Taxine long
Ukraine
Table of Contents
INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT Tacni Long (Tacni Long)
Composition:
Active substance: tacrolimus (as tacrolimus monohydrate);
Each prolonged-release hard capsule contains 0.5 mg, 1 mg, 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.
* Included only in the composition of the 5 mg strength capsule.
Pharmaceutical form. Prolonged-release hard capsules.
Main physicochemical characteristics:
0.5 mg capsules: hard gelatin capsules, size 5, filled with white to almost 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 almost 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 almost 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 almost white powder; body: light orange with radial inscription "5mg" in black; cap: grey-red with radial inscription "TR" in black.
Pharmacotherapeutic group. Immunosuppressants. Calcineurin inhibitors. 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 (FKBP12). The FKBP12-tacrolimus complex specifically and competitively binds to calcineurin and inhibits it, resulting in calcium-dependent suppression of T-cell signal transduction pathways, thereby preventing transcription of a discrete set of cytokine genes.
Tacrolimus is a highly potent immunosuppressant, as demonstrated in both in vitro and in vivo experiments.
In particular, tacrolimus suppresses the formation of cytotoxic lymphocytes, which play a key role in transplant rejection. 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 expression of the interleukin-2 receptor.
Pharmacokinetics.
Absorption
It has been established that tacrolimus is absorbed in the human gastrointestinal tract. Tacrolimus is generally rapidly absorbed. The medicinal product Takni Long—a prolonged-release formulation of tacrolimus—has an extended absorption profile after oral administration, with a median time to reach maximum blood concentration (Cmax) of approximately 2 hours (tmax).
Tacrolimus absorption is variable. The mean bioavailability of tacrolimus after oral administration (immediate-release capsules) is 20–25% (individual range in adult patients: 6–43%). The bioavailability of tacrolimus after oral administration in the form of prolonged-release capsules is reduced when taken with food. Administration of prolonged-release capsules with food resulted in decreased rate and extent of tacrolimus absorption.
Bile secretion does not affect tacrolimus absorption; therefore, treatment with Takni Long can be initiated orally.
After achieving steady-state concentrations of tacrolimus with prolonged-release capsules, a high correlation between AUC and trough blood levels of tacrolimus is observed. Therefore, monitoring of the minimum concentration of tacrolimus in whole blood allows assessment of systemic drug exposure.
Distribution
The distribution of tacrolimus in the human body after intravenous administration follows a biphasic pattern.
In systemic circulation, tacrolimus is extensively bound to erythrocytes, with a whole blood/plasma concentration ratio of approximately 20:1. In plasma, tacrolimus is highly bound (>98.8%) to plasma proteins, primarily serum albumin and α-1-acid glycoprotein.
Tacrolimus is widely distributed throughout the body. The steady-state volume of distribution based on plasma concentrations is approximately 1300 L (in healthy volunteers). The corresponding value based on whole blood averages 47.6 L.
Metabolism
Tacrolimus is extensively metabolized in the liver, primarily by cytochrome P450 3A4. Tacrolimus is also significantly metabolized 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 of the inactive metabolites is present in systemic circulation at low concentrations. Thus, metabolites do not contribute to the pharmacological activity of tacrolimus.
Excretion
Tacrolimus is a substance with low clearance. In healthy volunteers, the mean value of total clearance, determined based on drug concentration in whole blood, was 2.25 L/h. In adult patients with liver, kidney, and heart transplants, the values of this parameter 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 increase the unbound fraction of tacrolimus) or by concomitant use of corticosteroids, which enhance metabolic activity.
The elimination half-life of tacrolimus is prolonged and variable. In healthy volunteers, the mean elimination half-life in whole blood was approximately 43 hours.
After intravenous and oral administration of 14C-labeled tacrolimus, the majority of radioactivity was recovered in feces. Approximately 2% was excreted in urine. Less than 1% of unchanged tacrolimus was found in urine and feces, indicating that tacrolimus is almost completely metabolized prior to elimination, with biliary excretion being the primary route of elimination.
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 of the medicinal product.
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 gastrointestinal metabolism mediated by CYP3A4 in the intestinal wall. Concomitant administration of medicinal products, including herbal agents, that inhibit or induce CYP3A4 may affect tacrolimus metabolism and thereby decrease or increase its blood levels. Similarly, discontinuation of such medicinal products, including herbal agents, may influence the rate of tacrolimus metabolism and consequently its blood concentration.
Pharmacokinetic studies have demonstrated that increased blood levels of tacrolimus 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.
