PROGRAF instructions for use, description of the drug PROGRAF: contraindications, side effects, dosages, composition - capsules; concentrate for prepared solution and for introduction to the reference book

Pharmacological properties of the drug Prograf

At the molecular level, the effects of tacrolimus are determined by binding to a cytosolic protein (FKBP12), which is responsible for the intracellular accumulation of the drug. The FKBP12-tacrolimus complex specifically and competitively binds to and inhibits calcineurin, resulting in calcium-dependent inhibition of T cell signaling transduction pathways, thereby preventing the transcription of a discrete group of lymphokine genes. Tacrolimus is a highly active immunosuppressive substance that inhibits the formation of cytotoxic lymphocytes, which are mainly responsible for graft rejection, reduces T-cell activation, T-helper-dependent B-cell proliferation, and the formation of lymphokines (such as interleukins -2, -3 and γ-interferon), expression of the interleukin-2 receptor. Tacrolimus capsules are absorbed from the gastrointestinal tract; The main site of absorption is the upper gastrointestinal tract. Tacrolimus reaches peak plasma concentrations (Cmax) at approximately 1 to 3 hours. In some patients, the drug is absorbed over an extended period, achieving a relatively uniform absorption profile. The average absorption parameters are given below:

Population	Dosage (mg/kg/day)	Cmax (ng/ml)	Tmax (h)	Bioavailability (%)
Adult liver graft (steady state concentration)	0,30	74,1	3,0	21,8 (±6,3)
Pediatric liver graft (steady-state concentration)	0,30	37,0 (±26,5)	2,1 (±1,3)	25 (±20)
Adult kidney transplant (steady state concentration)	0,30	44,3 (±21,9)	1,5	20,1 (±11,0)

After oral administration (0.3 mg/kg per day) of the drug in patients with a liver transplant, most patients achieved equilibrium concentrations within 3 days. In stable liver transplant patients, the bioavailability of Prograf was reduced when the drug was administered orally after consuming a moderate fat meal. A decrease in AUC (27%), Cmax (50%) and an increase in Tmax (173%) in undiluted blood was also noted. When the drug was used simultaneously with food, the rate and degree of absorption of Prograf decreased. Bile secretion does not affect the absorption of the drug. There is a significant correlation between AUC and undiluted blood trough levels at steady state, and monitoring undiluted blood trough levels may assist in adequately assessing systemic drug exposure. The distribution pattern of tacrolimus after intravenous administration can be described as biphasic. In the systemic circulation, tacrolimus is largely bound to red blood cells. The ratio of undiluted blood/plasma concentration is 20:1. In blood plasma, the drug is significantly bound (98.8%) to proteins, mainly serum albumin and α-1-acid glycoprotein. Tacrolimus is widely distributed in the body. The steady-state volume of distribution (based on plasma concentration) is 1300 L (healthy volunteers). The corresponding figure based on undiluted blood is 47.6 l. Tacrolimus is a substance with low clearance. In healthy volunteers, the average total clearance, estimated from the concentration of the drug in undiluted blood, is 2.25 l/h. In adult patients with liver and kidney transplants, the value of this parameter is 4.1 and 6.7 l/h, respectively. In children with a liver transplant, the total clearance values are 2 times higher than in adult patients with a liver transplant. The half-life of tacrolimus is long and variable. In healthy volunteers, the mean half-life from undiluted blood is 43 hours. In adult and pediatric liver transplant patients, the mean half-life is 11.7 and 12.4 hours, respectively, compared with 15.6 hours in adult kidney transplant patients. Using in vitro models, 8 metabolites were identified, of which only 1 has important immunosuppressive activity. Tacrolimus is extensively metabolized by the hepatic microsomal cytochrome P450 3A4 isoenzyme CYP 3A4. Following oral administration of 14C-labeled tacrolimus, the majority of the radiolabeled drug was excreted in the feces. Approximately 2% is excreted in the urine. Less than 1% unchanged tacrolimus was observed in urine and feces, indicating that tacrolimus is almost completely metabolized before elimination. The main route of elimination is bile.

