Advagraf
Ukraine
Table of Contents
I N S T R U C T I O N for medical use of the medicinal product A D V A G R A F ® (ADVAGRAF®)
Composition:
Active substance: tacrolimus:
1 capsule contains tacrolimus (as hydrate) 0.5 mg or 1 mg or 3 mg or 5 mg;
Excipients: hypromellose, ethylcellulose, lactose monohydrate, magnesium stearate; capsule shell: titanium dioxide (E 171), yellow iron oxide (E 172), red iron oxide (E 172), gelatin, sodium lauryl sulfate; printing ink (Opacode S-1-15013): shellac, lecithin (soy), simethicone, red iron oxide (E 172), hydroxypropylcellulose.
Pharmaceutical form. Prolonged-release capsules.
Main physicochemical properties: 0.5 mg capsules: hard gelatin capsules size 5, with pale yellow cap printed in red with "0.5 mg", yellow-orange body printed in red with "647". Capsule contents: white powder;
1 mg capsules: hard gelatin capsules size 4, with white cap printed in red with "1 mg", yellow-orange body printed in red with "677". Capsule contents: white powder;
3 mg capsules: hard gelatin capsules size 1, with yellow-orange cap printed in red with "3 mg", yellow-orange body printed in red with "637". Capsule contents: white powder;
5 mg capsules: hard gelatin capsules size 0, with grey-red cap printed in red with "5 mg", yellow-orange body printed in red with "687". Capsule contents: white powder.
Pharmacotherapeutic group. Immunosuppressant. 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, providing calcium-dependent blockade of T-cell signal transduction pathways and preventing transcription of a discrete set of lymphokine genes.
Tacrolimus is a highly potent immunosuppressive agent. In both in vitro and in vivo experiments, tacrolimus markedly reduced the formation of cytotoxic lymphocytes, which play a key role in transplant rejection. Tacrolimus suppresses lymphokine production (interleukin-2, -3, γ-interferon), T-cell activation, interleukin-2 receptor expression, and T-helper cell-dependent B-cell proliferation.
Pharmacokinetics
Absorption
Tacrolimus is rapidly absorbed in the human gastrointestinal tract. Advagraf® (prolonged-release capsules) is a dosage form designed to provide sustained absorption of tacrolimus in the gastrointestinal tract. The mean time to reach Cmax is approximately 2 hours. Tacrolimus absorption is variable (absorption variability in adult patients ranges from 6–43%). The oral bioavailability of tacrolimus in capsule form averages 20–25%. Both the bioavailability and the rate and extent of tacrolimus absorption are reduced when administered with food. Biliary secretion does not affect drug absorption. After reaching steady-state concentrations with Advagraf**®**, there is a high correlation between AUC and trough (C0) blood levels of tacrolimus. Therefore, monitoring of trough (C0) concentrations of tacrolimus in blood allows assessment of systemic drug exposure.
Distribution and Elimination
Following intravenous administration, the distribution of tacrolimus in humans is biphasic. In systemic circulation, tacrolimus is highly bound to erythrocytes.
The ratio of tacrolimus concentrations in whole blood to plasma is approximately 20:1. A large proportion of plasma tacrolimus (>98.8%) is protein-bound, primarily to plasma proteins (serum albumin, α-1-acid glycoprotein).
Tacrolimus is widely distributed throughout the body. The volume of distribution at steady state, 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 metabolic rate and accelerate tacrolimus clearance.
The elimination half-life of tacrolimus is prolonged and variable. In healthy volunteers, the mean half-life in whole blood is nearly 43 hours.
Metabolism and Biotransformation
Tacrolimus is extensively metabolized in the liver, primarily by cytochrome P450-3A4 (CYP3A4) and cytochrome P450-3A5 (CYP3A5). Metabolism of tacrolimus also occurs intensively in the intestinal wall. Several metabolites of tacrolimus have been identified. In vitro studies have shown that only one metabolite exhibits immunosuppressive activity comparable to that of tacrolimus. Other metabolites have weak or no immunosuppressive activity. Only one metabolite of tacrolimus has been detected in systemic circulation, and only at low concentrations. Thus, 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 the administered radioactivity was found in urine. About 1% of tacrolimus was excreted unchanged in both urine and feces. Therefore, tacrolimus is almost completely metabolized prior to elimination, with biliary excretion being the primary route.
Clinical characteristics.
Indications.
Prevention and treatment of allogeneic liver and kidney transplant rejection in adult patients.
Treatment of allogeneic transplant rejection resistant to standard immunosuppressive regimens in adult patients.
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 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 medicinal products may affect the rate of tacrolimus metabolism and thus influence tacrolimus blood levels.
Pharmacokinetic studies have shown that increased tacrolimus blood levels when co-administered with CYP3A4 inhibitors are primarily due to increased oral bioavailability of tacrolimus resulting from inhibition of gastrointestinal metabolism. The effect on hepatic clearance is less pronounced.