When administered concomitantly with substances that may alter CYP3A4 metabolism, careful monitoring of tacrolimus blood levels under the supervision of a transplant specialist is strongly recommended, along with monitoring of graft function, QT interval prolongation (via ECG), renal function, and other adverse reactions (including neurotoxicity). If necessary, tacrolimus administration should be suspended or the dose adjusted to maintain appropriate tacrolimus exposure (see sections "Special warnings and precautions for use" and "Dosage and administration"). Careful monitoring of patients is also required when tacrolimus is used concomitantly with multiple medicinal products affecting CYP3A4, due to the potential for additive or neutralizing effects on tacrolimus exposure.
The table describes medicinal products that affect tacrolimus. The examples of drug interactions listed are not exhaustive or comprehensive; therefore, when using tacrolimus in combination with any medicinal product, information regarding metabolic pathways, potential interactions, risks, and warnings related to concomitant use, as provided in the product information of that medicinal product, should be consulted.
Medicinal products affecting tacrolimus
| Medicinal product / class or name of substance |
Manifestation of drug interaction |
Recommendations for concomitant use |
| Grapefruit or grapefruit juice |
Possible increase in trough whole blood concentration of tacrolimus and increased risk of severe adverse reactions (e.g., neurotoxicity, QT interval prolongation) (see section "Special precautions"). |
Avoid consumption of grapefruit or grapefruit juice. |
| Cyclosporine |
Possible increase in trough whole blood concentration of tacrolimus. In addition, a synergistic/additive nephrotoxic effect may occur. |
Avoid concomitant use of cyclosporine and tacrolimus (see section "Special precautions"). |
| Medicinal products with nephrotoxic or neurotoxic effects: aminoglycosides, mTOR inhibitors, vancomycin, sulfamethoxazole + trimethoprim, NSAIDs, ganciclovir, acyclovir, amphotericin B, ibuprofen, cidofovir, foscarnet |
Possible enhancement of nephrotoxic or neurotoxic effects of tacrolimus. |
Avoid concomitant use of tacrolimus with medicinal products having nephrotoxic effects. If concomitant use cannot be avoided, monitoring of renal function and other adverse reactions should be ensured, and the dose of tacrolimus adjusted as needed. |
| Strong 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, used alone or in combination with dasabuvir), nefazodone, pharmacokinetic booster cobicistat, kinase inhibitors idelalisib, ceritinib. Strong interaction has also been observed with the macrolide antibiotic erythromycin |
Possible increase in trough whole blood concentration of tacrolimus and increased risk of severe adverse reactions (e.g., nephrotoxicity, neurotoxicity, QT interval prolongation), requiring careful monitoring (see section "Special precautions"). A sudden and sharp increase in tacrolimus levels may occur within 1–3 days after concomitant use, despite immediate reduction of tacrolimus dose. Total tacrolimus concentration may increase by more than 5-fold. When used in combination with ritonavir, over 50-fold increase in tacrolimus concentration may occur. Most patients may require dose reduction or temporary discontinuation of tacrolimus therapy. The effect on tacrolimus blood concentration may persist for several days after discontinuation of concomitant therapy. |
Concomitant use is not recommended. If concomitant use with a strong CYP3A4 inhibitor cannot be avoided, consider omitting the tacrolimus dose on the day of initiation of the strong CYP3A4 inhibitor. Tacrolimus therapy should be resumed the next day with a reduced dose based on blood concentration. The dose and/or dosing frequency of tacrolimus should be individually adjusted with appropriate modifications based on trough tacrolimus concentration, which should be determined at the start of CYP3A4 inhibitor therapy, monitored regularly during therapy (starting from the first days), and evaluated at the end and some time after completion of CYP3A4 inhibitor therapy. After discontinuation of concomitant therapy, the dose and dosing frequency of tacrolimus should be determined based on blood concentration. Careful monitoring of renal function, ECG parameters (to detect QT interval prolongation), and other adverse reactions should be ensured. |
| 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, hepatitis C treatments elbasvir/grazoprevir and glecaprevir/pibrentasvir, antiviral agent for CMV infection letermovir, tyrosine kinase inhibitors nilotinib, crizotinib, and imatinib, as well as (Chinese) herbal medicinal products containing Schisandra sphenanthera extract |
Possible increase in trough whole blood concentration of tacrolimus and increased risk of serious adverse reactions (e.g., neurotoxicity, QT interval prolongation) (see section "Special precautions"). A sudden increase in tacrolimus levels may occur. |
Frequent monitoring of trough whole blood concentration of tacrolimus should be ensured, starting from the first days of concomitant use. The dose of tacrolimus may need to be reduced as needed (see section "Dosage and administration"). Careful monitoring of renal function, ECG parameters (to detect QT interval prolongation), and other adverse reactions should be ensured. |