Use of the drug Prograf

capsules are taken orally. Dosage must be adjusted depending on the individual characteristics of the patient’s body, taking into account the results of monitoring the level of the drug in the blood. If necessary, the contents of the capsules can be dissolved in water and administered through a nasogastric tube. It is recommended to distribute the daily oral dose into 2 doses (morning and evening). Capsules should be taken immediately after removing them from the blister pack. The capsules are swallowed with liquid (preferably water). To achieve maximum absorption, the drug should be taken on an empty stomach or at least 1 hour before or 2-3 hours after a meal. There was no effect of food intake on the absorption of the drug in patients with a kidney transplant. Liver transplantation Primary immunosuppression, adults. Oral therapy with Prograf begins at a dose of 0.1–0.2 mg/kg per day, dividing this dose into 2 doses (morning and evening). Start using the drug 12 hours after completion of the operation. If the patient's condition does not allow taking the drug orally, IV therapy is performed. Primary immunosuppression, children. The initial dose of the drug for oral administration is 0.3 mg/kg per day, divided into 2 doses (morning and evening). If the patient's clinical condition does not allow taking the drug orally, IV therapy is performed. Supportive therapy, adults and children. During maintenance therapy, the dose of Prograf is reduced. In some cases, concomitant immunosuppressive therapy drugs are discontinued, leaving Prograf as monotherapy. Improvement in the patient's condition after transplantation may change the pharmacokinetics of tacrolimus, so there is a need to adjust the dose of the drug. Treatment of rejection, adults and children. To treat rejection, higher doses of Prograf are used, along with additional GCS therapy and short courses of mono- or polyclonal antibodies. If signs of toxicity are observed, the dose of Prograf may be reduced. When transferring patients to Prograf therapy, the same initial doses are recommended as for primary immunosuppression. When transferring patients from cyclosporine therapy to Prograf (see SPECIAL INSTRUCTIONS). Kidney transplantation Primary immunosuppression, adults. Oral therapy with Prograf begins with a dose of 0.2–0.3 mg/kg per day, divided into 2 doses (morning and evening). Therapy begins within 24 hours after completion of the operation. If the patient's condition does not allow taking the drug orally, IV therapy is performed. Primary immunosuppression, children. Oral therapy with Prograf begins with a dose of 0.3 mg/kg per day, dividing this dose into 2 doses (morning and evening). If the patient's condition does not allow taking the drug orally, IV therapy is performed. Supportive therapy, adults and children. During maintenance therapy, the dose of Prograf is reduced. In some cases, it is possible to discontinue concomitant immunosuppressive therapy, leaving Prograf as the basic component of dual therapy. Improvement in the patient's condition after transplantation may change the pharmacokinetics of tacrolimus, so there is a need to adjust the dose of the drug. Treatment of rejection reactions, adults and children. To treat rejection, it is necessary to use higher doses of Prograf, along with additional GCS therapy and short courses of mono- or polyclonal antibodies. If signs of toxicity are observed, the dose of Prograf may be reduced. When transferring patients to Prograf therapy, the same initial doses are recommended as for primary immunosuppression. When transferring patients from cyclosporine therapy to Prograf (see SPECIAL INSTRUCTIONS). Heart transplantation Primary immunosuppression, adults. Prograf can be used together with antibody induction (taking into account the delayed start of Prograf therapy) or without the use of antibodies in clinically stable patients. After antibody induction, oral Prograf therapy is started with a dose of 0.075 mg/kg per day, divided into 2 doses (morning and evening). The use of the drug should be started within 5 days after completion of the operation, as soon as the patient’s clinical condition has stabilized. If the patient's condition does not allow taking the drug orally, IV therapy is performed. An alternative approach is to start oral tacrolimus within 12 hours of transplantation. This approach is intended for patients without signs of organ (kidney) dysfunction. In this case, tacrolimus at an initial dose of 2–4 mg/day is combined with mycophenolate mofetil and GCS or sirolimus and GCS. Primary immunosuppression, children. After heart transplantation in children, primary immunosuppression with Prograf can be carried out either in combination with antibody induction or independently. In cases where antibody induction is not performed, Prograf is administered as an intravenous infusion over 24 hours until the tacrolimus concentration in undiluted blood reaches 15–25 ng/ml. At the first clinical opportunity, it is necessary to transfer the patient to oral administration of the drug at an initial dose of 0.3 mg/kg per day, which is prescribed 8–12 hours after the end of the IV infusion. After antibody induction, oral Prograf therapy is started with a dose of 0.1–0.3 mg/kg per day, divided into 2 doses (morning and evening). Supportive therapy, adults and children. During maintenance therapy, the dose of Prograf is reduced. Improvement in the patient's condition after transplantation may change the pharmacokinetics of tacrolimus, so there is a need to adjust the dose of the drug. Treatment of rejection, adults and children. To treat rejection, it is necessary to use higher doses of Prograf together with additional GCS therapy and short courses of mono- or polyclonal antibodies. When transferring adult patients to Prograf therapy, the initial dose of the drug 0.15 mg/kg per day is divided into 2 doses (morning and evening). When transferring children to Prograf therapy, the initial dose of the drug 0.2–0.3 mg/kg per day is also divided into 2 doses (morning and evening). Information regarding the transfer of patients from cyclosporine therapy to Prograf (see SPECIAL INSTRUCTIONS). Recommended doses after allotransplantation of other organs. Recommendations regarding the dose of Prograf for patients after lung, pancreas and intestinal allotransplantation are based on data from individual clinical studies. After lung transplantation, Prograf is used at an initial dose of 0.1–0.15 