Prograf, 1 mg capsules 50 pcs

Pharmacotherapeutic group

immunosuppressive agent – calcineurin inhibitor

Pharmacodynamics:

At the molecular level, the effects and intracellular cumulation of tacrolimus are due to binding to the cytosolic protein (FKBP 12). The FKBP 12-tacrolimus complex specifically and competitively inhibits calcineurin to provide calcium-dependent blockade of T-cell signaling pathways and prevent transcription of a discrete series of lymphokine genes.

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

Pharmacokinetics:

Absorption

In humans, tacrolimus has been found to be rapidly absorbed in the gastrointestinal tract. When taking Prograf® orally the average time to reach Cmax is 1-3 hours. In some patients tacrolimus is absorbed for a long period of time providing a relatively gentle absorption profile. Bioavailability of tacrolimus when ingested Prograf® capsules averages 20-25%. In most patients after liver transplantation on oral administration (030 mg/kg/day) equilibrium concentrations of tacrolimus were reached within 3 days.

The bioequivalence of Prograf® 05 mg capsules 10 mg and 50 mg when taken in equal doses was demonstrated in studies with healthy volunteers.

The highest rate and degree of absorption of tacrolimus is achieved when Prograf® capsules are taken on an empty stomach. The rate and degree of absorption of tacrolimus with food decreases especially in case of high fat content of food.

The effect of food rich in carbohydrates on absorption of tacrolimus is less pronounced. In stable patients after liver transplantation the bioavailability was decreased when Prograf® capsules were taken at the same time with a moderate-fat food (34% of calories). There was also decreased area under the pharmacokinetic curve AUC (27%) of maximum Cmax concentration (50%) and increased tmax (173%) in whole blood.

In a study involving stable patients after kidney transplantation, when Prograf® capsules were taken immediately after a standard breakfast, the effect of food on the bioavailability of tacrolimus was less pronounced. There was a decrease in AUC (by 2-12%) and Cmax (by 15-38%) and an increase in tmax(Ha 38-80%).

The excretion of bile has no effect on the absorption of tacrolimus.

A high correlation between AUC and minimal tacrolimus concentrations in whole blood is observed during therapy with Prograf® capsules when equilibrium state is reached. Therefore, monitoring of minimum tacrolimus concentrations in whole blood may serve as a method to provide an adequate assessment of systemic tacrolimus exposure.

Distribution and elimination

In the systemic blood stream, tacrolimus binds well to erythrocytes. The ratio of tacrolimus concentrations in whole blood to plasma is ~ 20:1. A significant proportion of tacrolimus in plasma (> 988%) is bound to plasma proteins (serum albumin α-1-acid glycoprotein).

Tacrolimus is widely distributed in the body. The steady-state volume of distribution taking into account plasma concentrations is about 1300 l (in healthy people). The same figure calculated from whole blood is on average 476 liters.

Tacrolimus is a substance with low clearance. In healthy people, the average total clearance calculated from whole blood concentrations is 225 l/hour. In adult patients after kidney and heart liver transplantation, clearance values were 41 L/hour 67 L/hour and 39 L/hour, respectively. In children with liver transplantation, total clearance is about 2 times higher than in adult patients with liver transplantation. Low hematocrit and hypoproteinemia contribute to an increase in the unbound fraction of tacrolimus, accelerating tacrolimus clearance. Corticosteroids used in transplantation may also increase metabolic rate and accelerate tacrolimus clearance.

The half-life of tacrolimus is long and variable. In healthy people, the average half-life in whole blood is approximately 43 hours. In adults and children with a liver transplant, the half-life averages 117 hours and 124 hours, respectively, compared to 156 hours in adult patients with a kidney transplant.

Metabolism and biotransformation

Tacrolimus is actively metabolized in the liver primarily by cytochrome P450 CYP3A4. Tacrolimus is metabolized intensively in the intestinal wall. Several metabolites of tacrolimus have been identified. In in vitro experiments it was shown that only one of the metabolites has immunosuppressive activity close to that of tacrolimus. Other metabolites were characterized by weak immunosuppressive activity or its absence. Only one of the tacrolimus metabolites was detected in the systemic bloodstream in low concentrations. Thus, pharmacological activity is almost independent of the metabolites.