Close monitoring of tacrolimus blood levels under the supervision of a transplant specialist is strongly recommended, along with careful monitoring of graft function, QT interval prolongation (ECG), renal function, and other adverse effects including neurotoxicity when co-administering substances that have the potential to alter CYP3A4 activity. Dose interruption or adjustment of tacrolimus may be necessary to maintain equivalent tacrolimus exposure (see sections "Dosage and administration", "Special precautions").
Similarly, patients should be closely monitored when tacrolimus is co-administered with multiple substances 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 between medicinal products and individual substances are not intended to be exhaustive or comprehensive; therefore, the product information for each medicinal product used concomitantly with tacrolimus should be consulted to obtain information on the metabolic pathway, potential interactions, potential risks, and specific measures to be taken when considering concomitant use.
Medicinal products affecting the efficacy of tacrolimus
| Class or name of medicinal product/substance |
Effect of medicinal interaction |
Recommendations for concomitant use |
|
| Grapefruit or grapefruit juice. |
May increase the trough blood concentration of tacrolimus and increase the risk of serious adverse reactions (e.g. neurotoxicity, QT interval prolongation) (see section "Special precautions"). |
Avoid consumption of grapefruit or grapefruit juice. |
|
| Cyclosporine. |
May increase trough blood concentrations of tacrolimus. In addition, synergistic/additive nephrotoxic effects may occur. |
Concomitant use of cyclosporine and tacrolimus should be avoided (see section "Special precautions"). |
|
| Agents with nephrotoxic or neurotoxic effects: aminoglycosides, inhibitors of helicase, vancomycin, sulfamethoxazole + trimethoprim, NSAIDs, ganciclovir, acyclovir, amphotericin B, ibuprofen, cidofovir, foscarnet. |
May enhance the nephrotoxic or neurotoxic effect of tacrolimus. |
Concomitant use of tacrolimus with agents having nephrotoxic effects should be avoided. If concomitant use cannot be avoided, monitor renal function and other adverse effects, and adjust the tacrolimus dose if necessary. |
|
| Potent CYP3A4 inhibitors: antifungal agents (e.g. ketoconazole, itraconazole, posaconazole, voriconazole), macrolide antibiotics (e.g. telithromycin, troleandomycin, clarithromycin, josamycin), HIV protease inhibitors (e.g. ritonavir, nelfinavir, saquinavir), HCV protease inhibitors (e.g. telaprevir, boceprevir, and the combination of ombitasvir and paritaprevir with ritonavir, with or without dasabuvir), nefazodone, pharmacokinetic enhancer cobicistat, kinase inhibitors idelalisib, ceritinib. A pronounced interaction was also observed with the macrolide antibiotic erythromycin. |
May increase trough whole blood concentration of tacrolimus and increase the risk of serious adverse reactions (e.g. nephrotoxicity, neurotoxicity, QT interval prolongation), requiring careful monitoring (see section "Special precautions"). A rapid and pronounced increase in tacrolimus levels may occur within 1–3 days of concomitant use, despite immediate reduction of tacrolimus dose. Total exposure to tacrolimus may increase more than 5-fold. When co-administered with ritonavir-containing regimens, tacrolimus exposure may increase more than 50-fold. Most patients may require a dose reduction of tacrolimus, and temporary discontinuation of tacrolimus may also be necessary. The effect on tacrolimus blood concentration may persist for several days after discontinuation of concomitant therapy. |
Concomitant use is recommended to be avoided. If concomitant use of a potent CYP3A4 inhibitor cannot be avoided, consider withholding the tacrolimus dose on the day of initiation of the potent CYP3A4 inhibitor. Resume tacrolimus the next day at a reduced dose, based on blood tacrolimus concentration. Dose and/or dosing frequency adjustments of tacrolimus should be individualized and modified as needed based on trough tacrolimus concentrations, which should be assessed at initiation, frequently monitored (starting within the first few days), and re-evaluated at initiation and after discontinuation of the CYP3A4 inhibitor. After discontinuation of the CYP3A4 inhibitor, appropriate tacrolimus dose and dosing frequency should be re-established based on blood concentration. Monitor renal function, QT interval prolongation (on ECG), and other potential adverse effects. |
|
| Moderate or weak CYP3A4 inhibitors: antifungal agents (e.g. fluconazole, isavuconazole, clotrimazole, miconazole), macrolide antibiotics (e.g. azithromycin), calcium channel blockers (e.g. nifedipine, nicardipine, diltiazem, verapamil), amiodarone, danazol, ethinylestradiol, lansoprazole, omeprazole, antiviral agents (against hepatitis C) elbasvir/grazoprevir and glecaprevir/pibrentasvir, antiviral agent (CMV) letermovir, tyrosine kinase inhibitors nilotinib, crizotinib, imatinib, and (Chinese) herbal products containing extracts of Schisandra sphenanthera. |
May increase trough whole blood concentration of tacrolimus and increase the risk of serious adverse reactions (e.g. neurotoxicity, QT interval prolongation) (see section "Special precautions"). A rapid increase in tacrolimus levels may occur. |
