Instructions for Tacni Long prolonged-release capsules 1 mg blister No. 50
Composition
active substance: tacrolimus (as tacrolimus monohydrate);
1 hard prolonged-release capsule contains 0.5 mg or 1 mg, or 3 mg, or 5 mg of tacrolimus (as tacrolimus monohydrate);
excipients:
capsule contents: ethylcellulose, hypromellose (type 2910), lactose monohydrate (450M), lactose monohydrate (100M), magnesium stearate;
capsule shell: titanium dioxide (E 171), yellow iron oxide (E 172), red iron oxide (E 172), black iron oxide (E 172)*, ponceau 4R (E 124)*, gelatin.
* Only included in the 5 mg capsule.
Dosage form
The extended-release capsules are hard.
Main physicochemical properties:
0.5 mg capsules: hard gelatin capsules, size 5, filled with white to off-white powder; body: light orange with radial inscription "0.5mg" in black; cap: light yellow with radial inscription "TR" in black;
1 mg capsules: hard gelatin capsules, size 4, filled with white to off-white powder; body: light orange with radial inscription “1mg” in black; cap: white with radial inscription “TR” in black;
3 mg capsules: hard gelatin capsules, size 1, filled with white to off-white powder; body: light orange with radial inscription “3mg” in black; cap: light orange with radial inscription “TR” in black;
5 mg capsules: hard gelatin capsules size 0, filled with white to off-white powder; body: light orange with radial inscription "5mg" in black; cap: grayish-red with radial inscription "TR" in black.
Pharmacotherapeutic group
Immunosuppressants. Calcineurin inhibitors. ATX code L04A D02.
Pharmacological properties
Pharmacodynamics.
At the molecular level, the effects and intracellular accumulation of tacrolimus are mediated by binding to a cytosolic protein (FKBP12). The FKBP12-tacrolimus complex specifically and competitively binds to and inhibits calcineurin, resulting in calcium-dependent inhibition of T-cell signaling pathways, thereby preventing the transcription of a discrete set of cytokine genes.
Tacrolimus is a highly active immunosuppressant, as proven in in vitro and in vivo experiments.
In particular, tacrolimus inhibits the production of cytotoxic lymphocytes, which play a key role in the transplant rejection reaction. Tacrolimus inhibits T-cell activation and T-helper-dependent B-cell proliferation, as well as the production of lymphokines (such as interleukin-2, -3 and γ-interferon) and the expression of the interleukin-2 receptor.
Pharmacokinetics.
Absorption
It has been established that in humans tacrolimus can be absorbed from the gastrointestinal tract. Tacrolimus is usually rapidly absorbed. The drug Tacni Long is a prolonged-release dosage form of tacrolimus, has a prolonged absorption profile when administered orally, the mean time to reach maximum blood concentration (Cmax) is approximately 2 hours (tmax).
The absorption of tacrolimus is variable, with a mean oral bioavailability of tacrolimus (immediate-release capsules) of 20-25% (individual range in adult patients 6-43%). The oral bioavailability of tacrolimus as prolonged-release capsules was reduced when administered after food. Both the rate and extent of absorption of tacrolimus were reduced when the prolonged-release capsules were administered with food.
Bile secretion does not affect the absorption of tacrolimus, so treatment with Tacni Long can be initiated orally.
After reaching steady-state concentrations of tacrolimus with prolonged-release capsules, there is a high correlation between AUC and trough levels of tacrolimus in the blood. Therefore, monitoring of trough levels of tacrolimus in whole blood provides an opportunity to detect systemic exposure to the drug.
Distribution
The distribution of tacrolimus in humans after intravenous administration is biphasic.
In the systemic circulation, tacrolimus is extensively bound to erythrocytes, with a whole blood/plasma distribution ratio of approximately 20:1. In plasma, tacrolimus is extensively bound (>98.8%) to plasma proteins, primarily serum albumin and α-1-acid glycoprotein.
Tacrolimus is widely distributed in the body. The steady-state volume of distribution based on plasma concentrations is approximately 1300 l (healthy volunteers). The corresponding figure based on whole blood is on average 47.6 l.
Metabolism
Tacrolimus is extensively metabolised in the liver, mainly by cytochrome P450 3A4. Tacrolimus is also extensively metabolised in the intestinal wall. Several metabolites of tacrolimus have been identified. In vitro experiments have shown that only one of the metabolites has immunosuppressive activity similar to that of tacrolimus. The other metabolites have little or no immunosuppressive activity. Only one of the inactive metabolites is present in the systemic circulation at low concentrations. Thus, the metabolites do not contribute to the pharmacological activity of tacrolimus.