Excretion

After oral administration of 14C-labeled tacrolimus, the bulk of the radioactivity was detected in the feces at approximately 2% – with about 1% of tacrolimus detected unchanged in the urine. Consequently, tacrolimus was almost completely metabolized before elimination by the main route of elimination was bile.

Indications

Prevention of liver or heart allograft rejection.

Treatment of allograft rejection resistant to other immunosuppressive therapy regimens.

Active ingredient

Composition

Active ingredient:

Tacrolimus 1 mg

How to take, the dosage

Prograf® therapy requires close monitoring by appropriately qualified and equipped personnel. Only physicians experienced in immunosuppressive therapy in organ transplant patients should prescribe Prograf® or modify immunosuppressive therapy.

The uncontrolled transfer of patients from one tacrolimus medication to another (including switching from conventional capsules to prolonged capsules) is unsafe. This can lead to graft rejection or an increased incidence of side effects including hypo- or hyperimmunosuppression due to clinically significant differences in tacrolimus exposure. The patient should take one of the tacrolimus dosage forms and follow the recommended dosing regimen. A change in dosage form or dosing regimen should only be made under the supervision of a transplant specialist. After transfer, tacrolimus blood concentrations should be monitored closely and the dose of the drug should be adjusted to maintain systemic tacrolimus exposure at an adequate level.

If Prograf® capsules are missed, the next dose should be taken in time. A double dose of the drug should not be taken.

General

The initial doses listed below should be considered as recommendations only. In the initial postoperative period Prograf® is usually used in combination with other immunosuppressants. The dose may vary depending on the immunosuppressive therapy regimen. The choice of Prograf® dose should be based primarily on clinical evaluation of the risk of rejection and individual tolerance of the drug, as well as on data of tacrolimus blood concentration monitoring (see section “Recommendations for monitoring therapeutic tacrolimus blood concentrations” below).

If clinical signs of rejection occur, consideration should be given to the need to adjust the immunosuppressive therapy regimen.

Prograf® can be used both orally and intravenously. In most cases Progragraf® capsule form is taken orally; if necessary, the capsule can be mixed with water and given through a nasogastric tube.

Dosage method

The daily dose of Prograf® capsule form is divided into 2 doses (morning and evening) in equal doses. The capsules should be taken immediately after taking them out of the blister. The desiccant (bag with silica gel) enclosed in the package is not edible.

The capsules should be swallowed with liquid, preferably water. In order to achieve maximum absorption it is recommended to take the capsules on an empty stomach 1 hour before or 2-3 hours after a meal.

The duration of therapy

In order to prevent transplant rejection, immunosuppression must be maintained at all times so there is no limit to the duration of therapy.

Hepatic transplantation Primary immunosuppression – adults

The oral therapy with Prograf® capsules should be started at a dose of 010-020 mg/kg/day divided into two doses (e.g., in the morning and in the evening). If the patient’s condition allows taking capsules orally Prograf® capsules should be started approximately 12 hours after the end of the operation.

If the patient’s condition does not allow for oral administration, intravenous therapy should be started at a dose of 001 to 005 mg/kg/day administered as a continuous 24-hour infusion of Prograf®.

Primary immunosuppression – children

The initial dose of 030 mg/kg/day of Prograf® should be divided into two doses (e.g., in the morning and evening). If the patient’s clinical condition does not allow for oral dosing, intravenous Prograf® therapy should be started at a dose of 005 mg/kg/day as a continuous 24-hour infusion.

Supportive therapy – adults and children

In the post-transplant period, doses of Prograf® are usually reduced. In some cases, concomitant immunosuppressive therapy may be discontinued leaving Prograf® as monotherapy. Improvement of the patient after transplantation may change the pharmacokinetics of tacrolimus and a dose adjustment will be necessary.

Treatment of rejection – adults and children

Higher doses of Prograf® capsules should be used in combination with additional corticosteroid therapy and short courses of mono/polyclonal antibody therapy to treat episodes of rejection. If signs of toxicity are noted a reduction in the dose of the drug may be required.

When transferring patients to therapy with Prograf® capsules, the same starting doses as for initial immunosuppression are recommended. Information about switching patients from cyclosporine to Prograf® is provided at the end of the section “Dose Adjustment in Special Populations of Patients”.