| In vitro studies have shown that these substances are potential inhibitors of tacrolimus metabolism: bromocriptine, cortisone, dapsone, ergotamine, gestodene, lidocaine, mephenytoin, midazolam, nilvadipine, norethisterone, quinidine, tamoxifen |
Possible increase in trough whole blood concentration of tacrolimus and increased risk of serious adverse reactions (e.g., neurotoxicity, QT interval prolongation) (see section "Special precautions"). |
Monitoring of trough whole blood concentration of tacrolimus should be ensured and the dose of tacrolimus reduced as needed (see section "Dosage and administration"). Careful monitoring of renal function, ECG parameters (to detect QT interval prolongation), and other adverse reactions should be ensured. |
| Strong CYP3A4 inducers: rifampicin, phenytoin, carbamazepine, apalutamide, enzalutamide, mitotane, or St John's wort (Hypericum perforatum)-based medicinal products |
Possible decrease in trough whole blood concentration of tacrolimus and increased risk of rejection (see section "Special precautions"). Maximum effect on tacrolimus blood concentration may occur within 1–2 weeks after concomitant use. The effect may persist for 1–2 weeks after discontinuation of therapy. |
Concomitant use is not recommended. If unavoidable, an increase in tacrolimus dose may be required. The dose of tacrolimus should be individually adjusted with appropriate modifications based on trough tacrolimus concentration, which should be determined at the start of CYP3A4 inducer therapy, monitored regularly during therapy (starting from the first days), and evaluated at the end and some time after completion of CYP3A4 inducer therapy. After discontinuation of the CYP3A4 inducer, gradual dose adjustment of tacrolimus may be needed. Careful monitoring of graft function should be ensured. |
| Moderate CYP3A4 inducers: metamizole, phenobarbital, isoniazid, rifabutin, efavirenz, etravirine, nevirapine. |
Possible decrease in trough whole blood concentration of tacrolimus and increased risk of rejection (see section "Special precautions"). |
Trough whole blood concentration of tacrolimus should be monitored and the dose of tacrolimus increased as needed (see section "Dosage and administration"). Careful monitoring of graft function should be ensured. |
| Caspofungin |
Possible decrease in trough whole blood concentration of tacrolimus and increased risk of rejection. The mechanism of interaction is not established. |
Trough whole blood concentration of tacrolimus should be monitored and the dose of tacrolimus increased as needed (see section "Dosage and administration"). Careful monitoring of graft function should be ensured. |
| Cannabidiol (P-glycoprotein inhibitor) |
Increased blood levels of tacrolimus have been reported when used concomitantly with cannabidiol. This may be due to inhibition of intestinal P-glycoprotein, leading to increased bioavailability of tacrolimus. |
Concomitant use of tacrolimus and cannabidiol requires caution with careful monitoring of adverse reactions. Trough whole blood concentration of tacrolimus should be monitored and the dose of tacrolimus adjusted as needed (see sections "Special precautions" and "Dosage and administration"). |
| Medicinal products highly bound to plasma proteins, such as NSAIDs, oral anticoagulants, oral antidiabetic agents |
Tacrolimus is highly bound to plasma proteins. Potential interactions with other active substances known to have high affinity for plasma proteins should be considered. |
Trough whole blood concentration of tacrolimus should be monitored and the dose of tacrolimus adjusted as needed (see section "Dosage and administration"). |
| Prokinetic medicinal products: metoclopramide, cimetidine, magnesium and aluminium hydroxide |
Possible increase in trough whole blood concentration of tacrolimus and increased risk of serious adverse reactions (e.g., neurotoxicity, QT interval prolongation). |
Trough whole blood concentration of tacrolimus should be monitored and the dose of tacrolimus reduced as needed (see section "Dosage and administration"). Careful monitoring of renal function, ECG parameters (to detect QT interval prolongation), and other adverse reactions should be ensured. |
| Maintenance doses of corticosteroids |
Possible decrease in trough whole blood concentration of tacrolimus and increased risk of rejection (see section "Special precautions"). |
Trough whole blood concentration of tacrolimus should be monitored and the dose of tacrolimus increased as needed (see section "Dosage and administration"). Careful monitoring of graft function should be ensured. |
| High doses of prednisolone or methylprednisolone |
When used for treatment of acute rejection, may affect tacrolimus blood levels (increase or decrease). |
Trough whole blood concentration of tacrolimus should be monitored and the dose of tacrolimus adjusted as needed. |
| Direct-acting antivirals (DAA) |
Impact on tacrolimus pharmacokinetics may occur due to changes in liver function during DAA therapy associated with hepatitis virus clearance. Possible decrease in tacrolimus blood levels. However, when using certain DAAs capable of inhibiting CYP3A4 activity, this effect may be neutralized or an increase in tacrolimus blood levels may occur. |
Trough whole blood concentration of tacrolimus should be monitored and the dose of tacrolimus adjusted as needed to ensure stable 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).
