Prograf 1mg 50 capsules — Made in Ireland — Free Delivery
(Prograf 1mg )
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Description Prograf 1mg 50 capsules — Made in Ireland — Free Delivery
Indications
Capsules
- prevention of rejection during allotransplantation of the kidney, liver and heart;
- treatment of allograft rejection that is resistant to treatment with other immunosuppressive preparations.
Concentrate for preparation of solution for intravenous administration
Prevention and treatment of liver, kidney and heart allograft rejection.
Treatment of allograft rejection resistant to other modes of immunosuppressive therapy.
Application
Capsules. Prograf preparation therapy requires careful supervision by appropriately qualified and equipped personnel. this preparation can be prescribed and changed in the course of immunosuppressive therapy only by doctors who have experience in conducting immunosuppressive therapy in patients with transplanted organs.
Accidental, unintentional, or uncontrolled preparation changes with immediate or sustained release of tacrolimus are dangerous. This can lead to graft rejection or an increase in the incidence of adverse reactions, including insufficient or excessive immunosuppression, due to clinically significant differences in the systemic exposure of tacrolimus. Patients should follow a single tacrolimus dosage regimen with an appropriate daily dosing schedule; at the same time, a change in the dosage form or mode of application should occur only under the supervision of a transplant specialist (see SPECIAL INSTRUCTIONS, Side Effects). After switching to any other alternative dosage form, it is necessary to monitor the concentration of tacrolimus in the blood and make dose adjustments to maintain systemic exposure of tacrolimus at an adequate level.
General information
The dose of Prograf should be determined primarily on the basis of a clinical assessment of the risk of rejection and individual tolerance of the preparation, taking into account the data from monitoring the level of tacrolimus in the blood (see recommendations for determining the minimum concentration in the blood). When clinical symptoms of rejection appear, consideration should be given to the need to correct the regimen of immunosuppressive therapy.
Prograf can be used intravenously and orally, the dosage can be started with oral administration. In general, you can start with oral administration, if necessary, the contents of the capsules should be dissolved in water and administered through a nasogastric tube.
In the initial postoperative period, Prograf should usually be used concurrently with other immunosuppressive preparations. The dose of Prograf can be changed depending on the selected immunosuppressive therapy.
Mode of application
It is recommended to divide the daily oral dose into 2 doses (morning and evening). The capsules should be taken immediately after removing them from the blister pack. The capsules are swallowed with a liquid (preferably water). To achieve maximum absorption, the preparation should be taken on an empty stomach or at least 1 hour before or 2-3 hours after a meal.
To prevent graft rejection, the state of immunosuppression must be maintained constantly; therefore, the duration of therapy is limited.
Liver transplant
Prevention of transplant rejection. Adults. Oral therapy with Prograf is started at a dose of 0.1–0.2 mg / kg of body weight 2 times a day (morning and evening). The use of the preparation should be started 12 hours after the completion of the operation. If the patient's condition does not allow taking the preparation orally, inject intravenously infusion over 24 hours at a dose of 0.01–0.05 mg / kg / day.
Prevention of transplant rejection. Children. The initial dose of the preparation for oral administration of 0.3 mg / kg of body weight per day is divided into 2 doses (morning and evening). If the patient's clinical condition does not allow taking the preparation inside, administer by infusion over 24 hours at a dose of 0.05 mg / kg / day.
Supportive therapy. Adults and children. During maintenance therapy, the dose of Prograf is reduced. In some cases, preparations of concomitant immunosuppressive therapy are canceled, leaving Prograf as monotherapy. Improvement of the patient's condition after transplantation may alter the pharmacokinetics of tacrolimus, therefore, there is a need for dose adjustment of the preparation.
Rejection treatment. Adults and children. For the treatment of rejection, higher doses of Prograf are used together with additional GCS therapy and short courses of mono- or polyclonal antibodies. If signs of toxicity are detected (see SIDE EFFECTS), it may be necessary to reduce the dose of Prograf. When transferring patients to Prograf therapy, the same initial doses are recommended as for primary immunosuppression. When switching patients from cyclosporine therapy to Prograf, see Special Populations, Conversion from cyclosporine to tacrolimus.
Kidney transplant
Prevention of transplant rejection. Adults Oral therapy with Prograf is started at a dose of 0.2–0.3 mg / kg body weight 2 times a day (morning and evening). The use of the preparation should be started within 24 hours after the completion of the operation. If the patient's condition does not allow taking the preparation orally, inject it intravenously by infusion over 24 hours at a dose of 0.05-0.1 mg / kg / day.
Prevention of transplant rejection. Children. The initial dose of the preparation for oral administration of 0.3 mg / kg of body weight per day is divided into 2 doses (morning and evening). If the patient's clinical condition does not allow taking the preparation inside, administer by infusion over 24 hours at a dose of 0.075–0.1 mg / kg / day.
Supportive therapy. Adults and children. During maintenance therapy, the dose of Prograf is reduced. In some cases, preparations of concomitant immunosuppressive therapy are canceled, leaving Prograf as monotherapy. Improvement of the patient's condition after transplantation may alter the pharmacokinetics of tacrolimus, therefore, there is a need for dose adjustment of the preparation.