Primary immunosuppression – adults

The oral therapy with Prograf® capsules should be started at a dose of 020 – 030 mg/kg/day divided into two doses (e.g., morning and evening). Therapy with the drug should be started within 24 hours after the end of the operation. If the patient’s condition does not allow taking the drug orally, it is necessary to start intravenous therapy with a dose of 005 to 010 mg/kg/day as a continuous 24-hour infusion.

Primary immunosuppression – children

The starting dose of 030 mg/kg/day of Prograf® capsules should be divided into two doses (e.g., in the morning and in the evening). If the patient’s clinical condition does not allow for oral administration, intravenous therapy should be started at a dose of 0075-0100 mg/kg/day by intravenous infusion over 24 hours.

Supportive therapy – adults and children

The doses of Prograf® are usually reduced during supportive therapy. In some cases, it may be possible to discontinue concomitant immunosuppressants, leaving Prograf® as the base component of dual therapy. Improvement of patient’s condition after transplantation may change tacrolimus pharmacokinetics and a dose adjustment will be necessary.

The treatment of rejection reactions – adults and children

Higher doses of Prograf® in combination with additional corticosteroid therapy and short courses of mono/polyclonal antibody therapy are needed to treat episodes of rejection. If signs of toxicity are noted a reduction in the dose of the drug may be required.

When transferring patients to therapy with Prograf® capsules, the same starting doses as for initial immunosuppression are recommended. For information about switching patients from cyclosporine to Prograf® , see the section “Dose Adjustment in Special Populations of Patients” at the end.

Heart transplantation

Primary immunosuppression – adults

Prograf® may be used in combination with antibody induction therapy (which allows for delayed initiation of Prograf®) or without antibody administration in clinically stable patients. After antibody induction oral Prograf® capsules should be started at a dose of 0075 mg/kg/day divided into two doses (for example, in the morning and in the evening) for 5 days after the operation as soon as the patient’s clinical condition stabilizes. If the patient’s condition does not permit oral administration, intravenous therapy should be initiated with a dose of 001 to 002 mg/kg/day as a continuous 24-hour infusion. There is an alternative approach in which oral tacrolimus administration is started within 12 hours after transplantation. This approach is intended for patients without signs of internal organ dysfunction (e.g., kidneys). In this case, tacrolimus at an initial dose of 2-4 mg/day is combined with mycophenolate mofetil and corticosteroids or sirolimus and corticosteroids.

Primary immunosuppression – children

Primary immunosuppression with Prograf® after pediatric heart transplantation may be performed either in combination with antibody induction or alone. If antibody induction is not performed and Prograf® is administered intravenously, the recommended initial dose is 003-005 mg/kg/day in a continuous 24-hour infusion until tacrolimus concentration in whole blood is 15-25 ng/ml. At the first clinical opportunity, the patient should be switched to oral administration of the drug. The initial oral dose should be 030 mg/kg/day and administered 8-12 hours after stopping the intravenous infusion.

After antibody induction, oral administration of Prograf® capsules should be started at a dose of 010-030 mg/kg/day divided into two doses (for example, morning and evening).

Maintenance therapy – adults and children

Doses of Prograf® are usually reduced during maintenance therapy. Improvement of the patient after transplantation may change the pharmacokinetics of tacrolimus, and doses may need to be adjusted.

The treatment of rejection reactions – adults and children

The treatment of episodes of rejection requires higher doses of Pro-Graf® capsules in combination with additional corticosteroid therapy and short courses of mono/polyclonal antibody administration.

The initial daily dose (015 mg/kg/day in adults; 02-03 mg/kg/day in children) should be divided into two doses (e.g., morning and evening) when converting patients to Prograf® capsule therapy.

Information on switching patients from cyclosporine therapy to Prograf® is provided at the end of the section “Dose Adjustment in Special Populations of Patients”.

Recommended doses for the treatment of rejection after allotransplantation of other organs.

The dosing recommendations for Prograf® for patients after pancreatic and small intestine allotransplantation are based on data from selected prospective clinical studies. After lung transplantation Prograf® is used at a starting dose of 010-015 mg/kg/day pancreatic allotransplantation at a starting dose of 02 mg/kg/day. In patients after small intestine allotransplantation the initial dose of the drug is 03 mg/kg/day.