Tacrolimus is a substance with low clearance. In healthy volunteers, the mean total clearance, as determined by whole blood concentration, was 2.25 l/h. In adult liver, kidney and heart transplant recipients, the values were 4.1 l/h, 6.7 l/h and 3.9 l/h, respectively.
Clearance is increased by factors such as low hematocrit and hypoproteinemia (which lead to an increase in the unbound fraction of tacrolimus) or the use of corticosteroids, which increase the metabolic rate.
The elimination half-life of tacrolimus is long and variable. In healthy volunteers, the mean elimination half-life in whole blood was approximately 43 hours.
Following intravenous and oral administration of 14C-labeled tacrolimus, the majority of radioactivity was recovered in the faeces. Approximately 2% was excreted in the urine. Less than 1% of unchanged tacrolimus was recovered in the urine and faeces, indicating that tacrolimus is almost completely metabolised before excretion and the main route of elimination is via the bile.
Indication
Prevention and treatment of liver and kidney allograft rejection in adult patients.
Treatment of allograft rejection resistant to standard immunosuppressive regimens in adult patients.
Contraindication
Hypersensitivity to tacrolimus, other macrolides or to any of the excipients of the medicinal product.
Interaction with other medicinal products and other types of interactions
Metabolic interactions
Systemically available tacrolimus is metabolised in the liver by CYP3A4. There is also evidence of gastrointestinal metabolism, which occurs via CYP3A4 in the intestinal wall. Concomitant use of medicinal products, including herbal medicines, that inhibit or induce CYP3A4 may affect the metabolism of tacrolimus and thus reduce or increase its blood levels. Similarly, withdrawal of these medicinal products, including herbal medicines, may affect the rate of metabolism of tacrolimus and, consequently, its blood levels.
Pharmacokinetic studies have shown that the increase in tacrolimus blood levels when co-administered with CYP3A4 inhibitors is mainly due to an increase in the oral bioavailability of tacrolimus due to inhibition of gastrointestinal metabolism. The effect on hepatic clearance is less pronounced.
When used concomitantly with substances that may alter CYP3A4 metabolism, it is strongly recommended to closely monitor tacrolimus blood levels under the supervision of a transplant specialist, as well as monitor graft function, QT prolongation (by ECG), renal function and other adverse reactions (including neurotoxicity), and, if necessary, interrupt or adjust the tacrolimus dose to maintain appropriate tacrolimus exposure (see sections 4.4 and 4.2). It is also necessary to ensure close monitoring of patients when tacrolimus is used concomitantly with multiple drugs that affect CYP3A4, due to the possible potentiation or neutralization of the effect on tacrolimus exposure.
The table below describes the drugs that interact with tacrolimus. The examples of drug interactions provided are not exhaustive or comprehensive, so when using tacrolimus in combination with any drug, the information on metabolic pathways, possible interactions, potential risks and precautions for concomitant use, as set out in the instructions for use of that drug, should be consulted.
Drugs that affect tacrolimus
| Drug/class or name of substance | Manifestation of drug interaction | Recommendations for concomitant use |
| Grapefruit or grapefruit juice | Possible increase in tacrolimus trough concentrations in whole blood and increased risk of serious adverse reactions (e.g. neurotoxicity, QT prolongation) (see section 4.4). | Grapefruit or grapefruit juice should be avoided. |
| Cyclosporine | There may be an increase in tacrolimus trough concentrations in whole blood. In addition, a synergistic/additive nephrotoxic effect may occur. | Avoid concomitant use of cyclosporine and tacrolimus (see section "Special warnings and precautions for use"). |
| Drugs that have nephrotoxic or neurotoxic effects: aminoglycosides, gyrase inhibitors, vancomycin, sulfamethoxazole + trimethoprim, NSAIDs, ganciclovir, acyclovir, amphotericin B, ibuprofen, cidofovir, foscarnet | Possible enhancement of the nephrotoxic or neurotoxic effects of tacrolimus. | Concomitant use of tacrolimus with nephrotoxic drugs should be avoided. If such use cannot be avoided, renal function and other adverse reactions should be monitored and the tacrolimus dose adjusted as necessary. |