mg/kg per day, pancreas allotransplantation - at an initial dose of 0.2 mg/kg per day. In patients after intestinal allotransplantation, the initial dose is 0.3 mg/kg per day. Concentrate for the preparation of injection solution. Prograf concentrate for the preparation of solution for intravenous administration is used only intravenously. The drug should not be administered undiluted. Before use, it must be diluted with 5% dextrose solution or 0.9% sodium chloride solution in glass, polyethylene or polypropylene bottles. Only transparent and colorless solutions should be used. Injection of the drug is not recommended. The concentration of the solution for infusion should vary between 0.004–0.1 mg/ml. The total volume of infusion over 24 hours should range from 20–500 ml. Unused infusion concentrate in an open ampoule or unused reconstituted solution must be destroyed to avoid contamination. Liver transplantation Primary immunosuppression, adults. The use of the drug begins 12 hours after completion of the operation. If the patient’s condition does not allow taking the drug orally (capsules), IV therapy is carried out starting with a dose of 0.01–0.05 mg/kg per day, administering the drug as an IV infusion over 24 hours. Primary immunosuppression, children. If the patient's condition does not allow taking the drug orally (capsules), IV therapy is carried out starting with a dose of 0.05 mg/kg per day, in the form of an IV infusion for 24 hours. Maintenance therapy, adults and children. During maintenance therapy, the dose of Prograf is reduced. In some cases, concomitant immunosuppressive therapy drugs are discontinued, using Prograf as monotherapy. Improvement in the patient's condition after transplantation may alter the pharmacokinetics of tacrolimus, resulting in a need for dose adjustment. Treatment of rejection, adults and children. To treat rejection, higher doses of Prograf are used together with additional GCS therapy and short courses of mono- or polyclonal antibodies. When transferring adult patients to oral therapy with Prograf (capsules), the initial dose of the drug 0.15 mg/kg per day is divided into 2 doses (morning and evening). When transferring children to oral therapy with Prograf, the initial dose of 0.2–0.3 mg/kg per day is divided into 2 doses (morning and evening). Information regarding the transfer of patients from cyclosporine therapy to Prograf (see SPECIAL INSTRUCTIONS). Kidney transplantation Primary immunosuppression, adults. 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 (Prograf capsules), IV therapy should be started with a dose of 0.05–0.1 mg/kg/day, administering the drug as an IV infusion over 24 hours. Primary immunosuppression, children. If the patient's condition does not allow taking the drug orally (Prograf capsules), IV therapy should begin with a dose of 0.075–0.1 mg/kg/day, administering the drug as an IV infusion over 24 hours. Maintenance therapy, adults and children . During maintenance therapy, the dose of Prograf is reduced. In some cases, it is possible to discontinue concomitant immunosuppressive therapy, leaving Prograf as the basic component of combination therapy. Improvement in the patient's condition after transplantation may change the pharmacokinetics of tacrolimus, so it may be necessary to adjust the dose of the drug. Treatment of rejection reactions, adults and children. To treat episodes of rejection, it is necessary to use higher doses of Prograf, together with additional therapy with corticosteroids and short courses of mono/polyclonal antibodies. If signs of toxicity occur, a dose reduction of Prograf may be necessary. When transferring patients to Prograf therapy, it is recommended to use the same initial doses of the drug as for primary immunosuppression. When transferring patients from cyclosporine therapy to Prograf (see SPECIAL INSTRUCTIONS). Heart transplantation Primary immunosuppression, adults. Prograf is used together with antibody induction (taking into account the delayed start of Prograf therapy). After antibody induction, the drug should be started within 5 days after completion of the operation after stabilization of the patient’s clinical condition. If the patient’s condition does not allow taking the drug orally (Prograf capsules), IV therapy is carried out, starting with a dose of 0.01–0.02 mg/kg/day, administering the drug as an IV infusion over 24 hours. Primary immunosuppression , children . After heart transplantation in children, primary immunosuppression with Prograf can be carried out either in conjunction with antibody induction or independently. In cases where antibody induction is not carried out, Prograf is administered intravenously at an initial dose of 0.03–0.05 mg/kg/day, as an intravenous infusion over 24 hours until the tacrolimus concentration in undiluted blood reaches 15–25 ng/ml. If clinically possible, it is necessary to transfer the patient to oral administration of the drug (Prograf capsules) at an initial dose of 0.30 mg/kg/day with an interval of 8–12 hours after the end of the IV infusion. Supportive therapy, adults and children. During maintenance therapy, Prograf doses are reduced. Improvement in the patient's condition after transplantation may change the pharmacokinetics of tacrolimus, so there may be a need to adjust the dose of the drug. Treatment of rejection, adults and children . To treat episodes of rejection, it is necessary to use higher doses of Prograf together with additional therapy with corticosteroids and short courses of mono/polyclonal antibodies. When transferring adult patients to oral therapy with Prograf (capsules), the initial dose of the drug 0.15 mg/kg/day should be divided into 2 doses (for example, morning and evening). When transferring children to oral therapy with Prograf (capsules), the initial dose of the drug 0.2–0.3 mg/kg/day should be divided into 2 doses (for example, morning and evening). For information regarding transferring patients from cyclosporine therapy to Prograf, see SPECIAL INSTRUCTIONS). Recommended doses after allotransplantation of other organs. Recommendations regarding dosing of Prograf for patients after lung, pancreas and intestinal allotransplantation are based on data from clinical studies. After lung transplantation, Prograf is used at an initial dose of 0.1-0.15 mg/kg per day, pancreas allotransplantation - at an initial dose of 0.2 mg/kg per day. In patients after intestinal allotransplantation, the initial dose is 0.3 mg/kg per day.