Patients with severe hepatic impairment may require dose reduction in order to maintain the target minimum drug level within the recommended values.

Patients with renal impairment

Because the pharmacokinetics of tacrolimus do not change depending on renal function, no dose adjustment is required. However, due to the nephrotoxic effect of tacrolimus, careful monitoring of renal function (including serum creatinine concentration, creatinine clearance and diuresis levels) is recommended.

Children

Children usually require doses that are 15 to 2 times higher than doses for adults to achieve similar blood concentrations of the drug.

Elderly patients

There is currently no evidence of the need to adjust the dose of the drug in elderly patients.

Transfer from cyclosporine to Prograf®

The concomitant use of the drugs cyclosporine and tacrolimus may increase the elimination half-life of cyclosporine and exacerbate toxic effects. Therefore, caution should be exercised when transferring patients from cyclosporine to tacrolimus therapy. Prograf® treatment should be started after the evaluation of cyclosporine blood concentrations and clinical condition of a patient. Transition to Prograf® should be delayed if there are increased concentrations of cyclosporine in a patient’s blood. In practice, Prograf® is prescribed 12-24 hours after cyclosporine withdrawal. After transfer, the patient’s cyclosporine blood concentrations should continue to be monitored due to the possibility of impaired cyclosporine clearance.

Recommendations for monitoring therapeutic tacrolimus blood concentrations Selection of Prograf® capsule dosage should be based on data of clinical evaluation of rejection and tolerability of the drug in each individual patient. Tacrolimus concentrations in whole blood are determined by immune methods, including semi-automated enzyme-linked immunosorbent assay (ELISA), in order to optimize dosing. Comparisons of tacrolimus blood concentrations published in the literature with individual clinical values should be made with caution and based on knowledge and understanding of the assessment method used.

In the postoperative period, it is important to monitor minimum tacrolimus concentrations in whole blood. When Prograf® capsules are administered orally, blood samples should be obtained 12 hours after administration of the medication immediately prior to the next dose to determine minimum tacrolimus concentrations in the blood. The frequency of determining tacrolimus blood concentrations should depend on clinical needs. Since Prograf® is a low clearance drug after dose adjustment, the time to reach the equilibrium minimum tacrolimus blood concentration may be several days. Minimum tacrolimus blood concentrations should be monitored approximately twice weekly during the early postgraft period and periodically thereafter during maintenance therapy. Minimum tacrolimus blood concentrations should also be monitored after changing the dose of Prograf® capsules on immunosuppression or after co-administration with drugs that affect tacrolimus concentrations in whole blood.

The results of clinical studies indicate that treatment with Prograf® capsules is most successful when minimum tacrolimus blood concentrations are less than 20 ng/ml. When interpreting data on tacrolimus concentrations in whole blood, it is important to evaluate the clinical condition of the patient.

In clinical practice, in the early post-transplant period, minimum whole blood tacrolimus concentrations typically range from 5-20 ng/ml after liver transplantation and 10-20 ng/ml after kidney and heart transplantation. Thereafter, during maintenance therapy after renal and cardiac liver transplantation, tacrolimus blood concentrations range from 5 to 15 ng/ml.

Interaction

Metabolic interactions Tacrolimus in the systemic bloodstream is metabolized by the hepatic cytochrome CYP3A4. When administered orally, tacrolimus is also metabolized in the intestinal cytochrome CYP3A4 system.

The concomitant administration of drugs or medicinal plants with an established inhibitory or inducing effect on CYP3A4 may increase or decrease tacrolimus blood concentrations accordingly. To maintain adequate and consistent tacrolimus exposure when concomitantly prescribed with drugs that may alter CYP3A4 activity or have other effects on tacrolimus pharmacokinetics, it is recommended to monitor the tacrolimus blood concentration and adjust the dose or discontinue the drug if necessary. The QT interval (using electrocardiography) renal function and possible side effects should also be monitored.