Monitor trough whole blood concentrations of tacrolimus, starting within the first few days of concomitant use. Reduce the tacrolimus dose if necessary (see section "Dosage and administration"). Monitor renal function, QT interval prolongation (on ECG), and other potential adverse effects. |
|
| In vitro studies have shown that the following substances are potential inhibitors of tacrolimus metabolism: bromocriptine, cortisone, dapsone, ergotamine, gestodene, lidocaine, mephenytoin, midazolam, nilvadipine, norethisterone, quinidine, tamoxifen. |
May increase trough whole blood concentration of tacrolimus and increase the risk of serious adverse reactions (e.g. neurotoxicity, QT interval prolongation) (see section "Special precautions"). |
Monitor trough whole blood concentration of tacrolimus and, if necessary, reduce the tacrolimus dose (see section "Dosage and administration"). Monitor renal function, QT interval prolongation (on ECG), and other potential adverse effects. |
|
| Potent CYP3A4 inducers: rifampicin, phenytoin, carbamazepine, apalutamide, enzalutamide, mitotane, or St John's wort (Hypericum perforatum). |
May decrease trough whole blood concentration of tacrolimus and increase the risk of rejection (see section "Special precautions"). The maximum effect on tacrolimus blood concentration may be reached within 1–2 weeks of concomitant use. The effect may persist for 1–2 weeks after discontinuation of treatment. |
Concomitant use is recommended to be avoided. If concomitant use cannot be avoided, patients may require an increased tacrolimus dose. Dose adjustments of tacrolimus should be individualized and modified as needed based on trough tacrolimus concentrations, which should be assessed at initiation, frequently monitored (starting within the first few days), and re-evaluated during and after discontinuation of the CYP3A4 inducer. After discontinuation of the CYP3A4 inducer, gradual adjustment of tacrolimus dose may be required. Closely monitor graft function. |
|
| Moderate CYP3A4 inducers: metamizole, phenobarbital, isoniazid, rifabutin, efavirenz, etravirine, nevirapine; weak CYP3A4 inducers: flucloxacillin. |
May decrease trough whole blood concentration of tacrolimus and increase the risk of rejection (see section "Special precautions"). |
Monitor trough whole blood concentrations of tacrolimus and increase the tacrolimus dose if necessary (see section "Dosage and administration"). Closely monitor graft function. |
|
| Cannabidiol (P-gp inhibitor). |
There have been reports of increased blood levels of tacrolimus during concomitant use of tacrolimus and cannabidiol. This may be due to inhibition of intestinal P-glycoprotein, leading to increased bioavailability of tacrolimus. |
Tacrolimus and cannabidiol should be used with caution, carefully monitoring for adverse effects. Monitor trough whole blood concentrations of tacrolimus and adjust the tacrolimus dose as necessary (see sections "Dosage and administration" and "Special precautions"). |
|
| Caspofungin |
|
Monitor trough blood concentrations of tacrolimus and increase the dose of tacrolimus if necessary (see section "Dosage and administration"). Closely monitor transplanted organ function. |
|
| Agents known to have high plasma protein binding, e.g., NSAIDs, oral anticoagulants, oral antidiabetic agents. |
Tacrolimus is highly bound to plasma proteins. Potential interactions with other active substances with high plasma protein binding should be considered. |
Monitor trough concentrations of tacrolimus in whole blood and adjust the dose of tacrolimus if necessary (see section "Dosage and administration"). |
|
| Prokinetics: metoclopramide, cimetidine, and magnesium-aluminum hydroxide. |
May increase trough concentrations of tacrolimus in whole blood and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT interval prolongation). |
Monitor trough concentrations of tacrolimus in whole blood and reduce the dose of tacrolimus if necessary (see section "Dosage and administration"). Closely monitor renal function, QT interval prolongation (on ECG), and other adverse effects. |
|
| Concomitant corticosteroid maintenance therapy. |
May decrease trough concentrations of tacrolimus in whole blood and increase the risk of transplant rejection (see section "Special warnings and precautions for use"). |
Monitor trough concentrations of tacrolimus in whole blood and increase the dose of tacrolimus if necessary (see section "Dosage and administration"). Closely monitor transplanted organ function. |
|
| High-dose prednisolone or methylprednisolone. |
May affect blood levels of tacrolimus (increase or decrease) when used to treat acute rejection. |
Monitor trough concentrations of tacrolimus in whole blood and adjust the dose of tacrolimus if necessary. |
|
| Direct-acting antiviral agents (DAA). |
May affect the pharmacokinetics of tacrolimus due to changes in liver function during DAA therapy related to HCV virus elimination. Decreased blood levels of tacrolimus may occur. However, the CYP3A4 inhibitory potential of some DAAs may counteract this effect or lead to increased tacrolimus blood levels. |
Monitor trough concentrations of tacrolimus in whole blood and adjust the dose of tacrolimus as necessary to maintain efficacy and safety. |
Concomitant use of tacrolimus with a mammalian target of rapamycin (mTOR) inhibitor (e.g., sirolimus, everolimus) may increase the risk of thrombotic microangiopathy (including hemolytic uremic syndrome and thrombotic thrombocytopenic purpura) (see section "Special warnings and precautions for use").