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Side effects of the drug Prograf

Most of the following adverse reactions are reversible and/or their severity decreases with dose reduction. When taken orally, the frequency of side effects is lower than when administered intravenously. The following reactions are given depending on the frequency of occurrence: very often (1/10); often (1/100, but ≤1/10); sometimes (1/1000, but ≤1/100); rare (1/10,000, but ≤1/1000); very rare (≤1/10,000, including isolated cases). From the cardiovascular system: very often - hypertension (arterial hypertension); often - arterial hypotension, tachycardia, arrhythmias and cardiac conduction disturbances, thromboembolic and ischemic manifestations, angina pectoris, vascular disease; sometimes - ECG abnormalities, heart attack, heart failure, shock, myocardial hypertrophy, cardiac arrest. From the gastrointestinal tract and liver: very often - diarrhea, nausea and/or vomiting; often - gastrointestinal dysfunction (dyspepsia), abnormal levels of liver enzymes, abdominal pain, constipation, changes in body weight and appetite, inflammation and ulcers in the gastrointestinal tract, jaundice, diseases of the biliary tract and gallbladder; sometimes - ascites, intestinal obstruction (ileus), damage to the liver parenchyma, pancreatitis; rarely - liver failure. From the blood system: often - anemia, leukopenia, thrombocytopenia, hemorrhage, leukocytosis, coagulation disorders; sometimes - insufficiency of the hematopoietic system, including pancytopenia, thrombotic microangiopathy. From the urinary system: very often - impaired renal function (increased creatinine levels in the blood serum); often - damage to kidney tissue, renal failure; sometimes - proteinuria. From the side of metabolism and laboratory parameters: very often - hyperglycemia, hyperkalemia, diabetes mellitus; often - hypomagnesemia, hyperlipidemia, hypophosphatemia, hypokalemia, hyperuricemia, hypocalcemia, acidosis, hyponatremia, hypovolemia, other electrolyte imbalance, dehydration; sometimes - hypoproteinuria, hyperphosphatemia, increased amylase levels, hypoglycemia. From the musculoskeletal system: often - convulsions; sometimes - myasthenia gravis, a joint disease. From the nervous system and sensory organs: very often - tremor, headache, insomnia; often - impaired sensitivity (paresthesia), visual impairment, confusion, depression, dizziness, agitation, neuropathy, convulsions, incoordination, psychosis, anxiety, nervousness, sleep disturbance, consciousness, emotional lability, hallucinations, otological disorders, impaired thinking, encephalopathy; sometimes - increased muscle tone, eye disease, amnesia, cataracts, speech impairment, paralysis, coma, deafness; very rarely - blindness. From the respiratory system: often - impaired respiratory function (shortness of breath), pleural effusion; sometimes - atelectasis, asthma. Skin: often - itching, alopecia, rash, sweating, acne, photosensitivity; sometimes - hirsutism; rarely - Lyell's syndrome; very rarely - Stevens-Johnson syndrome. From the immune system. Allergic and anaphylactic reactions have been reported in patients taking tacrolimus. In addition, patients receiving immunosuppressive therapy are at increased risk of developing malignant tumors. The development of both benign and malignant tumors, including Epstein-Barr virus (EBV)-associated lymphoproliferative diseases and skin cancer, has been observed with the use of tacrolimus. The risk of developing infectious diseases (viral, bacterial, fungal, protozoan) also increases. The course of previously diagnosed infectious diseases may worsen. General manifestations: very often - localized pain (arthralgia); often - fever, peripheral edema, asthenia, difficulty urinating; sometimes - swelling and other disorders of the genitals in women. In isolated cases, the development of ventricular hypertrophy or hypertrophy of the interventricular septum of the heart, registered as cardiomyopathies, was noted. In most cases, these manifestations were reversible, occurring primarily in children with trough tacrolimus blood concentrations well above the recommended maximum levels. Other factors that increased the risk of developing such clinical conditions were pre-existing heart disease, use of corticosteroids, hypertension (arterial hypertension), kidney or liver dysfunction, infection, excess fluid in the body and edema. As with other potential immunosuppressive drugs, the development of EBV lymphoproliferative disorders has been observed in patients taking Prograf. In patients who have been switched to Prograf therapy, this may be caused by excessive immunosuppression before starting the drug. Patients who were transferred to Prograf therapy were prohibited from taking concomitant antilymphocyte therapy. In children (aged 2 years and older) with EBV-seronegative reaction, there is an increased risk of developing lymphoproliferative diseases (for this group of patients, serological determination of the EBV virus is necessary before using Prograf).