Since tacrolimus treatment may be associated with hyperkalemia or may exacerbate pre-existing hyperkalemia, high potassium intake or use of potassium-sparing diuretics (e.g., amiloride, triamterene, or spironolactone) should be avoided (see section "Special precautions"). Tacrolimus should be used with caution in combination with other medicinal products that increase serum potassium levels, particularly trimethoprim and co-trimoxazole (trimethoprim/sulfamethoxazole), as trimethoprim is known to act similarly to the potassium-sparing diuretic 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 agents. The elimination half-life of cyclosporine is prolonged when administered concomitantly with tacrolimus. In addition, a synergistic/additive nephrotoxic effect is possible. For these reasons, combination therapy with cyclosporine and tacrolimus is not recommended, and physicians should exercise caution when prescribing tacrolimus to patients previously treated with cyclosporine (see sections "Special precautions" and "Dosage and administration").
It has been established that tacrolimus increases phenytoin blood levels.
Since tacrolimus may decrease the clearance of hormonal contraceptives, leading to increased hormone exposure, particular caution should be exercised when considering 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 from combination therapy with cyclosporine—which interferes with enterohepatic recirculation of mycophenolic acid—to tacrolimus, which lacks this effect, as this may lead to altered exposure to mycophenolic acid. Medicinal products that interfere with the enterohepatic cycling of mycophenolic acid may reduce its plasma levels and efficacy. Therapeutic monitoring 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.
Medication errors have been reported with the use of the medicinal product, including accidental, unintentional, or uncontrolled substitution between immediate-release and prolonged-release formulations of tacrolimus. This has led to serious adverse reactions, including transplant rejection, or other adverse reactions that may result from subtherapeutic or supratherapeutic exposure to tacrolimus. Patients should be treated with one specific formulation of tacrolimus according to the appropriate daily dosing regimen; changes in formulation or dosing regimen should only be made under strict supervision by a transplant specialist (see sections "Method of administration and dosage" and "Adverse reactions").
The medicinal product Tacni Long is not recommended for use in children under 18 years of age due to limited safety and/or efficacy data.
In adult patients, there are no clinical data on the use of prolonged-release tacrolimus for the treatment of allograft rejection refractory to therapy with other immunosuppressants.
There are currently no clinical data on the use of prolonged-release tacrolimus for the prevention of transplant rejection following heart transplantation in adult patients.
During the early post-transplantation period, regular monitoring of the following parameters is required: blood pressure, ECG, neurological status and visual function, fasting blood glucose, electrolyte levels (especially potassium), liver and kidney function tests, hematological parameters, coagulation profile, and plasma protein levels. If clinically significant changes occur, immunosuppressive therapy should be adjusted accordingly.
Medicinal products that may interact with the drug
Due to the likelihood of drug interactions that may lead to serious adverse reactions, including rejection or toxicity, CYP3A4 inhibitors or inducers should only be used concomitantly with tacrolimus after consultation with a transplant specialist (see section "Interaction with other medicinal products and other forms of interaction").
Inhibitors of CYP3A4. 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 such concomitant use cannot be avoided, frequent monitoring of blood tacrolimus levels should be performed, starting from the first day of concomitant therapy under the supervision of a transplant specialist, to adjust the tacrolimus dose as needed to maintain consistent drug effect. Close monitoring of renal function, ECG parameters (including QT interval), and the patient's clinical status is also required. Dose adjustments should take into account the individual circumstances of each patient. An immediate dose reduction may be necessary at the start of treatment (see section "Interaction with other medicinal products and other forms of interaction"). Similarly, discontinuation of a CYP3A4 inhibitor may affect the biotransformation rate of tacrolimus and lead to subtherapeutic blood levels of tacrolimus; therefore, it should be performed under close supervision and monitoring by a transplant specialist.
Inducers of CYP3A4. Concomitant use with CYP3A4 inducers may decrease blood levels of tacrolimus, potentially increasing the risk of transplant rejection. It is recommended to avoid combination with potent CYP3A4 inducers (such as rifampicin, phenytoin, carbamazepine). If such combination cannot be avoided, frequent monitoring of blood tacrolimus levels should be conducted under the supervision of a transplant specialist, starting from the initial days of concomitant therapy, to adjust the dose as needed to maintain consistent drug effect. Transplant function should also be closely monitored (see section "Interaction with other medicinal products and other forms of interaction"). Similarly, discontinuation of a CYP3A4 inducer may affect the biotransformation rate of tacrolimus and lead to supratherapeutic blood levels of tacrolimus; therefore, it should be performed under close supervision and monitoring by a transplant specialist.
P-glycoprotein. Tacrolimus should be used with caution in combination with medicinal products that inhibit P-glycoprotein, due to the potential for increased tacrolimus levels. Close monitoring of tacrolimus concentration in whole blood and the patient's clinical status is required. Dose adjustment of tacrolimus may be necessary (see section "Interaction with other medicinal products and other forms of interaction").