Since treatment with tacrolimus may be associated with hyperkalemia or may exacerbate existing hyperkalemia, high dietary potassium intake or potassium-sparing diuretics (e.g., amiloride, triamterene, or spironolactone) should be avoided (see section "Special warnings and precautions for use"). 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 a potassium-sparing diuretic, similar to amiloride. Careful monitoring of serum potassium levels is recommended.
Effect of tacrolimus on the metabolism of other medicinal products
Tacrolimus is a known inhibitor of CYP3A4; therefore, concomitant administration of tacrolimus with medicinal products metabolized by CYP3A4 may affect the metabolism of such medicinal products.
The elimination half-life of cyclosporine is prolonged when administered concomitantly with tacrolimus. In addition, a synergistic effect/additive nephrotoxic effect 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 warnings and precautions for use").
Tacrolimus has been shown to increase blood levels of phenytoin.
Since tacrolimus may reduce the therapeutic range of hormonal contraceptives, typically leading to increased hormonal exposure, particular attention and caution should be exercised when selecting contraceptive methods. Currently, there is insufficient information on the interaction between tacrolimus and statins. Clinical data indicate that the pharmacokinetics of statins are not significantly altered by concomitant administration with tacrolimus.
Animal studies have shown that tacrolimus may potentially reduce the clearance and prolong the half-life of pentobarbital and antipyrine.
Mycophenolic acid
Caution should be exercised when switching patients receiving combination therapy with cyclosporine (which affects the enterohepatic recirculation of mycophenolic acid) to tacrolimus, which lacks this effect, as this may 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.
When switching from cyclosporine to tacrolimus or vice versa, therapeutic drug monitoring of mycophenolic acid may be advisable.
Immunosuppressants may affect the response to vaccination; therefore, vaccination during treatment with tacrolimus may be less effective. The use of live attenuated vaccines should be avoided (see section "Special warnings and precautions for use").
Special precautions for use.
Errors have been reported during the use of the medicinal product, including accidental, unintentional, or uncontrolled substitution between immediate-release and extended-release formulations of 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 formulation of tacrolimus 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").
Advagraf® is not recommended for use in children due to limited safety and/or efficacy data in this patient population.
In adult patients, there are no clinical data on the use of extended-release Advagraf® for the treatment of rejection resistant to other immunosuppressants.
Currently, there are no clinical data on the use of Advagraf® for prevention of transplant rejection in heart transplantation.
During the early post-transplant period, regular monitoring of the following parameters is required: blood pressure, ECG, neurological status and visual function, fasting blood glucose, electrolyte levels (particularly potassium), liver and kidney function tests, haematological parameters, coagulation profile, and serum protein levels. Adjustment of immunosuppressive therapy is necessary if clinically significant abnormalities occur.
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 leading to serious adverse reactions, including transplant rejection or toxicity (see section "Interaction with other medicinal products and other forms of interaction").
CYP3A4 inhibitors
Concomitant use with CYP3A4 inhibitors may increase blood levels of tacrolimus, potentially leading to serious adverse reactions, including nephrotoxicity, neurotoxicity, and QT interval prolongation. It is recommended to avoid concomitant use of potent 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 therapy, under the supervision of a transplant specialist, to adjust the tacrolimus dose as needed to maintain consistent tacrolimus exposure. Renal function, ECG (including QT interval), and the patient's clinical status should also be closely monitored.
Dose adjustments should be based on the individual clinical condition of each patient. 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, potentially leading to subtherapeutic blood levels of tacrolimus; therefore, such situations require careful monitoring and supervision by a transplant specialist.
CYP3A4 inducers
Concomitant use with CYP3A4 inducers may reduce blood levels of tacrolimus, potentially increasing the risk of transplant rejection. It is recommended to avoid concomitant use of potent CYP3A4 inducers (such as rifampicin, phenytoin, carbamazepine) with tacrolimus. If co-administration cannot be avoided, frequent monitoring of tacrolimus blood levels should be performed starting from the first few days of concomitant therapy, under the supervision of a transplant specialist, to adjust the tacrolimus dose as needed to maintain consistent tacrolimus exposure. The function of the transplanted organ should also be closely monitored (see section "Interaction with other medicinal products and other forms of interaction").