Rejection treatment. Adults and children. For the treatment of rejection, higher doses of Prograf are used together with additional GCS therapy and short courses of mono- or polyclonal antibodies. If signs of toxicity are detected (see SIDE EFFECTS), it may be necessary to reduce the dose of Prograf. When transferring patients to Prograf therapy, the same initial doses are recommended as for primary immunosuppression. When switching patients from cyclosporine therapy to Prograf, see Special Populations, Conversion from cyclosporine to tacrolimus.
Heart transplant
Prevention of transplant rejection. Adults. Prograf can be used concurrently with antibody induction (taking into account the delayed initiation of Prograf therapy) or without antibodies in clinically stable patients. After induction with antibodies, oral therapy with Prograf is started with a dose of 0.075 mg / kg / day, divided into 2 doses (morning and evening). The use of the preparation should be started within 5 days after the completion of the operation, as soon as the patient's clinical condition stabilizes. If the patient's condition does not allow taking the preparation inside, it is administered intravenously by infusion over 24 hours at a dose of 0.01–0.02 mg / kg / day.
There is an alternative approach in which oral administration of tacrolimus is started within 12 hours after transplantation. This approach is intended for patients without evidence of impaired visceral (kidney) function. In this case, tacrolimus at an initial dose of 2–4 mg / day is combined with mycophenolate mofetil and corticosteroids or sirolimus and corticosteroids.
Prevention of transplant rejection. Children. After heart transplantation in children, primary immunosuppression with Prograf can be performed both in combination with antibody induction or independently.
In cases where antibody induction is not performed, Prograf is administered as an intravenous infusion for 24 hours at a dose of 0.03–0.05 mg / kg / day until the concentration of tacrolimus in undiluted blood is 15–25 ng / ml. At the first clinical opportunity, it is necessary to transfer the patient to oral administration of the preparation at an initial dose of 0.3 mg / kg / day, which is prescribed 8–12 hours after the end of the intravenous infusion.
After induction with antibodies, oral therapy with Prograf begins with a dose of 0.1–0.3 mg / kg / day, divided into 2 doses (morning and evening).
Supportive therapy. Adults and children. With maintenance therapy, the dose of Prograf is reduced. Improvement of the patient's condition after transplantation may alter the pharmacokinetics of tacrolimus, therefore, there is a need for dose adjustment of the preparation.
Rejection treatment. Adults and children. For the treatment of rejection, it is necessary to use higher doses of Prograf together with additional corticosteroids therapy and short courses of mono- or polyclonal antibodies. When transferring adult patients to Prograf therapy, the initial dose of the preparation 0.15 mg / kg / day is divided into 2 doses (morning and evening). When children are transferred to Prograf therapy, the initial dose of the preparation 0.2-0.3 mg / kg / day is also divided into 2 doses (morning and evening).
For the transfer of patients from cyclosporine therapy to Prograf, see SPECIAL INSTRUCTIONS.
Rejection Treatment - Other Organ Transplant
Recommended doses for lung, pancreas, and bowel transplants are based on limited data from prospective clinical studies. Treatment of patients with lung transplantation with Prograf should be started with a dose of 0.1-0.15 mg / kg / day, patients with pancreatic transplantation should be started with a dose of 0.2 mg / kg / day, and with pancreas transplantation, treatment should be started with a dose of 0 , 3 mg / kg / day.
Special populations
Liver failure. In patients with severely impaired liver function, tacrolimus dose reduction may be required to maintain a minimum blood tacrolimus level within the recommended therapeutic range.
Renal failure Since renal function does not affect pharmacokinetic monitoring of renal function (including indicators of creatinine concentration in blood plasma, calculation of creatinine clearance and monitoring of urine output).
Elderly patients. There is no information that special doses are needed in elderly patients.
Conversion (transition) from cyclosporine to tacrolimus. Care should be taken when transferring patients with basic therapy with cyclosporine to preparations with basic therapy with tacrolimus (see SPECIAL INSTRUCTIONS and INTERACTIONS). Start the therapy with the preparation Prograf after determining the concentration of cyclosporine in the blood plasma and analyzing the clinical condition of the patient. Conversion should be postponed if plasma levels of cyclosporine are elevated. In practice, therapy with Prograf begins 12-24 hours after the discontinuation of cyclosporine. After the transition, it is recommended to control the level of cyclosporine in the blood, since it is possible to influence the clearance of cyclosporine in the blood plasma.
Recommendations for achieving the required level of preparation concentration in undiluted blood. The choice of the dose of the preparation should be based on the results of the clinical assessment of the process of rejection and the tolerance of the preparation by each patient individually.
In order to optimize the dose, the determination of the concentration of tacrolimus in undiluted blood using immune methods, including the semi-automatic enzyme-linked immunosorbent assay (MICA), is used. Comparison of published literature data on tacrolimus blood concentration with individual clinical parameters is done with caution and based on knowledge and understanding of the assessment method used. In modern medical practice, immune methods are used to determine the concentration of tacrolimus in undiluted blood.