Herbal medicinal products. When using tacrolimus, herbal preparations containing St. John's wort (Hypericum perforatum) or other herbal products should be avoided due to the risk of interactions leading to decreased blood concentration of tacrolimus and reduced therapeutic effect, or increased blood concentration of tacrolimus and risk of toxic effects (see section "Interaction with other medicinal products and other forms of interaction").
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 "Interaction with other medicinal products and other forms of interaction" and "Method of administration and dosage").
The intake of large amounts of potassium or potassium-sparing diuretics should also be avoided (see section "Interaction with other medicinal products and other forms of interaction").
Some combinations of tacrolimus with agents having nephrotoxic or neurotoxic effects may increase the risk of such 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
Tacrolimus may cause renal function impairment in post-transplant patients. Without appropriate intervention, acute renal failure may progress to chronic renal failure. Close monitoring of patients with impaired renal function is required, as dose reduction of tacrolimus may be necessary. The risk of nephrotoxicity may be increased when tacrolimus is used concomitantly with medicinal products associated with nephrotoxicity (see section "Interaction with other medicinal products and other forms of interaction"). Concomitant use of tacrolimus with nephrotoxic agents should be avoided. If such concomitant use cannot be avoided, close monitoring of minimum blood levels of tacrolimus and renal function is required, 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 severe or life-threatening conditions; appropriate treatment should be initiated immediately upon suspicion of such events. Since blood levels of tacrolimus may fluctuate significantly during episodes of diarrhea, additional monitoring of tacrolimus concentration is recommended during such episodes.
Cardiac disorders
Rare cases of ventricular hypertrophy or septal hypertrophy, reported as cardiomyopathy, have been observed in patients treated with immediate-release tacrolimus formulations; such cases may also occur with prolonged-release tacrolimus. Most cases were reversible and occurred primarily when blood concentrations of tacrolimus were significantly higher than the recommended maximum. 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 and 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 develop, consideration should be given to reducing the dose of Tacni Long or switching to another immunosuppressive agent. Tacrolimus may prolong the QT interval and cause torsades de pointes. Caution should be exercised when administering the drug to patients with risk factors for QT prolongation, including those with personal or family history of QT prolongation, patients with congestive heart failure, bradyarrhythmias, or electrolyte imbalances. Caution is also advised in patients with diagnosed or suspected congenital long QT syndrome or acquired QT prolongation, and in patients concurrently taking medicinal products that prolong the QT interval, cause electrolyte imbalances, or increase tacrolimus exposure (see section "Interaction with other medicinal products and other forms of interaction").
Lymphoproliferative disorders and malignancies
Lymphoproliferative disorders associated with Epstein-Barr virus (EBV), as well as other malignancies, including skin cancer and Kaposi's sarcoma, have been reported in patients treated with tacrolimus (see section "Adverse reactions"). The concomitant use of immunosuppressants with antilymphocyte antibodies (such as basiliximab, daclizumab) increases the risk of EBV-associated lymphoproliferative disorders. An increased risk of lymphoproliferative disorders has been reported in patients who are negative for Epstein-Barr virus capsid antigen (EBV-VCA). Therefore, serological testing for EBV-VCA should be performed in this patient group before initiating tacrolimus therapy. During treatment, close monitoring for EBV using polymerase chain reaction (PCR) is recommended. Positive EBV-PCR may persist for months and by itself does not indicate lymphoproliferative disease or lymphoma.
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.
As with other potent immunosuppressive agents, the risk of secondary malignancies is unknown.
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 high-protection sunscreen should be used.
Infections, including opportunistic infections
Patients receiving immunosuppressants, including tacrolimus, have an increased risk of infections, including opportunistic infections (bacterial, fungal, viral, protozoal), such as CMV infection, BK virus-associated nephropathy, and progressive multifocal leukoencephalopathy (PML) associated with JC virus. Patients also have an increased risk of viral hepatitis (e.g., new infection or reactivation of hepatitis B and C, as well as hepatitis E, which may become chronic). These infections are often associated with high overall immunosuppressive burden and may lead to serious outcomes, including transplant rejection or death, which 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 be carried out according to appropriate clinical guidelines.
Posterior reversible encephalopathy syndrome (PRES)
Posterior reversible encephalopathy syndrome (PRES) has been reported in patients treated with tacrolimus. If patients receiving tacrolimus develop symptoms of PRES, such as headache, mental status changes, seizures, or visual disturbances, appropriate diagnostic procedures (e.g., MRI) should be performed. Upon diagnosis of PRES, systemic administration of tacrolimus should be discontinued immediately, and appropriate management of blood pressure and seizures should be ensured. In most patients, complete recovery occurs after appropriate interventions.