Similarly, discontinuation of CYP3A4 inducers may affect the metabolism rate of tacrolimus, potentially leading to supratherapeutic blood levels of tacrolimus, and therefore requires careful monitoring and supervision by a transplant specialist.
P-glycoprotein
Caution should be exercised when 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 required (see section "Interaction with other medicinal products and other forms of interaction").
Herbal products
Administration of herbal products containing St. John’s wort (Hypericum perforatum) should be avoided during treatment with Advagraf® due to the risk of interactions leading to reduced blood levels of tacrolimus and reduced therapeutic effect of Advagraf®.
Other interactions
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").
High-potassium products 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. The use of live attenuated vaccines should be avoided.
Nephrotoxicity
In transplant patients, tacrolimus may cause kidney dysfunction. Acute renal failure, if not actively managed, may progress to chronic renal failure. Patients with impaired renal function should be closely observed, as dose reduction of tacrolimus may be required. The risk of nephrotoxicity may be 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, blood levels of tacrolimus and renal function should be closely monitored, and dose reduction should be considered if nephrotoxicity occurs.
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. Appropriate treatment should be initiated immediately upon suspicion of such events.
During diarrhoea, blood levels of tacrolimus may vary significantly; careful monitoring of tacrolimus blood concentrations is required if diarrhoea occurs.
Cardiac disorders
Cases of ventricular hypertrophy or septal hypertrophy, reported as cardiomyopathy, have been rarely observed but reported in patients receiving Prograf and therefore are possible during treatment with Advagraf®. In most cases, myocardial hypertrophy was 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 oedema. 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, consideration should be given to reducing the dose of Advagraf® or switching to another immunosuppressant.
Tacrolimus may prolong the QT interval and may cause torsades de pointes. Caution should be exercised when administering tacrolimus to patients with risk factors for QT prolongation, including patients with personal or familial history of prolonged QT interval, patients with congestive heart failure, bradyarrhythmias, or electrolyte imbalances. Caution is 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, including those causing electrolyte disturbances or known to increase electrolyte levels (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 tacrolimus (see section "Adverse effects"). The risk of developing post-transplant lymphoproliferative disorders (PTLD) associated with Epstein-Barr virus (EBV) is increased when immunosuppressants are used concomitantly with antilymphocyte antibodies (such as basiliximab, daclizumab). There are also reports of increased risk of lymphoproliferative disorders in patients who are EBV-VCA (viral capsid antigen) negative. Therefore, serological testing for EBV-VCA should be performed before initiating Advagraf® in this patient group. During treatment, careful monitoring for EBV using polymerase chain reaction (PCR) is recommended. A positive EBV-PCR result may persist for 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").
As with other immunosuppressive agents, due to the potential risk of skin malignancies, exposure to sunlight and ultraviolet radiation should be limited; protective clothing should be worn and sunscreen with a high protection factor should be used.
Infections, including opportunistic infections
Patients receiving immunosuppressants, including Advagraf®, have an increased risk of developing opportunistic infections (bacterial, fungal, viral, and protozoal), particularly cytomegalovirus (CMV) infection, BK virus-associated nephropathy, and progressive multifocal leukoencephalopathy (PML) caused by JC virus. Patients also have an increased risk of infectious viral hepatitis (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 (TMA) (including haemolytic uraemic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP))
The diagnosis of TMA, including thrombotic thrombocytopenic purpura (TTP) and haemolytic uraemic syndrome (HUS), which may sometimes lead to renal failure or death, should be considered in patients presenting with haemolytic anaemia, thrombocytopenia, fatigue, fluctuating neurological symptoms, renal dysfunction, and fever. If TMA is diagnosed, immediate treatment is required, and discontinuation of tacrolimus should be considered at the physician’s discretion.
Concomitant use of tacrolimus with a mammalian target of rapamycin (mTOR) inhibitor (e.g., sirolimus, everolimus) may increase the risk of thrombotic microangiopathy (including haemolytic uraemic syndrome and thrombotic thrombocytopenic purpura).
Posterior reversible encephalopathy syndrome (PRES)
Posterior reversible encephalopathy syndrome (PRES) has been reported in patients receiving tacrolimus. If patients receiving tacrolimus develop symptoms of PRES, such as headache, altered mental status, seizures, or visual disturbances, appropriate diagnostic procedures (e.g., MRI) should be performed. Upon diagnosis of PRES, systemic tacrolimus therapy should be discontinued immediately, and adequate control of blood pressure and seizures should be ensured. Most patients fully recover after appropriate treatment.
Visual disorders
Visual disturbances, sometimes progressing to vision loss, have been reported in patients receiving tacrolimus. In individual cases, switching to alternative immunosuppressive therapy has been considered. Patients should be advised to report changes in visual acuity, colour vision, blurred vision, or visual field defects; immediate ophthalmological evaluation is recommended, with referral to an ophthalmologist if necessary.