In the early period after surgery, tacrolimus levels in undiluted blood should be monitored. For oral administration, trough levels of tacrolimus in undiluted blood should be monitored every 12 hours immediately before the next dose. The frequency of monitoring the level of the preparation in the blood should depend on the clinical need. Since Prograf is a preparation with a low level of clearance, adjusting the dosage regimen may take several days before changes in blood levels of the preparation become apparent. The minimum blood levels of the preparation should be monitored approximately 2 times a week during the early post-transplant period, and then periodically during maintenance therapy. It is also necessary to monitor the minimum blood levels of tacrolimus after changing the dose of the preparation, immunosuppressive regimen, or after concomitant use with preparations that may affect the concentration of tacrolimus in undiluted blood (see INTERACTIONS).
Clinical studies suggest that most patients can be successfully treated if trough blood levels of tacrolimus are maintained below 20 ng / mL. When interpreting data on the concentration of the preparation in undiluted blood, it is important to assess the clinical condition of the patient.
In clinical practice, during the early period after transplantation, the minimum levels of the preparation in undiluted blood usually ranged from 5–20 ng / ml after liver transplantation and 10–20 ng / ml after kidney and heart transplantation. Further, with maintenance therapy after liver, kidney and heart transplantation, the preparation concentration in the blood varies from 5 to 15 ng / ml.
Concentrate for preparation of solution for intravenous administration. Treatment with Prograf requires careful monitoring, which is carried out by highly qualified personnel and using appropriate equipment. Prescribing this preparation and making changes to immunosuppressive therapy can only be a doctor who has experience in conducting immunosuppressive therapy in patients with transplanted organs.
The preparation is administered parenterally if the patient's condition does not allow taking capsules. As soon as the patient's clinical condition improves, he is transferred to oral administration of the preparation in the form of Prograf capsules.
The duration of intravenous therapy should not exceed 7 days.
After transferring a patient from parenteral to oral administration in the form of tacrolimus capsules, it should be borne in mind that in practice errors have been noted in the use of tacrolimus preparations. Accidental, unintentional or uncontrolled transfer of a patient from one oral dosage form of tacrolimus (standard or long-acting) to another is dangerous. This can lead to graft rejection or an increased incidence of side effects, including insufficient or excessive immunosuppression, due to the corresponding clinical differences in systemic exposure to tacrolimus.
The patient should be prescribed tacrolimus as a single dosage form with an appropriate daily dosing regimen, modified by the transplant specialist. For the subsequent transition to any other alternative dosage forms, it is necessary to monitor the effect of the preparation and adjust the dose to comply with systemic exposure to tacrolimus.
General information. The recommended dosages for the initial stage of treatment are presented below as recommendations. The dosage of the Prograf preparation should be based mainly on a clinical assessment of the risk of rejection and the individual tolerance of the preparation in each patient, as well as on the data of monitoring the concentration of tacrolimus in the blood (see SPECIAL INSTRUCTIONS, recommendations for achieving the required level of preparation concentration in undiluted blood).
When clinical indicators of rejection appear, it is worth considering the possibility of correcting the immunosuppressive therapy regimen.
Prograf should be used parenterally or orally. In general, dosing can be started orally, if necessary by applying the contents of the capsule, dissolved in water, through the nasogastric tube.
Prograf is usually used in combination with other immunosuppressive preparations at the initial postoperative stage. The dosage of the preparation Prograf may differ depending on the selected immunosuppressive regimen.
Prograf concentrate for the preparation of a solution for intravenous administration is used only intravenously. Do not administer the preparation undiluted. Before use, it must be diluted with 5% glucose solution or 0.9% sodium chloride solution in glass, polyethylene or polypropylene vessels. Only transparent and colorless solutions should be used.
Jet injection of the preparation is not recommended!
The concentration of the solution for infusion should vary within the range of 0.004–0.1 mg / ml. The total volume of infusion in 24 hours should be in the range of 20-500 ml.
Unused concentrate for infusion in an open ampoule or unused reconstituted solution must be discarded immediately to avoid contamination (contamination).
Liver transplant
Prevention of transplant rejection. Adults. The use of the preparation should be started approximately 12 hours after the completion of the operation.
If the patient's condition does not allow taking the preparation inside (Prograf capsules), therapy is carried out starting at a dose of 0.01-0.05 mg / kg / day, injecting the preparation as an intravenous infusion for 24 hours.
Prevention of transplant rejection. Children. If the patient's condition does not allow taking the preparation inside (Prograf capsules), therapy is carried out starting with a dose of 0.05 mg / kg / day as an intravenous infusion for 24 hours.
Supportive therapy. Adults and children. During maintenance therapy, the dose of Prograf is usually reduced. In some cases, it is possible to cancel the preparations of concomitant immunosuppressive therapy, using Prograf as monotherapy. Improvement of the patient's condition after transplantation may alter the pharmacokinetics of tacrolimus, therefore, there is a need for dose adjustment of the preparation.