Ocular disorders
Ocular disorders, sometimes progressing to vision loss, have been reported 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 evaluation and referral to an ophthalmologist should be arranged if necessary.
Thrombotic microangiopathy (TMA) (including hemolytic-uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP))
TMA, including TTP and HUS, which may sometimes lead to renal failure or death, should be considered in patients presenting with hemolytic anemia, thrombocytopenia, fatigue, fluctuating neurological symptoms, renal dysfunction, and fever. If TMA is diagnosed, immediate treatment is required, and discontinuation of tacrolimus should be considered at the physician's discretion. Concomitant use of tacrolimus with mammalian target of rapamycin (mTOR) inhibitors (e.g., sirolimus, everolimus) may increase the risk of TMA (including HUS and TTP).
Pure red cell aplasia (PRCA)
Cases of pure red cell aplasia (PRCA) have been reported in patients treated with tacrolimus. All patients had risk factors for PRCA, such as parvovirus B19 infection, underlying disease, or concomitant use of medications associated with PRCA.
Special populations
Experience with the use of the drug in patients not of Caucasian ethnicity and in patients with high immunological risk (e.g., retransplantation, presence of panel-reactive antibodies [PRA]) is limited.
Patients with severe hepatic impairment may require dose reduction of the medicinal product (see section "Method of administration and dosage").
Excipients
Lactose. This medicinal product is contraindicated in patients with rare hereditary conditions of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption.
Ponceau 4R. This substance may cause allergic reactions.
Use during pregnancy or breastfeeding.
Pregnancy. Data on the use of the medicinal product in humans show that tacrolimus crosses the placenta in women. Limited data from organ transplant recipients do not indicate an increased risk of adverse effects on pregnancy course or outcome with tacrolimus compared to other immunosuppressive agents. However, cases of spontaneous abortion have been reported. Currently, other relevant epidemiological data are lacking. Treatment with tacrolimus during pregnancy should only be considered if no safer alternative exists and if the potential benefit justifies the potential risk to the fetus. To detect potential adverse reactions of tacrolimus, monitoring of newborns whose mothers received tacrolimus during pregnancy is recommended (especially renal function). There is a risk of preterm delivery (<37 weeks) (frequency 66/123 births, i.e., 53.7%), although data show that 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%), which, however, resolves spontaneously. In rat and rabbit studies, tacrolimus caused embryofetal toxicity at doses associated with maternal toxicity.
Breastfeeding period. Data indicate that tacrolimus passes into human breast milk. Since adverse effects of tacrolimus on the newborn cannot be excluded, women taking the medicinal product Tacni Long should discontinue breastfeeding.
Fertility. In rats, tacrolimus showed a negative effect on male fertility, manifested by reduced sperm count and motility.
Ability to affect reaction speed when driving or operating machinery.
Tacrolimus may cause visual and neurological disturbances, especially when combined with alcohol. There are no studies on the effect of tacrolimus on the ability to drive or operate machinery.
Administration and Dosage
Takni Long is an oral formulation of tacrolimus administered once daily. Therapy with Takni Long requires careful monitoring by qualified personnel with access to appropriate equipment. Only physicians experienced in immunosuppressive therapy in organ transplant recipients may prescribe Takni Long and make adjustments to the ongoing immunosuppressive regimen. Different oral formulations of tacrolimus should not be substituted without clinical supervision.
Accidental, unintentional, or unmonitored substitution of different oral formulations of tacrolimus with varying release profiles is dangerous. This may lead to transplant rejection or increased incidence of adverse reactions, including insufficient or excessive immunosuppression, due to clinically significant differences in systemic exposure to tacrolimus. Patients should adhere strictly to one specific formulation of tacrolimus with an appropriate 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" and "Adverse Reactions"). After switching to any alternative formulation, blood concentrations of tacrolimus must be monitored and dosage adjusted to maintain adequate systemic exposure to tacrolimus.
Administration
The recommended initial doses provided below are approximate. During the early postoperative period, Takni Long is typically administered concomitantly with other immunosuppressive agents. The dose may be adjusted depending on the chosen immunosuppressive regimen. The dosage of Takni Long 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 patients, the AUC0–24 of tacrolimus for prolonged-release capsules was 30% and 50% lower on Day 1, respectively, compared to the same dose of immediate-release tacrolimus capsules. By Day 4, systemic exposure to tacrolimus (measured as trough levels) was equivalent between the two formulations in both kidney and liver transplant recipients. To ensure adequate tacrolimus exposure during the first 2 weeks after transplantation when using Takni Long, regular and careful monitoring of trough blood concentrations 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 Takni Long.
To prevent transplant rejection, immunosuppression must be maintained continuously; therefore, the duration of therapy is indefinite.