Special instructions for the use of Prograf

Drug dose adjustment in special groups of patients. Patients with severe hepatic impairment may require dose reductions to maintain minimum drug levels within recommended levels. Since the pharmacokinetics of tacrolimus are not affected by renal function, no dosage adjustment is necessary in patients with renal impairment. However, due to the nephrotoxicity of tacrolimus, careful monitoring of renal function (including serum creatinine concentration, creatinine clearance and urine output) is recommended. To achieve the required levels of the drug in the blood, children need doses 1.5–2 times higher than adults. There are no data regarding the need for dose adjustment in elderly patients. Transition from cyclosporine therapy. Concomitant use of cyclosporine and Prograf may prolong the half-life of cyclosporine and increase toxic effects. Therefore, caution must be exercised when transferring patients from cyclosporine to Prograf therapy. Treatment with Prograf begins after assessing the concentrations of cyclosporine in the patient’s blood and his clinical condition. The drug is stopped if the level of cyclosporine in the blood is elevated. In practice, treatment with Prograf was started 12–24 hours after stopping cyclosporine. After transfer of the patient, it is necessary to continue monitoring the levels of cyclosporine in the patient's blood due to the possibility of impaired clearance of cyclosporine. Recommendations regarding achieving the required level of drug concentration in undiluted blood. The choice of drug dose should be based on the results of a clinical assessment of the rejection process and tolerability of the drug by each patient individually. To optimize the dosage of the drug, determination of the concentration of tacrolimus in undiluted blood is used using immune methods, including a semi-automated microparticle enzyme-linked immunosorbent assay (MIEA). Comparison of tacrolimus blood concentrations published in the literature with individual clinical values is based on the assessment method used. In the early period after surgery, monitor the minimum levels of tacrolimus in undiluted blood. For oral administration, blood samples should be obtained 12 hours after dosing to determine trough blood levels, immediately prior to the next dose. The frequency of monitoring drug blood levels depends on clinical need. Because Prograf is a drug with a low clearance rate, dosage adjustments may take several days before changes in drug blood levels become apparent. Minimum drug levels in the blood are monitored 2 times a week during the early post-transplant period and periodically during maintenance therapy. It is also necessary to monitor tacrolimus blood trough levels after changes in drug dosage, immunosuppressive regimen, or after coadministration with drugs that may affect undiluted blood concentrations of tacrolimus. Results from clinical studies suggest that most patients can be treated successfully if tacrolimus blood trough levels are maintained below 20 ng/mL. When interpreting data regarding drug concentrations in undiluted blood, it is important to assess the patient's clinical condition. In clinical practice during the early period after transplantation, undiluted blood trough levels typically ranged from 5–20 ng/mL after liver transplantation and 10–20 ng/mL after kidney and heart transplantation. Subsequently, during maintenance therapy after liver, kidney and heart transplantation, drug concentrations in the blood vary from 5 to 15 ng/ml. During the initial period after transplantation, routine monitoring of the following parameters should be carried out: blood pressure, ECG, neurological and visual status, fasting blood glucose, electrolytes (especially potassium), liver and kidney function, clinical blood test parameters, coagulation parameters and protein determination. fractions in blood plasma. As with other immunosuppressive drugs, due to the potential risk of developing malignant changes in the skin, it is necessary to limit exposure to sunlight and ultraviolet radiation by protecting the skin with clothing and using creams with a high protection factor. Tacrolimus is incompatible with polyvinyl chloride. If the contents of the capsules must be administered through a nasogastric tube, the latter should not contain polyvinyl chloride. Grapefruit juice increases blood levels of tacrolimus by inhibiting CYP3A4 activity. Tacrolimus may cause visual and neurological disturbances. Patients who develop such impairments should not drive vehicles or operate machinery. This effect may be enhanced when Prograf is taken concomitantly with alcohol. The drug can cross the placenta. Since the safety of Prograf in pregnant women has not been established, this drug should not be prescribed during pregnancy unless the expected benefit of treatment outweighs the potential risk to the fetus. Tacrolimus is excreted in breast milk. Since a negative effect on infants cannot be ruled out, women taking the drug should stop breastfeeding.