Rejection treatment. Adults and children. For the treatment of rejection, it is necessary to use the preparation Prograf in higher doses together with additional corticosteroids therapy and short courses of mono- / polyclonal antibodies. If signs of toxicity occur, the dose of Prograf may be reduced.
When transferring patients to therapy with Prograf, the same initial doses are recommended as in the prevention of immunosuppression. When transferring patients from cyclosporine therapy to Prograf, see SPECIAL INSTRUCTIONS, preparation dose adjustment in special patient groups, Transferring from cyclosporine therapy.
Kidney transplant
Prevention of transplant rejection. Adults. Therapy should be started within 24 hours after the completion of the operation.
If the patient's condition does not allow taking the preparation inside (Prograf capsules), IV therapy should be started with a dose of 0.05–0.1 mg / kg / day, administering the preparation as an IV infusion for 24 hours.
Prevention of transplant rejection. Children. If the patient's condition does not allow taking the preparation inside (Prograf capsules), intravenous therapy should be started with a dose of 0.075-0.1 mg / kg / day, administering the preparation as an intravenous infusion for 24 hours.
Supportive therapy. Adults and children. During maintenance therapy, the doses of Prograf are reduced. In some cases, it is possible to cancel the preparations of concomitant immunosuppressive therapy, leaving Prograf as the basic component of dual therapy. Improvement of the patient's condition after transplantation may alter the pharmacokinetics of tacrolimus, therefore, there is a need for dose adjustment of the preparation.
Treatment of rejection reactions. Adults and children. For the treatment of rejection, it is necessary to use the preparation Prograf in higher doses together with additional corticosteroids therapy and short courses of mono- / polyclonal antibodies. If signs of toxicity occur, the dose of Prograf may be reduced.
When transferring patients to therapy with Prograf, it is recommended to adjust the dose of the preparation in special groups of patients, Transfer from therapy with cyclosporine.
Heart transplant
Prevention of transplant rejection. Adults. Prograf should be used in conjunction with antibody induction (taking into account the delayed initiation of therapy with Prograf). After induction with antibodies, the preparation should be taken within 5 days after the completion of the operation, as soon as the patient's clinical condition is stabilized. If the patient's condition does not allow taking the preparation inside (Prograf capsules), it is necessary to carry out intravenous therapy, starting with a dose of 0.01-0.02 mg / kg / day, administering the preparation as an infusion over 24 hours.
Prevention of transplant rejection. Children. After heart transplantation in children, primary immunosuppression with Prograf can be performed both together with antibody induction or independently.
In cases where antibody induction is not performed, Prograf should be administered intravenously at an initial dose of 0.03–0.05 mg / kg / day, administering the preparation as an infusion for 24 hours until the concentration of tacrolimus in undiluted blood is 15– 25 ng / ml. At the first clinical opportunity, it is necessary to transfer the patient to oral administration of the preparation (Prograf capsules) at an initial dose of 0.30 mg / kg / day, which is prescribed 8–12 hours after the end of the infusion.
Supportive therapy. Adults and children. During maintenance therapy, the doses of Prograf are reduced. Improvement of the patient's condition after transplantation may alter the pharmacokinetics of tacrolimus, therefore, there is a need for dose adjustment of the preparation.
Rejection treatment. Adults and children. For the treatment of rejection, it is necessary to use the preparation Prograf in higher doses together with additional corticosteroids therapy and short courses of mono- / polyclonal antibodies.
When transferring adult patients to oral therapy with Prograf capsules, the initial dose of 0.15 mg / kg / day is divided into 2 doses (morning and evening).
When children are transferred to oral therapy with Prograf capsules, the initial dose of 0.2–0.3 mg / kg / day should be divided into 2 doses (morning and evening).
Information on the transfer of patients from cyclosporine therapy to Prograf is described in the SPECIAL INSTRUCTIONS section, preparation dose adjustment in special patient groups. Transition from cyclosporine therapy.
Contraindications
Hypersensitivity to tacrolimus (or other macrolides) and other inactive ingredients of the preparation.
Side effects
Due to the peculiarities of the underlying disease and the large number of preparations used simultaneously after transplantation, the profile of the side effects of immunosuppressants is difficult to establish accurately.
Many of the side effects listed below are reversible and / or dose dependent. In each group, adverse reactions are listed in order of decreasing severity. With oral administration of the preparation, there are fewer cases of adverse reactions compared with intravenous administration.
Adverse reactions are classified by organs and systems, are given below depending on the frequency of occurrence: very often (1/10); often (1/100, but 1/10); infrequently (1/1000, but 1/100); rarely (1/10 000, but 1/1000); very rare (1/10 000), unknown (not enough data to establish the frequency).
From the side of the vessels: very often - AH; often - bleeding, thromboembolic and ischemic complications, impaired peripheral circulation, arterial hypotension; infrequently - heart attack, deep vein thrombosis of the extremities, shock.
From the side of the heart: often - ischemic coronary disorders, tachycardia; infrequently - ventricular arrhythmia and cardiac arrest, heart failure, cardiomyopathy, ventricular hypertrophy, supraventricular arrhythmia, tachycardia, ECG changes, disturbed rhythm, heart rate and pulse, pericarditis; rarely, pericardial effusion; very rarely - a change in echocardiography.