Metabolic inhibitors

Based on clinical experience, it has been found that the following drugs can significantly increase tacrolimus blood concentrations: Antifungal agents (ketoconazole fluconazole itraconazole voriconazole) macrolide antibiotics (erythromycin) HIV protease inhibitors (ritonavir nelfinavir saquinavir) or hepatitis C virus protease inhibitors (such as telaprevir boceprevir). When prescribing these drugs with tacrolimus, it may be necessary to reduce the dose of tacrolimus in almost all patients. Less pronounced drug interactions have been observed with clotrimazole clarithromycin jozamycin nifedipine nicardipine diltiazem verapamil amiodarone danazol ethinylestradiol omeprazole and nefazodone.

The following substances have been shown in in vitro studies to be potential inhibitors of tacrolimus metabolism: bromocriptine cortisone dapsone ergotamine gestoden lidocaine mephenytoin miconazole midazolam nilvadipine norethisterone quinidine tamoxifen (triacetyl)olsandomycin. It is recommended that grapefruit juice be avoided due to the possibility of increased tacrolimus blood levels. Lansoprazole and cyclosporine may potentially inhibit CYP3A4-mediated metabolism of tacrolimus and increase its blood concentration.

Metabolism inducers Based on clinical experience it was found that the following drugs can significantly reduce tacrolimus blood concentration: rifampicin phenytoin Hypericum perforatum. If these drugs are administered simultaneously with tacrolimus, it may be necessary to increase the doses of Prograf in almost all patients.

Clinically significant interactions were observed with phenobarbital.

Corticosteroids at maintenance doses generally decrease tacrolimus blood concentrations. High doses of prednisolone or methylprednisolone used to treat acute rejection may increase or decrease tacrolimus blood levels.

Carbamazepine methamizole and isoniazid can decrease the blood concentration of tacrolimus. Effect of tacrolimus on the metabolism of other drugs Tacrolimus inhibits CYP3A4 and concomitant administration may affect drugs metabolized by CYP3A4. The elimination half-life of cyclosporine is prolonged when concomitantly used with tacrolimus. Syergic/additive nephrotoxic effects may also be observed. For these reasons, concomitant administration of cyclosporine and tacrolimus is not recommended, and caution should be exercised when prescribing tacrolimus to patients who have previously taken cyclosporine.

Tacrolimus increases blood levels of phenytoin.

Because tacrolimus may decrease clearance of hormonal contraceptives, it is important to use caution when choosing contraception.

The data on interactions of tacrolimus with statins are limited. Clinical observations suggest that the pharmacokinetics of statins do not change with tacrolimus.

Experimental studies in animals have shown that tacrolimus has the potential to decrease clearance and increase the half-life of pentobarbital and phenazole.

Other potential interactions that increase systemic exposure to tacrolimus

Prokinetic agents (metoclopramide cisapride). Cimetidine. Magnesium and aluminum hydroxide.

Other potentially adverse drug interactions Concomitant use of tacrolimus with drugs with nephro- or neurotoxicity (e.g., aminoglycosides gyrase inhibitors vancomycin cotrimoxazole non-steroidal anti-inflammatory drugs haptcyclovir acyclovir) may contribute to these effects.

Tacrolimus combined with amphotericin B and ibuprofen resulted in increased nephrotoxicity.

Because tacrolimus may contribute to or exacerbate hyperkalemia, high doses of potassium or potassium-saving diuretics (amiloride triamterene spironolactone) should be avoided.

The immunosuppressants may alter the body’s response to vaccination: vaccination during treatment with tacrolimus may be less effective. Live, attenuated vaccines should be avoided.

Protein binding Tacrolimus actively binds to plasma proteins. Possible competitive interaction of tacrolimus with drugs with high affinity for plasma proteins (hysteroid pesticides oral anticoagulants oral antidiabetic agents) should be considered. Incompatibilities

Incompatibilities

Special Instructions

The following parameters should be routinely monitored during the initial period after transplantation: BP, ECG, neurological and ophthalmological status, fasting blood glucose levels, electrolytes (especially potassium), liver and renal function, clinical blood count parameters, coagulation indices and plasma protein determinations.

As with other immunosuppressive drugs, because of the potential risk of malignant changes in the skin, exposure to sunlight and UV radiation should be limited by protecting the skin with clothing and using high protection factor creams.

If accidentally injected into an artery or perivascularly, Prograf ® concentrate for infusion at 5 mg/ml may cause irritation in the area of injection.

