and infestations

Due to treatment 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 infections may occur.

In patients receiving immunosuppressants, including tacrolimus, CMV infections, BK virus-associated nephropathy, and progressive multifocal leukoencephalopathy associated with JC virus have been reported.

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

Patients receiving immunosuppressive therapy are at increased risk of developing malignant neoplasms. With the use of tacrolimus, both benign and malignant neoplasms have been reported, including Epstein-Barr virus-associated lymphoproliferative disorders, skin malignancies, and Kaposi’s sarcoma.

Immune system disorders

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

Blood and lymphatic system disorders

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

Endocrine disorders

Rare: hirsutism.

Metabolism and nutrition disorders

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

Psychiatric disorders

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

Nervous system disorders

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

Eye disorders

Common: eye disorders, blurred vision, photophobia.
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: heart failure, ventricular arrhythmias and cardiac arrest, supraventricular arrhythmias, cardiomyopathies, ventricular hypertrophy, palpitations.
Rare: pericarditis.
Very rare: torsades de pointes arrhythmia.

Vascular disorders

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

Respiratory, thoracic and mediastinal disorders

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

Gastrointestinal disorders

Very common: diarrhea, nausea.
Common: gastrointestinal symptoms and signs, vomiting, abdominal and gastrointestinal tract pain, inflammatory gastrointestinal disorders, gastrointestinal hemorrhage, gastrointestinal ulcers and perforations, ascites, stomatitis and ulcers, constipation, dyspeptic symptoms and signs, flatulence, bloating and abdominal distension, loose stools.
Uncommon: acute and chronic pancreatitis, paralytic ileus, gastroesophageal reflux disease, impaired gastric emptying.
Rare: pancreatic pseudocysts, partial intestinal obstruction (subileus).

Hepatobiliary disorders

Very common: liver function abnormalities.
Common: biliary tract disorders, hepatocellular injury and hepatitis, cholestasis and jaundice.
Rare: hepatic veno-occlusive disease, hepatic artery thrombosis.
Very rare: liver failure.

Skin and subcutaneous tissue disorders

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

Musculoskeletal and connective tissue disorders

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

Renal and urinary disorders

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

Reproductive system and breast disorders

Uncommon: dysmenorrhea and uterine bleeding.

General disorders and administration site conditions

Common: pyrexia, pain and discomfort, asthenic conditions, edema, thermoregulatory disorders.
Uncommon: influenza-like syndrome, anxiety, worsening of general condition, multiorgan failure, chest pressure, temperature perception disturbances.
Rare: falls, ulcers, chest tightness, thirst.
Very rare: increase in fat tissue mass.
Frequency not known: febrile neutropenia.

Investigations

Very common: changes in liver function tests.
Common: increased blood alkaline phosphatase levels, weight gain.
Uncommon: elevated blood amylase levels, abnormal ECG findings, disturbances in heart rate, pulse and rhythm, weight loss, elevated blood lactate dehydrogenase levels.
Very rare: echocardiogram changes, QT interval prolongation on electrocardiogram.

Injury, poisoning and procedural complications

Common: primary graft dysfunction.

Medication errors have been reported, including accidental, unintentional, or uncontrolled substitution of immediate- or extended-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. This is typically a bilateral, symmetric, severe, ascending pain in the lower limbs, which may be associated with high therapeutic levels of tacrolimus. The syndrome may respond to a reduction in the tacrolimus dose. In some cases, switching to an alternative immunosuppressive regimen was necessary.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after drug authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life. 2 years.

After opening the aluminum pouch — 1 year.

Storage conditions.

Store at temperatures not exceeding 25°C in the original packaging (aluminum pouch) to protect from light and moisture.

Keep out of reach of children.

Packaging. 10 capsules in a blister; 5 blisters in an aluminum pouch; 1 aluminum pouch in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

Lek Pharmaceuticals d.d.

Manufacturer’s address and place of business.

Trilin, 2d, Lenart, 9220, Slovenia.