From the digestive system: very often - diarrhea, nausea; often - inflammatory diseases of the gastrointestinal tract, the occurrence of ulcers and perforation of the gastrointestinal tract, gastrointestinal bleeding, stomatitis and the formation of ulcers of the oral mucosa, ascites, vomiting, abdominal pain, dyspepsia, constipation, flatulence, a feeling of bloating and distention in the abdomen, diarrhea; infrequently - paralytic intestinal obstruction (paralytic ileus), peritonitis, acute and chronic pancreatitis, increased amylase levels in the blood plasma, gastroesophageal reflux disease, impaired gastric evacuation function; rarely - partial intestinal obstruction (subileus), pancreatic pseudocyst.
On the part of the hepatobiliary system: often - an increase in the level of liver enzymes, abnormal liver function, cholelithiasis and jaundice, damage to liver cells and hepatitis, cholangitis; rarely - thrombosis of the hepatic artery, obliterating endophlebitis of the hepatic veins; very rarely - liver failure, bile duct stenosis.
On the part of the blood and lymphatic system: very often - leukocytosis; often - anemia, leukopenia, thrombocytopenia, leukocytosis, changes in eamma, pancytopenia, neutropenia; rarely - thrombotic thrombocytopenic purpura, hypoprothrombinemia; unknown - myasthenic crisis, interstitial pneumonia.
From the urinary system: very often - impaired renal function, increased concentration of creatinine, pN-microglobulin, increased N-acetyl-beta-D-glucosaminidase in urine, proteinuria; often - renal failure, acute renal failure, oliguria, acute tubular necrosis, toxic nephropathy, urinary syndrome, disorders of the bladder and urethra; infrequently - anuria, hemolytic uremic syndrome; very rarely - nephropathy, hemorrhagic cystitis.
From the side of metabolism and digestion: very often - hyperglycemia, diabetes mellitus, increased levels of glycosylated hemoglobin, hyperuricemia, hypomagnesemia, hyperkalemia; often - hypomagnesemia, hypophosphatemia, hypokalemia, hypocalcemia, hyponatremia, glucosuria, hypervolemia, hyperuricemia, loss of appetite, anorexia, metabolic acidosis, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, electrolyte disturbances; infrequently - dehydration, hypoproteinemia, hyperphosphatemia, hypoglycemia.
From the musculoskeletal system and connective tissue: often - arthralgia, muscle cramps, pain in the limbs, back pain; infrequently - joint disorders.
From the nervous system: very often - tremor, headache; often - impaired consciousness, paresthesia and dysesthesia, peripheral neuropathy, dizziness, dysgraphia, dysfunction of the nervous system; infrequently - coma, cerebral hemorrhage and cerebrovascular accident, paralysis and paresis, encephalopathy, speech and articulation disorders, amnesia; rarely - increased muscle tone; very rarely - myasthenia gravis.
From the respiratory system and mediastinal organs: very often - nasopharyngitis; often - shortness of breath, pulmonary disorders, pleural effusion, pharyngitis, cough, nasal congestion, rhinitis; infrequently - respiratory failure, respiratory disorders, asthma; rarely, acute respiratory distress syndrome.
On the part of the skin and subcutaneous tissue: often - itching, rash, alopecia, acne, hyperhidrosis; infrequently - dermatitis, photosensitivity; rarely - toxic epidermal necrolysis (Lyell's syndrome); very rarely - Stevens-Johnson syndrome.
General disorders and complications: often - asthenia, fever, edema, pain and discomfort, an increase in the level of alkaline phosphatase in the blood plasma, an increase in body weight, a violation of thermoregulation; infrequently - multiple organ failure, flu-like syndrome, impaired thermal sensitivity, a feeling of compression in the chest cavity, anxiety, deterioration of health, an increase in the level of LDH in the blood plasma, a decrease in body weight; rarely - thirst, loss of balance (falling), difficulty in movement; very rarely - an increase in adipose tissue mass.
Benign, malignant and unidentified neoplasms: infrequently / often - lymphoma or other malignant tumor; patients receiving immunosuppressive therapy have a higher risk of malignant tumors; with the use of tacrolimus, the occurrence of both benign and malignant neoplasms was noted, including the Epstein-Barr virus (EBV) -associated lymphoproliferative diseases and skin cancer.
From the side of the immune system (allergic reactions): in patients taking tacrolimus, allergic and anaphylactic reactions were noted (see SPECIAL INSTRUCTIONS).
From the side of the immune system (infections and invasions): against the background of tacrolimus therapy, like other immunosuppressants, the risk of developing local and generalized infectious diseases (viral, bacterial, fungal, protozoal) increases. The course of previously diagnosed infectious diseases may worsen.
Cases of BK virus-associated nephropathy, as well as progressive multifocal leukoencephalopathy associated with JC-virus, were noted against the background of immunosuppressive therapy, including Prograf therapy.