Prograf® concentrate for preparation of 5 mg/ml infusion solution contains polyoxyethylated hydrogenated castor oil, which has been noted to cause anaphylactic reactions. The risk of developing an anaphylactic reaction can be reduced by administering reconstituted Prograf® concentrate for 5 mg/ml infusions at a low rate or by first administering an antihistamine.

Prograf®, 0.5; 1 and 5 mg capsules

Tacrolimus is not compatible with polyvinyl chloride (PVC). If the contents of the capsules must be inserted through a nasogastric tube, the latter must not contain PVC.

Prograf®, concentrate for preparation of infusion solution containing 5 mg/ml

Tacrolimus is absorbed by polyvinyl chloride plastic. Tubes, syringes and any other equipment used to prepare and administer Prograf® , infusion concentrate containing 5 mg/ml must not contain polyvinyl chloride.

Impact on driving and operating machinery

Tacrolimus may cause visual and neurological impairment. Patients who develop these abnormalities should not drive a car or operate machinery. These effects may be exacerbated if Prograf® is taken concomitantly with alcohol.

Contraindications

Known hypersensitivity to tacrolimus or other macrolides.

Known hypersensitivity to polyoxyethylated hydrogenated castor oil (HCO-60) or structurally related components.

Side effects

Many of the adverse reactions presented below are reversible and/or reduced with dose reduction. Oral administration is associated with a lower risk of adverse reactions compared to intravenous administration. Within each frequency group, adverse events are presented in descending order of severity. The adverse reactions classified by organs and systems are listed below in descending order of frequency of occurrence: Very common (> 1/10) common (> 1/100 to < 1/10) infrequent (> 1/1000 to < 1/100) rare (>_1/10 000 to < 1/1 000) very rare (< 1/10 000) frequency unknown (there is not enough data to establish frequency).

frequent: bleeding thromboembolic and ischemic complications peripheral circulatory disorders vascular hypotension; infrequent: infarction deep vein thrombosis of extremities shock.

Blood and lymphatic system disorders

often: anemia leukopenia thrombocytopenia leukocytosis decrease or increase in hemoglobin and/or hematocrit deviations in erythrocyte analysis; infrequent: coagulopathies deviations in coagulogram values pancytopenia neutropenia; rare: thrombotic thrombocytopoietic purpura hypoprothrombinemia; incidence unknown: partial red cell aplasia agranulocytosis hemolytic anemia.

Nervous system disorders

very common: tremor headache; common: convulsions impaired consciousness paresthesias and dysesthesias peripheral neuropathies dizziness disordered writing nervous system disorders; infrequent coma central nervous system hemorrhage and cerebral circulation disorders paralysis and paresis encephalopathy speech and articulation disorders amnesia; rare: increased muscle tone; very rare: myasthenia gravis.

Visual disorders frequently: blurred vision photophobia ocular disorders visual impairment; infrequently: cataract; rarely: blindness.

Hearing and labyrinth disorders frequently: tinnitus (ringing) in the ears; infrequent: decreased hearing; rare: neurosensory deafness; very rare: hearing loss.

Respiratory system disorders of the thorax and mediastinum

often: dyspnea pulmonary parenchymal disorders pleural effusion pharyngitis cough nasal congestion rhinitis; infrequent: respiratory failure respiratory disorders asthma; rare: acute respiratory distress syndrome.

Gastrointestinal tract disorders

very common: diarrhea nausea; common: gastrointestinal inflammatory diseases gastrointestinal ulcers and perforations gastrointestinal bleeding stomatitis and oral mucosal ulceration ascites vomiting gastrointestinal and abdominal pain dyspepsia constipation flatulence bloating and distention feelings in the stomach liquid stool symptoms of gastrointestinal tract disorders; infrequent: paralytic intestinal obstruction (paralytic ileus) peritonitis acute and chronic pancreatitis increased blood amylase levels gastroesophageal reflux disease impaired gastric evacuation function; rare: subileus pancreatic pseudocysts.

very common: impaired renal function;

often: renal failure acute renal failure oliguria acute tubular necrosis toxic nephropathy urinary syndrome disorders of the bladder and urethra; infrequent: anuria hemolytic uremic syndrome; very rare: nephropathy hemorrhagic cystitis.