Cases of pure red cell aplasia (PRCA)
Cases of pure red cell aplasia (PRCA) have been reported in patients receiving tacrolimus. All affected 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 racial groups and in patients at increased risk of immunological complications (e.g., re-transplantation, presence of panel-reactive antibodies (PRA)) is limited.
Patients with severe hepatic impairment may require dose reduction (see section "Dosage and administration").
Excipients
Advagraf® capsules contain lactose (a 0.5 mg capsule contains 51.09 mg lactose, a 1 mg capsule contains 102.17 mg lactose, a 3 mg capsule contains 306.52 mg lactose, a 5 mg capsule contains 510.9 mg lactose, respectively); therefore, the product should not be administered to patients with rare hereditary conditions of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.
The printing ink used to mark Advagraf® capsules contains a negligible amount (traces) of soy lecithin (0.48% of the total printing ink composition). For patients with hypersensitivity to peanuts or soy products, the benefit of using Advagraf® should be weighed against the potential risk and severity of hypersensitivity reactions.
One Advagraf® capsule (0.5 mg, 1 mg, 3 mg, and 5 mg) contains less than 1 mmol sodium (23 mg) per capsule, i.e., practically "sodium-free".
Use during pregnancy or breastfeeding.
Pregnancy
Human data show that tacrolimus crosses the placenta in women. Limited data from organ transplant recipients show no evidence of increased risk of adverse effects on pregnancy course or outcome with tacrolimus compared to other immunosuppressive 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 be permitted only when no safer alternative exists and when the potential benefit to the mother justifies the potential risk to the fetus. To detect potential adverse effects of tacrolimus, monitoring of neonates born to mothers who received tacrolimus during pregnancy is recommended (particularly renal function). There is a risk of preterm delivery (<37 weeks) (frequency 66/123 births, i.e., 53.7%), although data indicate that most newborns had normal birth weight for gestational age. There is also a risk of neonatal hyperkalaemia (frequency 8 out of 111 newborns, i.e., 7.2%), which, however, resolves spontaneously.
In rat and rabbit studies, tacrolimus caused signs of embryofetal toxicity at doses associated with maternal toxicity.
Fertility.
In rats, tacrolimus showed a negative effect on male fertility, including reduced sperm count and motility.
Breastfeeding period
Data show that tacrolimus passes into breast milk. Since adverse effects of tacrolimus on the newborn cannot be excluded, women taking Advagraf® should discontinue breastfeeding.
Ability to affect reaction speed when driving or operating machinery.
Tacrolimus may cause visual and neurological disturbances, especially when Advagraf® is combined with alcohol.
There are no studies on the effect of tacrolimus (Advagraf®) on the ability to drive or operate machinery.
Method of Administration and Dosage.
Advagraf**®** is an oral formulation of tacrolimus administered once daily. Therapy with Advagraf**®** requires careful monitoring by qualified personnel with access to appropriate equipment. Only physicians experienced in immunosuppressive therapy in organ transplant recipients should 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 between different oral formulations of tacrolimus with varying release profiles is hazardous. 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 strictly to one specific formulation of tacrolimus with a consistent daily dosing schedule; changes 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 alternative formulation, blood concentration of tacrolimus must be monitored and dosage adjusted to maintain adequate systemic exposure to tacrolimus.
Method of Administration
The recommended initial doses listed below are intended as guidelines.
During the initial postoperative period, Advagraf**®** is generally administered concomitantly with other immunosuppressive agents. The dose may be adjusted depending on the chosen immunosuppressive regimen. Advagraf**®** dosage should be determined primarily based on clinical assessment of rejection risk and individual drug tolerability, as well as therapeutic drug monitoring data (see section "Therapeutic Drug Monitoring" below). If clinical signs of rejection occur, adjustment of the immunosuppressive regimen should be considered.
In de novo kidney and liver transplant recipients, the AUC0-24 of tacrolimus for Advagraf**®** on Day 1 was approximately 30% and 50% lower, respectively, compared to that observed with the same dose of the immediate-release capsule formulation (Prograf**®). By Day 4, systemic exposure to tacrolimus (measured as trough plasma levels) was comparable between the two formulations in both kidney and liver transplant recipients. To ensure adequate tacrolimus exposure during the first 2 weeks of Advagraf®** therapy post-transplantation, regular and careful monitoring of trough blood concentrations of tacrolimus is recommended. Since tacrolimus is a low-clearance drug, several days may be required to reach steady-state concentrations after any dose adjustment of Advagraf**®**.
To prevent graft rejection, immunosuppression must be maintained continuously; therefore, the duration of therapy is indefinite.
Prevention of Kidney Allograft Rejection
Oral therapy with Advagraf**®** should be initiated at a daily dose of 0.2–0.3 mg/kg administered once daily in the morning. Treatment should be started within 24 hours after transplantation.