Strong CYP3A4 inhibitors: antifungals (e.g. ketoconazole, itraconazole, posaconazole, voriconazole), macrolide antibiotics (e.g. telithromycin, troleandromycin, 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, when used alone or with dasabuvir), nefazodone, the pharmacokinetic enhancer cobicistat and the kinase inhibitors idelalisib, ceritinib. A strong interaction has also been observed with the macrolide antibiotic erythromycin | Possible increase in tacrolimus trough concentrations in whole blood and increased risk of serious adverse reactions (e.g. nephrotoxicity, neurotoxicity, QT prolongation) requiring close monitoring (see section 4.4). Sudden and sharp increases in tacrolimus levels may occur as early as 1-3 days after concomitant use, despite immediate reduction of the tacrolimus dose. Total tacrolimus concentrations may increase by more than 5-fold. When used in combination with ritonavir, a more than 50-fold increase in tacrolimus concentrations in the body may be observed. Almost all patients may require a reduction in the tacrolimus dose or temporary discontinuation of tacrolimus therapy. The effect on tacrolimus blood concentrations may persist for several days after discontinuation of concomitant use. | It is recommended to avoid concomitant use. If concomitant use with a strong CYP3A4 inhibitor cannot be avoided, consideration should be given to skipping a dose of tacrolimus on the day of initiation of treatment with the strong CYP3A4 inhibitor. Tacrolimus therapy should be resumed the following day, with the dose reduced based on the tacrolimus blood concentration. The tacrolimus dose and/or frequency of administration should be adjusted on an individual basis, taking into account the trough tacrolimus concentration determined at the start of CYP3A4 inhibitor therapy, regularly monitored during therapy (starting from the first days), and assessed at and some time after discontinuation of CYP3A4 inhibitor therapy. After discontinuation of concomitant therapy, the tacrolimus dose and frequency of administration should be determined based on the tacrolimus blood concentration. Careful monitoring of renal function, ECG (for QT prolongation) and other adverse reactions should be ensured. | | Moderate or weak CYP3A4 inhibitors: antifungals (e.g. fluconazole, isavuconazole, clotrimazole, miconazole), macrolide antibiotics (e.g. azithromycin), calcium channel blockers (e.g. nifedipine, nicardipine, diltiazem, verapamil), amiodarone, danazol, ethinyl estradiol, lansoprazole, omeprazole, hepatitis C agents elbasvir/grazoprevir and glecaprevir/pibrentasvir, the CMV antiviral letermovir, the tyrosine kinase inhibitors nilotinib, crizotinib and imatinib, and (Chinese) herbal medicines containing Schisandra sphenanthera extract | Possible increase in tacrolimus trough concentrations in whole blood and increased risk of serious adverse reactions (e.g. neurotoxicity, QT prolongation) (see section 4.4). Possible sudden increase in tacrolimus levels. | Frequent monitoring of tacrolimus trough concentrations in whole blood should be ensured, starting from the first days of concomitant use. If necessary, the tacrolimus dose should be reduced (see section 4.2). Careful monitoring of renal function, ECG (for QT prolongation) and other adverse reactions should be ensured. |
| 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 | Possible increase in tacrolimus trough concentrations in whole blood and increased risk of serious adverse reactions (e.g. neurotoxicity, QT prolongation) (see section 4.4). | Whole blood trough concentrations of tacrolimus should be monitored and the tacrolimus dose reduced if necessary (see section 4.2). Renal function, ECG (for QT prolongation) and other adverse reactions should be closely monitored. |
| Strong CYP3A4 inducers: rifampicin, phenytoin, carbamazepine, apalutamide, enzalutamide, mitotane or St. John's wort (Hypericum perforatum) medicines | It is recommended to avoid concomitant use. If this is not possible, patients may need to increase their tacrolimus dose. The tacrolimus dose should be adjusted individually for each patient, with appropriate adjustments based on the trough tacrolimus concentration, which is determined at the start of therapy with a CYP3A4 inducer, monitored regularly during therapy (starting from the first days), and assessed at the time of and some time after discontinuation of therapy with a CYP3A4 inducer. After discontinuation of the CYP3A4 inducer, a gradual adjustment of the tacrolimus dose may be necessary. Careful monitoring of graft function should be ensured. |
Moderate CYP3A4 inducers: metamizole, phenobarbital, isoniazid, rifabutin, efavirenz, etravirine, nevirapine. Weak CYP3A4 inducers: flucloxacillin | A decrease in tacrolimus trough concentrations in whole blood and an increase in the risk of rejection are possible (see section "Special warnings and precautions for use"). | Whole blood trough concentrations of tacrolimus should be monitored and the tacrolimus dose increased as necessary (see section 4.2). Graft function should be closely monitored. |