Prevention of Kidney Transplant Rejection
Oral therapy with Takni Long should be initiated at a daily dose of 0.2–0.3 mg/kg/day administered as a single morning dose. Initiate drug administration within 24 hours after transplantation.
The dose of Takni Long is generally reduced during the post-transplant period. In some cases, concomitant immunosuppressive therapy may be discontinued, resulting in monotherapy with Takni Long. Post-transplant changes in the patient's condition may alter the pharmacokinetics of tacrolimus and require further dose adjustments of Takni Long.
Prevention of Liver Transplant Rejection
Oral therapy with Takni Long should be initiated at a daily dose of 0.1–0.2 mg/kg once daily in the morning. Initiate drug administration 12–18 hours after transplantation.
The dose of Takni Long is generally reduced during the post-transplant period. In some cases, concomitant immunosuppressive therapy may be discontinued, resulting in monotherapy with Takni Long. Post-transplant changes in the patient's condition may alter the pharmacokinetics of tacrolimus and require further dose adjustments of Takni Long.
Conversion from Immediate-Release Tacrolimus to Takni Long
For patients after allograft transplantation who have been receiving immediate-release tacrolimus capsules twice daily at a maintenance dose and require conversion to once-daily Takni Long, the daily dose ratio during transition should be 1:1 (mg:mg). Takni Long should be administered in the morning.
In stable patients converted from immediate-release tacrolimus (twice daily) to prolonged-release tacrolimus capsules (once daily) at a 1:1 (mg:mg) total daily dose, systemic exposure to tacrolimus (AUC0–24) with the prolonged-release formulation was approximately 10% lower than with immediate-release tacrolimus. The relationship between trough concentration (C24) and systemic exposure (AUC0–24) for prolonged-release capsules is similar to that of immediate-release tacrolimus capsules. When switching from immediate-release tacrolimus to Takni Long capsules, trough drug concentrations should be measured before and during the first two weeks after conversion. After conversion, trough levels of tacrolimus should be monitored and the dose adjusted as necessary to maintain equivalent systemic exposure. 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 baseline cyclosporine therapy to baseline tacrolimus therapy (see sections "Interaction with Other Medicinal Products and Other Forms of Interaction" and "Special Warnings and Precautions for Use"). Concomitant administration of cyclosporine and tacrolimus is not recommended. Therapy with Takni Long should be initiated after determining blood cyclosporine concentration and evaluating the patient's clinical status. Conversion should be delayed if blood cyclosporine levels are elevated. In practice, tacrolimus therapy is typically 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 Takni Long may be necessary.
Treatment of Kidney or Liver Allograft Rejection
When switching from other immunosuppressants to Takni Long, therapy should be initiated with the recommended initial oral doses for prevention of kidney or liver transplant rejection, respectively.
Treatment of Heart Allograft Rejection
For adult patients converted to Takni Long, the initial oral dose is 0.15 mg/kg/day administered in the morning.
Treatment of Allograft Rejection after Other Organ Transplantations
There is no clinical experience with the use of prolonged-release tacrolimus capsules for the treatment of patients after lung, pancreas, or intestinal transplantation. Immediate-release tacrolimus capsules have been used in 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 tolerance, as well as monitoring data of therapeutic trough levels of tacrolimus in blood.
Several methods are used to determine tacrolimus concentration in whole blood for dose optimization. When comparing monitoring results published in the literature with those from a specific clinic, the method used to determine blood tacrolimus concentration must be taken into account. In current clinical practice, blood tacrolimus levels 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 (prolonged-release and immediate-release capsules).
Trough blood levels of tacrolimus should be monitored during the post-transplant period. The trough level should be measured approximately 24 hours after the last dose, just before the next dose of Takni Long. 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 tacrolimus to Takni Long, after dose adjustments, changes in immunosuppressive regimen, or concomitant use of drugs that may affect tacrolimus blood concentration (see section "Interaction with Other Medicinal Products and Other Forms of Interaction"). Monitoring frequency should be determined based on clinical need. Since tacrolimus is a low-clearance drug, several days may be required to achieve steady-state blood concentrations after dose adjustment of Takni Long.
According to clinical trial data, successful treatment is generally achieved with therapeutic trough blood levels of tacrolimus not exceeding 20 ng/mL. When interpreting data on therapeutic trough concentrations of tacrolimus in blood, the patient's clinical condition must be considered. 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 in liver, kidney, or heart transplant recipients typically range between 5–15 ng/mL.
Special Populations
Hepatic Impairment. Patients with severe hepatic dysfunction may require dose reduction to maintain blood trough 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 is recommended (including serum creatinine levels, creatinine clearance calculation, and urine output monitoring).
Race. Patients of non-Caucasian race may require higher tacrolimus doses than Caucasian patients to achieve similar trough concentrations.