From the endocrine system: rarely - hirsutism.
From the side of the organ of vision: often - blurred vision, photophobia, eye diseases; infrequently - cataract; rarely, blindness.
On the part of the organ of hearing and balance: often - tinnitus; infrequently - hearing loss; rarely - sensorineural hearing loss; very rarely - hearing impairment.
Injury, poisoning, complications of procedures: often - primary graft dysfunction.
From the reproductive system and breast: infrequently - dysmenorrhea and uterine bleeding.
From the side of the psyche: very often - insomnia; often - anxiety, confusion and disorientation, depression, depressed mood, emotional disturbances, nightmares, hallucinations; infrequently - psychotic disorders.
Special instructions
Correction of the dose of the preparation in special groups of patients
Patients with hepatic impairment. Patients with impaired futacrolimus in blood plasma.
In patients with severe hepatic impairment, it may be necessary to reduce the dose in order to maintain the minimum level of the preparation within the recommended gradation.
Patients with renal impairment. Since the pharmacokinetics of tacrolimus do not change with renal function, dose adjustment is not required. However, due to the nephrotoxic effect of tacrolimus, it is recommended to carefully monitor renal function (including plasma creatinine concentration, creatinine clearance and urine output).
Use in the elderly. Due to the fact that elderly patients have reduced renal and hepatic function, as well as the function of the immune and other systems, it is necessary to prescribe the preparation to this category of patients with extreme caution, regularly monitoring the patient's condition. In elderly patients with rheumatoid arthritis, treatment should be started with low doses (1.5 mg once a day).
Transition from cyclosporine therapy. The concomitant use of cyclosporine and Prograf can lengthen the T½ of cyclosporine and increase the toxic effects. Therefore, care must be taken when transferring patients from cyclosporine to Prograf therapy. Treatment with Prograf begins after assessing the concentration of cyclosporine in the patient's blood and his clinical condition. The preparation is stopped when the level of cyclosporine in the blood is elevated. In practice, treatment with Prograf was started 12-24 hours after cessation of cyclosporine. After the patient is transferred to Prograf therapy, it is necessary to continue monitoring the level of cyclosporine in his blood due to the possibility of impaired cyclosporine clearance.
Recommendations for achieving the required level of preparation concentration in undiluted blood. The choice of the dose of the preparation should be based on the results of the clinical assessment of the process of rejection and the tolerance of the preparation by each patient individually. To optimize the dosage of the preparation, the determination of the concentration of tacrolimus in undiluted blood using immune methods, including the semi-automatic enzyme-linked immunosorbent assay (MICA), is used. Comparison of data on the concentration of tacrolimus in the blood, published in the literature, with individual clinical parameters is carried out on the basis of the applied assessment method.
In the early period after surgery, the minimum level of tacrolimus in undiluted blood is monitored. For oral administration, to determine the minimum level of the preparation in the blood, it is necessary to obtain blood samples 12 hours after taking it, immediately before using the next dose. The frequency of monitoring the level of the preparation in the blood depends on the clinical need. Since Prograf is a preparation with a low level of clearance, dosage adjustments may take several days before changes in the level of the preparation in the blood become apparent. The minimum blood level of the preparation is monitored 2 times a week during the early post-transplant period and periodically during maintenance therapy. It is also necessary to monitor the minimum level of tacrolimus in the blood after changing the dose of the preparation, immunosuppressive regimen or after simultaneous use with preparations that may affect the concentration of tacrolimus in undiluted blood.
Clinical studies suggest that most patients can be successfully treated if the trough blood tacrolimus level does not exceed 20 ng / ml. When interpreting data on the concentration of the preparation in undiluted blood, it is important to assess the clinical condition of the patient.
In clinical practice, in the early period after transplantation, the minimum level of the preparation in undiluted blood usually ranged from 5–20 ng / ml after liver transplantation and 10–20 ng / ml after kidney and heart transplantation. Later, during maintenance therapy after liver, kidney and heart transplantation, the concentration of the preparation in the blood varies from 5 to 15 ng / ml.
During the initial period after transplantation, it is necessary to regularly monitor the following parameters: blood pressure, ECG, neurological and ophthalmological status, fasting blood glucose, electrolytes (especially potassium), liver and kidney function, CBC parameters, coagulation parameters and protein determination. fractions in blood plasma. If clinically significant changes are detected, correction of immunosuppressive therapy is necessary.
When using Prograf, you should avoid prescribing herbal preparations containing St. John's wort (Hypericum perforatum), as well as other herbal remedies that can cause a decrease (change) in the concentration of tacrolimus in the blood and affect the clinical effect of Prograf.
With diarrhea, plasma tacrolimus levels can vary significantly, so close monitoring of plasma tacrolimus concentrations is necessary.