| Caspofungin | Possible decrease in tacrolimus trough concentration in whole blood and increased risk of rejection. The mechanism of interaction has not been established. | Whole blood trough concentrations of tacrolimus should be monitored and the tacrolimus dose increased as necessary (see section 4.2). Graft function should be closely monitored. |
| Cannabidiol (P-glycoprotein inhibitor) | Increased blood levels of tacrolimus have been reported when tacrolimus is co-administered with cannabidiol. This may be due to inhibition of P-glycoprotein in the intestine, leading to increased bioavailability of tacrolimus. | Concomitant use of tacrolimus and cannabidiol requires caution and close monitoring of adverse reactions. Whole blood trough concentrations of tacrolimus should be monitored and the tacrolimus dose adjusted as necessary (see sections 4.4 and 4.2). |
| Drugs that have high affinity for plasma proteins, such as NSAIDs, oral anticoagulants, oral antidiabetic drugs | Tacrolimus is highly bound to plasma proteins. The possibility of interactions with other active substances known to have high affinity for plasma proteins should be considered. | Whole blood trough concentrations of tacrolimus should be monitored and the tacrolimus dose adjusted as necessary (see section 4.2). |
| Prokinetic drugs: metoclopramide, cimetidine, magnesium and aluminum hydroxide | Possible increase in tacrolimus trough concentrations in whole blood and increased risk of serious adverse reactions (e.g. neurotoxicity, QT prolongation). | Whole blood trough concentrations of tacrolimus should be monitored and the tacrolimus dose reduced if necessary (see section 4.2). Close monitoring of renal function, ECG (for QT prolongation) and other adverse reactions should be ensured. |
| Maintenance doses of corticosteroids | Possible decrease in tacrolimus trough concentration in whole blood and increased risk of rejection (see section "Special warnings and precautions for use"). | Whole blood trough concentrations of tacrolimus should be monitored and the tacrolimus dose increased as necessary (see section 4.2). Graft function should be closely monitored. |
| High doses of prednisolone or methylprednisolone | When used to treat acute rejection, they may affect the level of tacrolimus in the blood (increase or decrease). | Whole blood tacrolimus trough concentrations should be monitored and the tacrolimus dose adjusted as necessary. |
| Direct-acting antivirals (DAAs) | Tacrolimus pharmacokinetics may be affected by changes in liver function during DAA treatment, associated with clearance of hepatitis virus. Tacrolimus blood levels may be reduced. However, when certain DAAs are used that are capable of inhibiting CYP3A4 activity, this effect may be counteracted or tacrolimus blood levels may be increased. | Whole blood trough concentrations of tacrolimus should be monitored and the tacrolimus dose adjusted as necessary to ensure continued efficacy and safety. |
Since treatment with tacrolimus may be associated with hyperkalaemia or may exacerbate pre-existing hyperkalaemia, increased potassium intake or the use of potassium-sparing diuretics (e.g. amiloride, triamterene or spironolactone) should be avoided (see section 4.4). Caution should be exercised when tacrolimus is administered concomitantly with other medicinal products that increase serum potassium levels, in particular trimethoprim and co-trimoxazole (trimethoprim/sulfamethoxazole), as trimethoprim is known to have a similar effect to the potassium-sparing diuretic amiloride. Close monitoring of serum potassium is recommended.
Effect of tacrolimus on the metabolism of other drugs
Tacrolimus is a known inhibitor of CYP3A4, therefore concomitant use of tacrolimus with medicinal products metabolised by CYP3A4 may affect the metabolism of such medicinal products. The half-life of ciclosporin is prolonged when co-administered with tacrolimus. In addition, synergistic/additive nephrotoxic effects are possible. For these reasons, the combined use of ciclosporin and tacrolimus is not recommended and physicians should exercise caution when prescribing tacrolimus to patients who have previously received ciclosporin (see sections 4.4 and 4.2).
Tacrolimus has been shown to increase blood levels of phenytoin.
Since tacrolimus may reduce the clearance of hormonal contraceptives, leading to increased hormone exposure, special care should be taken when deciding on contraceptive methods.
There is currently insufficient information on the interaction between tacrolimus and statins. Clinical data suggest that the pharmacokinetics of statins are not significantly altered by co-administration with tacrolimus.
Animal studies have shown that tacrolimus has the potential to reduce the clearance and increase the half-life of pentobarbital and antipyrine.