Prograf 1 mg No. 50 capsules

Pharmacodynamics

At the molecular level, the effects of tacrolimus are mediated by binding to the cytosolic protein FKBP12, which is responsible for the intracellular accumulation of the drug. The FKBP12-tacrolimus complex specifically and competitively binds to and inhibits calcinerin, which leads to calcium-dependent inhibition of T-cell signaling transduction pathways, thereby preventing the transcription of a discrete group of lymphokine genes.

Tacrolimus is a highly active immunosuppressive drug: it suppresses the formation of cytotoxic lymphocytes, which are mainly responsible for transplant rejection, reduces the activation of T cells, T-helper-dependent proliferation of B cells, as well as the formation of lymphokines (such as interleukins-2, -3 and γ-interferon), expression of the interleukin-2 receptor.

Indications

Prevention and treatment of liver, kidney and heart allograft rejection, incl. with resistance to standard immunosuppressive therapy regimens.

Contraindications

known hypersensitivity to tacrolimus or other macrolides;
known hypersensitivity to polyoxyethylated hydrogenated castor oil (HCO-60) or structurally related components.

Use during pregnancy and breastfeeding

Since the safety of Prograf® in pregnant women has not been sufficiently established, this drug should not be prescribed to them unless the possible benefit of treatment justifies the potential risk to the fetus.

Women taking Prograf should stop breastfeeding.

Side effects

Cardiovascular system: hypertension, hypotension, tachycardia, angina pectoris, conduction disturbances.
Diseases of the gastrointestinal tract and liver: diarrhea, nausea, vomiting, gastrointestinal dysfunction, abdominal pain, constipation, inflammation and ulcers of the gastrointestinal tract, changes in body weight and appetite.
Blood and lymphatic system: anemia, leukopenia, thrombocytopenia, hemorrhage, leukocytosis, coagulation disorders.
Kidneys: impaired renal function (for example, increased serum creatinine levels), kidney tissue damage, renal failure.
Metabolism and electrolytes: hyperglycemia, hyperkalemia, diabetes mellitus, hypomagnesemia, hyperlipidemia, hypophosphatemia, hypokalemia, hyperuricemia, hypocalcemia, acidosis, hyponatremia, hypovolemia, dehydration.
Musculoskeletal system: seizures, myasthenia gravis, joint diseases.
Nervous/sensory system: tremor, headache, insomnia, sensory disturbance (eg, paresthesia), visual disturbance, confusion, depression, dizziness, agitation, neuropathy, seizures, uncoordination, psychosis, anxiety, nervousness, sleep disturbance, disorder consciousness, emotional lability, hallucinations, hearing impairment, thinking disorder, encephalopathy.
Respiratory system: respiratory dysfunction (eg, shortness of breath), pleural effusion.
Skin: itching, alopecia, rash, sweating, acne, photosensitivity.
Mixed manifestations: localized pain (eg, arthralgia), peripheral edema, asthenia, urinary dysfunction.
Neoplasms: Patients receiving immunosuppressive therapy are at increased risk of developing malignancies.
Hypersensitivity reactions: allergic and anaphylactic reactions.
Infections: in patients receiving tacrolimus, as in treatment with other immunosuppressive drugs, there is an increased risk of developing infectious diseases (viral, bacterial, fungal, protozoal). The course of previously diagnosed infectious diseases may worsen.

Directions for use and doses

Orally, intravenously. If necessary, the contents of the capsules can be dissolved in water and administered through a nasogastric tube.