Gender. There is no evidence that different doses are required for male and female patients to achieve similar trough concentrations.
Elderly Patients. There is no evidence that elderly patients require specific dosage adjustments.
Method of Administration
The recommended daily oral dose of Takni Long should be taken once daily in the morning. Prolonged-release capsules of Takni Long should be taken immediately after removal from the blister pack. Patients should be warned about the presence of a desiccant in the packaging, which is not intended for ingestion. Capsules should be swallowed whole with liquid (preferably water). To achieve maximum absorption, Takni Long should be taken on an empty stomach or at least 1 hour before or 2–3 hours after food (see section "Pharmacokinetics"). A missed morning dose should be taken as soon as possible on the same day. A double dose should not be taken the next morning.
For patients unable to take oral medications immediately after organ transplantation, intravenous tacrolimus therapy may be initiated (see prescribing information for tacrolimus 5 mg/mL concentrate for solution for infusion) at a dose approximately 1/5 of the recommended oral dose for the respective indication.
Children
The safety and efficacy of Takni Long in children under 18 years of age have not been established. Limited data are available, but no dosage recommendations can be made based on them.
Overdose
Information on overdose is limited. Several cases of accidental tacrolimus overdose have been reported, with symptoms including tremor, headache, nausea, vomiting, infections, urticaria, lethargy, elevated blood urea nitrogen, elevated serum creatinine, and elevated alanine aminotransferase.
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 expected to be ineffective. In individual patients with very high plasma concentrations, hemofiltration or diafiltration may be effective in reducing toxic concentrations. 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, the precise adverse reaction profile of immunosuppressants is difficult to establish.
The most common adverse reactions (reported in >10% of patients) are tremor, renal dysfunction, 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 (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); frequency not known (cannot be estimated due to insufficient data). Within each frequency group, adverse reactions are listed in decreasing order of severity.
Infections and infestations. During therapy with tacrolimus, as with other potent immunosuppressants, patients are at increased risk of developing infections (viral, bacterial, fungal, protozoal). Pre-existing infections may worsen. Both localized and generalized infections may occur.
In patients receiving immunosuppressants, including tacrolimus in the form of prolonged-release capsules, cases of CMV infection, BK virus-associated nephropathy, and progressive multifocal leukoencephalopathy (PML) associated with JC virus have been reported.
Benign, malignant and unspecified neoplasms (including cysts and polyps). Patients receiving immunosuppressive therapy have an increased risk of developing malignant neoplasms. With the use of tacrolimus, both benign and malignant neoplasms have been reported, including Epstein–Barr virus (EBV)-associated lymphoproliferative disorders, skin malignancies, and Kaposi’s sarcoma.
Blood and lymphatic system disorders: common – anemia, thrombocytopenia, leukopenia, abnormalities in erythrocyte counts, 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 system 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, night terrors; 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 disturbances; 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 – exudative 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, respiratory tract disorders, asthma; rare – acute respiratory distress syndrome.
Gastrointestinal disorders: very common – diarrhea, nausea; common – gastrointestinal manifestations and symptoms, vomiting, abdominal and gastrointestinal pain, inflammatory gastrointestinal diseases, gastrointestinal hemorrhage, gastrointestinal ulcers and perforations, ascites, stomatitis and ulcers, constipation, dyspeptic manifestations and symptoms, 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 and biliary tract disorders: very common – hepatic function abnormalities; common – biliary tract disorders, hepatocellular injury and hepatitis, cholestasis and jaundice; rare – hepatic veno-occlusive disease, hepatic artery thrombosis; very rare – hepatic 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 dysfunction; 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, malaise, multi-organ failure, chest tightness, altered perception of ambient temperature; rare – falls, ulcers, chest pressure, thirst; very rare – increase in fat tissue mass.
Investigations: very common – liver function test abnormalities; common – increased blood alkaline phosphatase levels, weight gain; uncommon – increased blood amylase levels, ECG abnormalities, pulse and heart rate abnormalities, weight loss, increased blood lactate dehydrogenase levels; very rare – echocardiogram abnormalities, QT interval prolongation on electrocardiogram.
Injury, poisoning and procedural complications: common – primary graft dysfunction.
Medication errors have occurred, including accidental, unintentional, or uncontrolled substitution between immediate-release and prolonged-release formulations of tacrolimus. Cases of transplant rejection have been reported (frequency cannot be estimated from available data).
Description of selected adverse reactions
Limb pain has been described in several published case reports as part of calcineurin inhibitor-induced pain syndrome (CIPS). This pain is typically bilateral, symmetric, severe, ascending in the lower limbs, and may be associated with excessively high therapeutic levels of tacrolimus. This syndrome may respond to a reduction in tacrolimus dose. In some cases, switching to