Cases of hypertrofardiomyopathy were rare, but were observed in patients taking Prograf, and therefore are possible with treatment with this preparation. In most cases, myocardial hypertrophy was reversible and was observed at blood tacrolimus concentrations higher than recommended. Other factors that increase the risk of this side effect include the presence of heart disease, the use of corticosteroids, hypertension, renal and hepatic dysfunction, infections, hypervolemia, edema. Patients belonging to risk groups, as well as receiving intensive immunosuppressive therapy, before and after transplantation (after 3 and 9–12 months) should undergo echocardiography and ECG monitoring. If changes are detected, it is necessary to consider reducing the dose of Prograf or replacing it with another immunosuppressant.
Tacrolimus can cause prolongation of the Q – T interval, while cardiac arrhythmias such as pirouette (bidirectional fusiform ventricular tachycardia) have not been observed. When treating patients with a diagnosed congenital long Q – T interval syndrome or suspicion of such a condition, special care should be taken.
Patients taking tacrolimus may develop post-transplant lymphoproliferative diseases (PTLD) associated with the Epstein-Barr virus (EBV). With the simultaneous use of the preparation with anti-lymphocytic antibodies, the risk of developing PTLD increases. There is also evidence of an increased risk of PTLD in patients with identified Epstein-Barr virus capsid antigen (EBV-VCA). Therefore, before the appointment of Prograf this group of patients should undergo a serological study for EBV-VCA. Careful monitoring of EBV using polymerase chain reaction (PCR) is recommended during treatment. Positive EBV-PCR can persist for months. By itself, it is not a confirmation of the presence of PTLD or lymphoma.
There are reports of the occurrence of a syndrome of reversible posterior encephalopathy during therapy with tacrolimus. If a patient taking tacrolimus develops symptoms characteristic of reversible posterior encephalopathy syndrome - headache, mental disorders, seizures and visual impairments - it is necessary to perform magnetic resonance imaging. When the diagnosis is confirmed, adequate blood pressure control and therapy for seizures should be carried out, as well as urgently discontinue systemic administration of tacrolimus. With the application of these measures, the mentioned condition is completely reversible in most patients.
Patients undergoing immunosuppressive therapy, including Prograf, have an increased risk of opportunistic infections (caused by bacteria, fungi, viruses, protozoa). Among these infections, VK-virus-associated nephropathy and JC-virus-associated progressive multifocal leukoencephalopathy (PML) are noted.
Such infections are most often associated with extensive suppression of the immune system and can lead to severe or fatal consequences, which must be taken into account when conducting differential diagnostics in patients with signs of impaired renal function or neurological symptoms on the background of immunosuppressive therapy.
Immunosuppressive therapy increases the risk of malignant neoplasms. It is recommended to limit sun exposure and ultraviolet radiation, wear appropriate clothing, and use sunscreens with a high protection factor.
The risk of developing secondary cancer is unknown.
Cases of true erythrocyte aplasia were detected in a small number of patients who used tacrolimus. All patients had the following risk factors: comorbidities, parvovirus B19 infection, and combination therapy.
Prograf, a concentrate for the preparation of a solution for intravenous administration, contains polyoxyethylated hydrogenated castor oil, which can cause anaphylactic reactions. The risk of developing an anaphylactic reaction can be reduced if the reconstituted Prograf concentrate is injected at a low rate or if an antihistamine is administered in advance.
If accidentally injected into an artery or perivascularly reconstituted concentrate, Prograf for intravenous injection may cause irritation at the injection site.
Prograf capsules contain lactose, so you should be especially careful when prescribing the preparation to patients with rare hereditary diseases associated with galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.
The printing ink used to mark capsules of the preparation Prograf contains soy lecithin. Patients with hypersensitivity to peanut or soy products should weigh the benefits of using Prograf against the possible risk and severity of hypersensitivity reactions.
Interaction with food. It is noted that grapefruit juice increases the level of tacrolimus in the blood by inhibiting the activity of CYP 3A4. During treatment, you should not consume alcoholic beverages.
During pregnancy and breastfeeding. Pregnancy. Preclinical results in humans indicate that the preparation can cross the placenta. There are reports of preterm birth (37 weeks), as well as cases of self-regressive hyperkalemia in infants (8 out of 111 (7.2%) infants). Since the safety of using tacrolimus during pregnancy has not been fully established, the preparation should not be prescribed to pregnant women, unless the intended benefit of treatment justifies the potential risk to the fetus. In order to identify potential adverse reactions when using tacrolimus, it is recommended to monitor the condition of infants whose mothers took tacrolimus during pregnancy (in particular, renal function).
Lactation. Based on clinical experience, tacrolimus passes into breast milk. Since it is impossible to exclude the adverse effect of tacrolimus on an infant, women taking Prograf should stop breastfeeding.
Fertility The negative effect of tacrolimus on fertility in male rats was established, and a decrease in the number of spermatozoa and their motility was noted.
Children. To achieve a similar level of the preparation in the blood of children, the adult dose should be increased 1.5–2 times.
The ability to influence the reaction rate when driving and working with other mechanisms. Tacrolimus can cause visual and neurological impairment. Patients who develop such disorders should not drive vehicles or operate machinery. This effect can increase with the simultaneous administration of Prograf and the use of alcohol.