Mycophenolic acid: Caution should be exercised when switching combination therapy from ciclosporin, which inhibits the enterohepatic recirculation of mycophenolic acid, to tacrolimus, which does not have this effect, as this may result in altered exposure to mycophenolic acid. Medicinal products that inhibit the enterohepatic recirculation of mycophenolic acid may reduce plasma levels and efficacy of mycophenolic acid. Therapeutic monitoring of mycophenolic acid may be appropriate when switching from ciclosporin to tacrolimus or vice versa.
Immunosuppressants may affect the response to vaccination, therefore vaccination may be less effective during treatment with tacrolimus. The use of live attenuated vaccines should be avoided (see section 4.4).
Application features
Medication errors have been reported, including accidental, unintentional or uncontrolled substitution of immediate-release or prolonged-release tacrolimus formulations. This has resulted in serious adverse reactions, including graft rejection, or other adverse reactions that may result from under- or overexposure to tacrolimus in the body. Patients should be treated with a single formulation of tacrolimus with the appropriate daily dosing regimen; changes in formulation or regimen should only be made under the close supervision of a transplant specialist (see sections 4.8 and 4.8).
The drug Tacni Long is not recommended for use in children under 18 years of age due to limited data on safety and/or efficacy.
There are no clinical data in adult patients on the use of tacrolimus extended-release in the treatment of allograft rejection refractory to therapy with other immunosuppressants.
To date, there are no clinical data on the use of long-acting tacrolimus for the prevention of graft rejection in heart transplant patients in adult patients.
In the initial post-transplant period, the following parameters should be regularly monitored: blood pressure, ECG, neurological and visual status, fasting blood glucose, electrolyte levels (especially potassium), liver and kidney function tests, hematological parameters, coagulogram, and plasma protein levels. In the presence of clinically significant changes, correction of immunosuppressive therapy is necessary.
Medicines that may interact with the drug
CYP3A4 inhibitors. Concomitant use with CYP3A4 inhibitors may increase tacrolimus blood levels, which may lead to serious adverse reactions, including nephrotoxicity, neurotoxicity and QT 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 such use cannot be avoided, frequent monitoring of tacrolimus blood levels should be performed, starting from the first day of concomitant use, under the supervision of a transplant specialist, to adjust the tacrolimus dose, if necessary, to maintain the same level of drug exposure. Close monitoring of renal function, ECG parameters, including QT interval, and the patient's clinical status should also be ensured. Dose adjustment should take into account the individual situation of each patient. An immediate dose reduction may be required at the start of treatment (see section 4.5). Similarly, withdrawal of a CYP3A4 inhibitor may affect the rate of biotransformation of tacrolimus and result in subtherapeutic levels of tacrolimus in the blood and should therefore be carried out under close supervision and control by the transplant specialist.
CYP3A4 inducers. Concomitant use with CYP3A4 inducers may decrease tacrolimus blood levels, which may increase the risk of graft rejection. It is recommended to avoid the use of potent CYP3A4 inducers (such as rifampicin, phenytoin, carbamazepine) in combination with tacrolimus. If this cannot be avoided, frequent monitoring of tacrolimus blood levels under the supervision of a transplant specialist should be carried out from the first days of concomitant use, in order to adjust its dose, if necessary, in order to maintain the same degree of drug exposure. Graft function should also be closely monitored (see section “Interaction with other medicinal products and other types of interactions”). Similarly, withdrawal of a CYP3A4 inducer may affect the rate of biotransformation of tacrolimus and cause supratherapeutic levels of tacrolimus in the blood and should therefore be carried out under close supervision and control of a transplant specialist.
P-glycoprotein: Tacrolimus should be used with caution with medicinal products that inhibit P-glycoprotein due to the potential for increased tacrolimus levels. Close monitoring of tacrolimus whole blood concentrations and the patient's clinical status is necessary. Tacrolimus dose adjustment may be required (see section 4.5).
Herbal medicinal products: Herbal medicinal products containing St. John's wort (Hypericum perforatum) or other herbal medicinal products should be avoided when using tacrolimus due to the risk of interactions leading to a decrease in tacrolimus blood concentrations and a decrease in the therapeutic effect of tacrolimus or an increase in tacrolimus blood concentrations and a risk of tacrolimus toxicity (see section 4.5).
Other interactions: Concomitant use of ciclosporin and tacrolimus should be avoided and tacrolimus should be used with caution in patients who have previously used ciclosporin (see sections “Interaction with other medicinal products and other forms of interaction” and “Method of administration and dosage”).