The dose of Advagraf**®** is generally reduced during the post-transplant period. In some cases, concomitant immunosuppressive therapy may be discontinued, resulting in monotherapy with Advagraf**®. Post-transplant changes in the patient's condition may alter tacrolimus pharmacokinetics and require further dose adjustments of Advagraf®**.
Prevention of Liver Allograft Rejection
Oral therapy with Advagraf**®** should be initiated at a daily dose of 0.1–0.2 mg/kg once daily in the morning. Treatment should be started 12–18 hours after transplantation.
The dose of Advagraf**®** is generally reduced during the post-transplant period. In some cases, concomitant immunosuppressive therapy may be discontinued, resulting in monotherapy with Advagraf**®. Post-transplant changes in the patient's condition may alter tacrolimus pharmacokinetics and require further dose adjustments of Advagraf®**.
Conversion from Prograf to Advagraf®
When converting patients after allogeneic transplantation who have been receiving Prograf**®** (capsules) at a maintenance dose twice daily to Advagraf**®** once daily, the daily dose ratio during transition should be 1:1 (mg:mg). Advagraf**®** should be administered in the morning.
In stable patients converted from Prograf**®** capsules (twice daily) to Advagraf**®** (once daily) at a 1:1 (mg:mg) total daily dose ratio, systemic exposure to tacrolimus (AUC 0-24) with Advagraf**®** was approximately 10% lower than with Prograf**®. The relationship between trough concentration (C24) and systemic exposure (AUC 0-24) is similar for Advagraf®** and Prograf**®. When switching from Prograf®** capsules to Advagraf**®** capsules, trough drug concentrations in plasma should be measured before and for at least two weeks after conversion. After conversion, trough levels of tacrolimus in plasma should be monitored and the dose adjusted as necessary to maintain systemic exposure at the prior level. Dose adjustments are required to maintain systemic exposure to tacrolimus at the previous level.
Conversion 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. Advagraf**®** therapy should be initiated after determining cyclosporine plasma concentration and assessing the patient's clinical status. Conversion should be delayed if blood cyclosporine 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
To manage allograft rejection, the following approaches are recommended: 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 Advagraf**®** may be necessary.
Treatment of Kidney or Liver Allograft Rejection
When switching from other immunosuppressants to Advagraf**®**, treatment should be initiated with the recommended initial oral doses for prevention of kidney or liver allograft rejection, respectively.
Treatment of Heart Allograft Rejection
For adult patients converted to Advagraf**®**, the initial oral dose is 0.15 mg/kg/day administered in the morning.
Treatment of Allograft Rejection Following Other Organ Transplants
There is no clinical experience with Advagraf**®** for the treatment of patients after lung, pancreas, or intestinal transplantation. The medicinal product Prograf**®** should be used for treatment of patients after lung transplantation at an initial oral dose of 0.10–0.15 mg/kg/day, after pancreas transplantation at an initial oral dose of 0.2 mg/kg/day, and after intestinal transplantation 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 tolerability, as well as on therapeutic monitoring of trough blood levels of tacrolimus.
Several methods for measuring tacrolimus concentration in whole blood should be used to determine optimal dosing. When comparing monitoring results published in the literature with those from a specific clinic, the assay method used for measuring tacrolimus blood concentration must be taken into account. In current clinical practice, blood levels of tacrolimus are predominantly monitored using immunoassay methods. The correlation between trough concentration (C24) and systemic exposure (AUC0-24) of tacrolimus in blood is practically identical for both formulations (Advagraf**®** and Prograf**®**).
During the post-transplant period, trough levels of tacrolimus in blood should be monitored. The trough level should be measured approximately 24 hours after the last dose of Advagraf**®, immediately before the next dose. During the first 2 weeks after transplantation, more frequent monitoring of trough levels is recommended, followed by periodic monitoring during maintenance therapy. Therapeutic trough levels of tacrolimus in blood should be carefully monitored after conversion from Prograf®** to Advagraf**®, after dose adjustments, changes in the 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"). The frequency of drug level monitoring should be determined based on clinical necessity. Since tacrolimus is a low-clearance drug, several days may be required to achieve steady-state concentrations after any dose adjustment of Advagraf®**.
According to clinical trial data, most patients are successfully treated when therapeutic trough blood levels of tacrolimus do not exceed 20 ng/mL. When interpreting data on therapeutic trough concentration of tacrolimus in blood, the patient's clinical condition should be considered. Available data indicate that during the early post-transplant period, the therapeutic blood level range is 5–20 ng/mL for liver transplant recipients and 10–20 ng/mL for kidney or heart transplant recipients. During maintenance immunosuppressive therapy, blood concentrations of the drug in liver, kidney, or heart transplant recipients are generally maintained within the range of 5–15 ng/mL.
Special Populations
Hepatic Impairment
Patients with severe hepatic dysfunction may require dose reduction of Advagraf**®** 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 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.