Interactions
Pharmacokinetic interactions. tacrolimus is largely metabolized by the hepatic microsomal cytochrome p450 3a4 isoenzyme (cyp 3a4). concomitant use of preparations or herbal products that inhibit or induce cyp 3a4 may affect tacrolimus metabolism and decrease or increase blood levels of tacrolimus.
Tacrolimus affects CYP 3A4-dependent metabolism; the simultaneous use of tacrolimus with preparations that are metabolized by CYP 3A4-dependent pathways can affect the metabolism of these preparations (cortisone, testosterone).
Tacrolimus is highly associated with blood plasma proteins. Consideration should be given to possible interactions with other preparations that have a high affinity for blood proteins (NSAIDs, oral anticoagulants, or oral antidiabetic preparations).
Pharmacodynamic interactions. Concomitant use of tacrolimus with preparations with nephrotoxic or neurotoxic effects may increase the level of toxicity (aminoglycosides, gyrase inhibitors (DNA topoisomerase II), vancomycin, co-trimoxazole, NSAIDs, ganciclovir, or acyclovir).
Because tacrolimus treatment may be associated with the development of hyperkalemia or may exacerbate preexisting hyperkalemia, the following should be avoided:
- excessive intake of potassium,
- the use of potassium-sparing diuretics (for example, amiloride, triamterene or spironolactone).
Other interactions. During the use of tacrolimus, the effectiveness of vaccines decreases and it is necessary to avoid the administration of live attenuated vaccines (for example, inactivated influenza A vaccine, etc.).
Clinically significant interactions. The following interactions of tacrolimus with concomitant medications have been observed in clinical trials. The basic interaction mechanism is known. Preparations marked with an asterisk require tacrolimus dose adjustments in virtually all patients. Other preparations listed below may require dose adjustment in some cases.
Preparations that inhibit CYP 3A4 and increase blood levels of tacrolimus:
- ketoconazole, fluconazole, itraconazole, clotrimazole, voriconazole;
- nifedipine, nicardipine;
- erythromycin, clarithromycin, josamycin;
- inhibitors of HIV proteases;
- danazol, ethinyl estradiol;
- omeprazole;
- calcium channel antagonists such as diltiazem;
- nefazodone.
Preparations that induce CYP 3A4 and lower blood levels of tacrolimus:
- rifampicin;
- phenytoin;
- phenobarbital;
- St. John's wort.
Tacrolimus increased blood levels of phenytoin. It was noted that methylprednisolone both increased and decreased plasma levels of tacrolimus. There has been an increase in nephrotoxicity after using any of the following preparations in conjunction with tacrolimus:
- amphotericin B;
- ibuprofen.
It has been shown that the T1 / 2 of cyclosporine increased when used concomitantly with tacrolimus. In addition, synergistic / additive effects may develop. Given these reasons, 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 CYP 3A4 system. Based on the results of in vitro studies, such substances can be considered as potential inhibitors of mefenytoin, miconazole, midazolam, nilvadipine, quinidine, tamoxifen (triacetin), oleandomycin and verapamil.
Substances inducing the cytochrome CYP 3A4 system: carbamazepine, metamizole, isoniazid.
Inhibition by tacrolimus of metabolism mediated by the cytochrome CYP 3A4 system and other substances. Since tacrolimus can interfere with the metabolism of steroidal contraceptives, special attention should be paid to contraceptive methods.
Tacrolimus is not stable in an alkaline environment. Avoid the use of Prograf, a concentrate for the preparation of a solution for intravenous administration, with other rpreparations that substantially alkalize the solution (for example, acyclovir and gacyclovir).
Incompatibility. Tacrolimus is absorbed into PVC plastic. Tubes, syringes and other equipment used for the preparation and administration of the preparation Prograf concentrate for the preparation of a solution for intravenous injection, containing 5 mg / ml, should not contain polyvinyl chloride.
Overdose
Clinical experience with overdose treatment is limited. there were several cases of accidental preparation overdose, while the following symptoms were observed: tremor, headache, nausea, vomiting, infections, urticaria, lethargy, an increase in blood urea nitrogen and an increase in serum creatinine concentrations, an increase in alat levels.
There is no specific antidote for Prograf. In case of overdose, it is necessary to carry out standard supportive and symptomatic therapy.
Due to the high molecular weight, poor water solubility and binding to red blood cells and to a large extent to blood plasma proteins, dialysis is not expected to be effective in overdose of tacrolimus. In selected patients with very high plasma levels of the preparation, hemofiltration and diafiltration were effective in reducing toxic preparation concentrations. With the development of intoxication after oral administration of the preparation, gastric lavage and / or the use of adsorbents (activated carbon) may help.
Storage conditions
Capsules: in a dry place in their original packaging at a temperature not exceeding 25 ° С; shelf life after opening the primary packaging (sealed aluminum bag) - 1 year.
Concentrate for the preparation of the solution: in a dark place at a temperature not exceeding 25 ° C.
After dilution, the solution is stored at a temperature of 2–8 ° C for 24 hours in glass, polyethylene or polypropylene containers.
ALL / 2017/0003 / UA / Dec / 2017 / Morion / 15000
Tags: Prograf
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