Skin and subcutaneous tissue disorders

often: itching rash alopecia acne hyperhidrosis;

infrequent: dermatitis photosensitization;

rare: toxic epidermal necrolysis (Lyell’s syndrome);

very rare: Stevens-Johnson syndrome.

Musculoskeletal and connective tissue disorders frequently: arthralgia muscle cramps pain in the extremities back pain; infrequent: joint disorders.

Endocrine system disorders

rarely: hirsutism.

Metabolic and nutritional disorders

very common: hyperglycemia diabetes hyperkalemia; often: hypomagnesemia hypophosphatemia hypocalcemia hyponatremia hyponatremia hypervolemia hyperuricemia decreased appetite anorexia metabolic acidosis hyperlipidemia hypercholesterolemia hypertriglyceridemia electrolyte disorders; infrequent: dehydration hypoproteinemia hyperphosphatemia hypoglycemia.

Immune system disorders

An allergic and anaphylactic reactions have been observed in patients taking tacrolimus.

Infectious and parasitic diseases

With tacrolimus therapy as well as other immunosuppressants the risk of local and generalized infectious diseases (viral bacterial fungal prognostic) increases. The course of previously diagnosed infectious diseases may worsen. Cases of nephropathy associated with BK-virus and progressive multifocal leukoencephalopathy (PML) associated with JC-virus have been observed against the background of immunosuppressive therapy including Prograf® therapy.

Injury intoxication and complications of manipulation often: primary graft dysfunction.

In practice, errors in the use of tacrolimus preparations have been observed including unwarranted unintentional or uncontrolled transfer of patients from one form of tacrolimus (standard or prolonged) to another and associated cases of graft rejection have been reported (the incidence cannot be estimated from the available data).

Benign malignant and unspecified neoplasms (including cysts and polyps)

Patients receiving immunosuppressive therapy have a higher risk of malignancy. Both benign and malignant neoplasms, including Epstein-Barr virus-associated lymphoproliferative diseases and skin cancer, have been reported with tacrolimus. General disorders and disorders at the site of administration often: asthenia febrile states edema pain and discomfort increased alkaline phosphatase activity in the blood weight gain body temperature perception disorders;

infrequent multi-organ failure flu-like syndrome disturbances in perception of ambient temperature feeling of tightness in chest feeling of anxiety worsening of well-being increasing lactate dehydrogenase activity in blood decreasing body weight; rare: thirst loss of balance (falling) feeling of stiffness in chest difficulty moving ulcer; very rare: increased fatty tissue mass.

Liver and biliary tract disorders

often: increased levels of liver enzymes liver function abnormal changes in liver functional tests cholestasis and jaundice liver cell lesions and hepatitis cholangitis;

rarely: hepatic artery thrombosis obliterating endophlebitis of hepatic veins; very rare: liver failure hepatic duct stenosis.

Gender and mammary gland disorders infrequent: dysmenorrhea and uterine bleeding.

Mental disorders very common: insomnia; common: anxiety confusion and disorientation depression depressed mood affective disorders nightmares hallucinations mental disorders; infrequent: psychotic disorders.

Overdose

The reports of overdose are limited. Several episodes of accidental overdose have been reported in patients taking tacrolimus medication. Symptoms included tremors headache nausea vomiting infection urticaria lethargic state elevated blood urea nitrogen serum creatinine and alanine aminotransferase.

There are currently no antidotes to tacrolimus. In case of overdose, standard measures should be taken and symptomatic treatment should be administered.

With regard to the high molecular weight of tacrolimus poor water solubility and marked binding to red blood cells and plasma proteins, dialysis is ineffective. Hemofiltration or diafiltration were effective in individual patients with very high concentrations of tacrolimus in the blood. In cases of oral overdose, gastric lavage and/or the use of adsorbents (e.g. activated charcoal) may be effective if these measures are taken soon after taking the drug.

Pregnancy use

The results of preclinical studies and studies conducted in humans show that the drug may pass through the placenta.

As the safety of Prograf in pregnant women is not well established, the drug should not be prescribed unless the possible benefit of treatment justifies the potential risk to the fetus.

The results of preclinical and human studies show that tacrolimus is excreted with breast milk.

Because adverse effects on newborns cannot be ruled out, women taking Prograf should not breastfeed.

Similarities