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 different doses are required for male and female patients to achieve similar trough plasma concentrations.
Elderly Patients
There is no evidence that elderly patients require special dosing.
Administration Method.
The recommended once-daily oral dose of Advagraf**®** should be taken in the morning.
Extended-release Advagraf**®** capsules should be taken immediately after removal from the blister pack. Patients should be advised that the packaging contains a desiccant (silica gel packet), which is not intended for ingestion. Capsules should be swallowed whole with liquid (preferably water). To achieve maximum absorption, Advagraf**®** should be taken on an empty stomach: at least 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 following morning.
For patients unable to take oral medication immediately after organ transplantation, intravenous tacrolimus therapy may be initiated (see medical instructions for Prograf**®**, 5 mg/mL concentrate for solution for infusion) at a dose approximately 1/5 of the recommended oral dose for the corresponding indication.
Children.
The safety and efficacy of Advagraf**®** in children have not been established. Limited data are available, but no dosing recommendations can be made based on these data.
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 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 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 after transplantation, it is difficult to precisely define the adverse effect profile of immunosuppressants.
The most common adverse reactions (reported in >10% of patients) are tremor, renal failure, hyperglycemic conditions, diabetes mellitus, hyperkalemia, infections, 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 group, adverse effects are listed in order of decreasing 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 infections may occur.
In patients receiving immunosuppressants, including Advagraf**®**, cases of CMV infection, BK virus-associated nephropathy, and progressive multifocal leukoencephalopathy (PML) associated with JC virus have been reported.
Benign and malignant neoplasms, unspecified (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 (EBV)-associated lymphoproliferative disorders and skin malignancies.
Blood and lymphatic system disorders
Common: anemia, thrombocytopenia, leukopenia, abnormalities in erythrocyte parameters, 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.
Immune system disorders
Allergic and anaphylactoid reactions have been observed in patients receiving tacrolimus (see section "Special precautions").
Endocrine disorders
Rare: hirsutism.
Metabolism and nutrition disorders
Very common: diabetes mellitus, hyperglycemic states, 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 disorders and disturbances, 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 (PRES).
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 impairment.
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: 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, disorders of the respiratory tract, asthma.
Rare: acute respiratory distress syndrome.
Gastrointestinal disorders
Very common: diarrhea, nausea.
Common: gastrointestinal symptoms and signs, vomiting, abdominal and gastrointestinal 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 evacuatory function.
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: arthralgia, back pain, muscle spasms, limb pain.
Uncommon: joint disorders.
Rare: decreased mobility.
Renal and urinary disorders
Very common: renal failure.
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, feeling of anxiety, worsening of general condition, multi-organ failure, chest pressure, altered perception of ambient temperature.
Rare: falls, ulcers, constricting chest pain, thirst.
Very rare: increase in fat tissue mass.
Investigations
Very common: changes in liver function tests.
Common: increased blood alkaline phosphatase levels, increased body weight.
Uncommon: elevated blood amylase levels, abnormal ECG findings, disturbances in heart rate and pulse, decreased body weight, 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 (CIPS). This pain is typically bilateral, symmetric, severe, ascending pain in the lower limbs and may be associated with high therapeutic levels of tacrolimus. The syndrome may respond to a reduction in tacrolimus dose. In some cases, switching to an alternative immunosuppressive regimen was necessary.
Special precautions for disposal and other handling
Due to the immunosuppressive effect of tacrolimus, inhalation or direct skin or mucous membrane contact with the injectable solution or powder contained in the medicinal product packaging should be avoided. If such contact occurs, wash the skin and rinse the affected eye(s).
Shelf life.
3 years.
After opening the aluminum pouch – 1 year.
The medicinal product should not be used after the expiry date stated on the packaging.
Storage conditions.
Store in the original packaging at a temperature not exceeding 25 °C.
Keep out of reach and sight of children.
Packaging.
Extended-release capsules of 0.5 mg, 1 mg, 3 mg, or 5 mg. 10 capsules per blister, 5 blisters per sealed aluminum pouch with a sachet containing 1 g of silica gel.
1 aluminum foil pouch per cardboard box.
Prescription status. Prescription only.
Manufacturer. Astellas Ireland Co. Ltd / Astellas Ireland Co. Ltd.
Manufacturer's address.
Killorglin, Co. Kerry, V93 FC86, Ireland / Killorglin, Co. Kerry, V93 FC86, Ireland.
Marketing Authorisation Holder. Astellas Pharma Europe B.V. / Astellas Pharma Europe B. V.
Address of the Marketing Authorisation Holder.
Sylviusweg, 62, 2333 BE Leiden, the Netherlands / Sylviusweg, 62, 2333 BE Leiden, the Netherlands.
Representative in Ukraine: 13, Pimonенka St., bldg. 7-V, office 41, Kyiv, 04050.