It is also necessary to avoid taking large amounts of potassium or potassium-sparing diuretics (see section “Interaction with other medicinal products and other types of interactions”).
Some combinations of tacrolimus with drugs that have nephrotoxic or neurotoxic effects may increase the risk of such effects (see section “Interaction with other medicinal products and other types of interactions”).
Vaccination
Immunosuppressants may affect the response to vaccination, vaccination may be less effective during treatment with tacrolimus. Live attenuated vaccines should be avoided.
Nephrotoxicity
Tacrolimus may cause renal impairment in transplant patients. If appropriate measures are not taken, acute renal failure may progress to chronic renal failure. Patients with renal impairment should be closely monitored as a reduction in the tacrolimus dose may be required. The risk of nephrotoxicity may be increased when tacrolimus is used concomitantly with medicinal products associated with nephrotoxicity (see section 4.5). Concomitant use of tacrolimus with medicinal products known to be nephrotoxic should be avoided. If such use cannot be avoided, tacrolimus blood trough levels and renal function should be closely monitored and a dose reduction considered in the event of nephrotoxicity.
Gastrointestinal perforations have been reported in patients receiving tacrolimus. Gastrointestinal perforation is a medically important complication that can lead to serious or life-threatening conditions; appropriate treatment should be initiated immediately if suspicious symptoms or signs occur. As tacrolimus blood levels may fluctuate significantly during episodes of diarrhoea, additional monitoring of tacrolimus concentrations is recommended during episodes of diarrhoea.
Heart disorders
In patients receiving immediate-release tacrolimus, rare cases of ventricular hypertrophy or septal hypertrophy have been reported as cardiomyopathies; such cases may also occur with prolonged-release tacrolimus. Most cases were reversible and occurred mainly at tacrolimus blood concentrations well above the recommended maximum. Other factors that increase the risk of this adverse event include: pre-existing cardiac disease, use of corticosteroids, hypertension, renal and hepatic dysfunction, infections, hypervolemia, edema. Patients at high risk and receiving intensive immunosuppressive therapy should be monitored with echocardiography and ECG before and after transplantation (after 3 months and then after 9-12 months). If abnormalities develop, consideration should be given to reducing the dose of Tacrolimus or switching to another immunosuppressive agent. Tacrolimus may prolong the QT interval and cause torsades de pointes. Caution should be exercised when administering the medicinal product to patients with risk factors for QT prolongation, including patients with a personal or family history of QT prolongation, patients with congestive heart failure, bradyarrhythmia, electrolyte abnormalities. Caution should also be exercised when administering the medicinal product to patients with known or suspected congenital long QT syndrome or acquired long QT prolongation and patients taking concomitant medicinal products known to prolong the QT interval, cause electrolyte abnormalities or increase tacrolimus exposure (see section 4.5).
Lymphoproliferative diseases and malignant neoplasms
Epstein-Barr virus (EBV)-associated lymphoproliferative disorders have been reported in patients treated with tacrolimus (see section 4.8). Concomitant use of immunosuppressants with antilymphocyte antibodies (such as basiliximab, daclizumab) increases the risk of Epstein-Barr virus-associated lymphoproliferative disorders. Patients who are negative for the Epstein-Barr virus capsid antigen (EBV-VCA) have been reported to be at increased risk of developing lymphoproliferative disorders. Therefore, serological testing for EBV-VCA should be performed in this group of patients before initiating tacrolimus treatment. Close monitoring of EBV by polymerase chain reaction (PCR) is recommended during treatment. A positive EBV-PCR may persist for months and is not in itself evidence of lymphoproliferative disease or lymphoma.
As with other potent immunosuppressive agents, the risk of secondary cancer is unknown (see section 4.8).
As with other immunosuppressive drugs, 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 tacrolimus, are at increased risk of developing infections, including opportunistic infections (bacterial, fungal, viral, protozoal), such as CMV infection, VC-associated nephropathy, and JC-associated progressive multifocal leukoencephalopathy (PML). Patients are also at increased risk of viral hepatitis (e.g., new infection or reactivation of hepatitis B and C, and hepatitis E, which may become chronic). These infections are often associated with a high overall immunosuppressive burden and can lead to serious consequences, including transplant rejection, or fatal outcome, which should be considered by physicians when making a differential diagnosis in immunocompromised patients with worsening liver or kidney function or neurological symptoms. Prophylaxis and treatment should be in accordance with appropriate clinical guidelines.
Posterior reversible encephalopathy syndrome (PRES)
Posterior reversible encephalopathy syndrome has been reported in a patient