The dosage of Prograf® must be adjusted depending on the individual needs of the patient, taking into account the results of monitoring drug levels in the patient's blood.

Prograf®, capsules 0.5; 1 and 5 mg

It is recommended to divide the daily oral dose of the drug into 2 doses (for example, morning and evening). Capsules should be taken immediately after removing them from the blister pack. The capsules must be swallowed with liquid (preferably water).

To achieve maximum absorption, capsules should be taken on an empty stomach (on an empty stomach) or at least 1 hour or 2-3 hours after meals.

There was no significant effect of food on the absorption of the drug in patients with a kidney transplant.

Prograf®, concentrate for the preparation of solution for intravenous administration

The concentrate for intravenous administration should be used only after dilution with an appropriate diluent.

Prograf®, concentrate for infusion containing 5 mg/ml, should not be administered undiluted.

Prograf®, concentrate for infusion containing 5 mg/ml, must be diluted with 5% dextrose solution or physiological saline solution in glass, polyethylene or polypropylene vials. Only clear and colorless solutions should be used.

Injection of the drug is not recommended.

The concentration of the solution for infusion should vary between 0.004–0.1 mg/ml. The total volume of infusions over 24 hours should range from 20–500 ml.

Unused infusion concentrate in an open ampoule or unused reconstituted solution should be discarded immediately.

Dosage Recommendations

Liver transplantation

Interactions of the drug Prograf

Pharmacokinetic interactions. Tacrolimus is extensively metabolized by the hepatic microsomal cytochrome P450 3A4 isoenzyme (CYP 3A4). Concomitant use of drugs or herbal products that inhibit or induce CYP 3A4 may affect the metabolism of tacrolimus and reduce or increase tacrolimus blood levels. Tacrolimus affects CYP3A4-dependent metabolism; co-administration of tacrolimus with drugs that are metabolized by CYP 3A4-dependent pathways may affect the metabolism of these drugs (cortisone, testosterone). Tacrolimus is highly bound to plasma proteins. It is necessary to take into account possible interactions with other drugs that have high affinity for blood proteins (NSAIDs, oral anticoagulants or oral antidiabetic drugs). Pharmacodynamic interactions. Concomitant use of tacrolimus with drugs that have nephrotoxic or neurotoxic effects may increase the level of toxicity (aminoglycosides, gyrase inhibitors (type II DNA topoisomerase), vancomycin, co-trimoxazole, NSAIDs, ganciclovir or acyclovir). Since treatment with tacrolimus may be accompanied by the development of hyperkalemia or may worsen pre-existing hyperkalemia, excess potassium intake and the use of potassium-sparing diuretics (amiloride, triamterene or spironolactone) should be avoided. Other interactions. During the use of tacrolimus, the effectiveness of vaccines is reduced and administration of live attenuated vaccines should be avoided. Clinically significant interactions. Drugs marked with an asterisk require tacrolimus dose adjustments in almost all patients. Other drugs listed below may require dosage adjustment in individual cases. Drugs that inhibit CYP 3A4 and increase tacrolimus blood levels: ketoconazole*, fluconazole*, itraconazole*, clotrimazole, voriconazole*; nifedipine, nicardipine; erythromycin*, clarithromycin, josamycin; HIV protease inhibitors; danazol, ethinyl estradiol; omeprazole; calcium channel antagonists such as diltiazem; nefazodone. Drugs that induce CYP 3A4 and reduce tacrolimus blood levels: rifampicin*; phenytoin*; phenobarbital; St. John's wort. Tacrolimus increased phenytoin blood levels. Methylprednisolone both increases and decreases plasma tacrolimus levels. Increased nephrotoxicity has been observed following use of any of the following drugs in combination with tacrolimus: amphotericin B, ibuprofen. The half-life of cyclosporine was increased when administered concomitantly with tacrolimus. In addition, synergistic/additive effects may occur. Given this, the combined use of cyclosporine and tacrolimus is not recommended when prescribing tacrolimus to patients who have previously received cyclosporine. Potential interactions. Substances that inhibit the cytochrome P450 3 A system. Based on the results of in vitro , such substances can be considered as potential metabolic inhibitors: bromocriptine, cortisone, dapsone, ergotamine, gestodene, lidocaine, mephenytoin, miconazole, midazolam, nilvadipine, quinidine, tamoxifen (triacetin) , oleandomycin and verapamil. Substances that induce the cytochrome P450 3 A system : carbamazepine, metamizole, isoniazid. Inhibition by tacrolimus of metabolism mediated by the cytochrome P450 3 A system of other substances. Since tacrolimus may affect the metabolism of steroid contraceptives, special attention should be paid to methods of contraception. Tacrolimus is not stable in an alkaline environment.

Overdose of the drug Prograf, symptoms and treatment

symptoms : tremor, headache, nausea, vomiting, infectious diseases, urticaria, lethargy, increased blood urea nitrogen and serum creatinine concentrations and ALT levels. Treatment. There is no specific antidote. Therapy is symptomatic. Dialysis is not effective. In patients with high plasma drug levels, hemofiltration and diafiltration have been effective in reducing toxic drug concentrations. In cases of intoxication developing after oral administration, gastric lavage and/or taking adsorbents (activated carbon) may help.

special instructions

When starting to use the drug after transplantation, it is necessary to constantly monitor the following parameters: fasting blood glucose level, ophthalmological and neurological status, electrocardiogram, blood pressure, electrolytes (mainly potassium), kidney and liver activity, coagulation parameters, determination of proteins in the blood plasma, clinical blood test parameters. If significant changes are detected, adjustment of immunosuppressive treatment is required.

Due to the potential threat of developing malignant skin tumors during treatment with Prograf, it is necessary to limit ultraviolet radiation and insolation using sunscreens with a high protection factor and appropriate clothing.

If the solution is accidentally introduced into an artery or perivascularly, irritation may occur in the injection area.

To reduce the risk of developing an anaphylactic reaction (due to the presence of polyoxyethylated hydrogenated castor oil in the concentrate), it is recommended to administer the solution at a low speed or use an antihistamine first.

Since tacrolimus is incompatible with polyvinyl chloride (PVC), if it is necessary to administer the contents of the capsules through a nasogastric tube, the latter should not contain polyvinyl chloride. When using Prograf concentrate, syringes, tubing or any other equipment used for the preparation and administration of the drug should also not contain polyvinyl chloride.

If neurological and visual impairments develop during therapy, patients are not recommended to drive vehicles or other complex mechanisms. These negative manifestations may increase when the drug is combined with alcohol.

Storage conditions for the drug Prograf

Capsules: in a dry place in the original packaging at a temperature not exceeding 25 ° C; Shelf life after opening the primary packaging (sealed aluminum bag) is 1 year. Concentrate for the preparation of injection solution: in a place protected from light at a temperature not exceeding 25 °C. After dilution, the drug is stored in glass, polyethylene or polypropylene bottles at a temperature of 2–8 °C. Use the reconstituted concentrate within 24 hours.

List of pharmacies where you can buy Prograf:

Moscow
Saint Petersburg

Release form and composition

Dosage forms of Prograf:

Concentrate for the preparation of a solution for intravenous administration: colorless transparent liquid (1 ml in a clear, colorless glass ampoule (USP type I) with a nominal capacity of 2 ml, with a ring and a dot, 10 ampoules in a plastic blister pack);
5 mg capsules: gelatin, hard, size No. 4, cap and body are grayish-red, opaque, on the cap there is a white overprint “5 mg”, on the body – “[f]657”, the contents of the capsules are white powder (according to 10 pcs in a PVC/aluminum foil blister, 5 blisters with a silica gel bag in a sealed aluminum bag, 1 bag in a cardboard box);
1 mg capsules: gelatin, hard, size No. 5, cap and body are white, opaque, on the cap there is a red imprint “1 mg”, on the body – “[f]617”, the contents of the capsules are white powder (10 pcs. . in a PVC/aluminum foil blister, 5 blisters with a silica gel bag in a sealed aluminum bag, 1 bag in a cardboard box);
Capsules 0.5 mg: gelatin, hard, size No. 5, cap and body are pale yellow, opaque, on the cap there is a red overprint “0.5 mg”, on the body – “[f]607”, capsule contents – white powder (10 pcs. in a PVC/aluminum foil blister, 5 blisters with a silica gel bag in a sealed aluminum bag, 1 bag in a cardboard box).

Composition of 1 ml of concentrate for the preparation of solution for intravenous administration:

Active substance: tacrolimus – 5 mg;
Additional components: anhydrous alcohol and castor oil, hydrogenated polyoxyethylene (HCO-60).

Composition of 1 capsule:

Active substance: tacrolimus – 0.5, 1 or 5 mg;

Additional components: croscarmellose sodium, hydroxypropyl methylcellulose, magnesium stearate, lactose;
Shell: gelatin, titanium dioxide, purified water, yellow iron oxide (0.5 mg capsules), red iron oxide (5 mg capsules).

Pharmacological properties of the drug Prograf

Population

Dosage (mg/kg/day)

Cmax (ng/ml)

Tmax (h)

Bioavailability (%)