Composition, form of production and packaging
Tablets, film-coated 1 tab.
mycophenolate mofetil 500 mg
10 pieces. - packings cellular planimetric (3) - packs cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2010.
PHARMACHOLOGIC EFFECT
Immunosuppressant, inhibitor of inosine monophosphate dehydrogenase
Mycophenolate mofetil (MMF) is a 2-morpholinoethyl ester, which is a prodrug of immunosuppressive mycophenolic acid (MPA), which is produced by several species of the genus Penicillium. The mechanism of IFC action is oppression of purine synthesis. IFC is a reversible noncompetitive inhibitor of inosine monophosphate dehydrogenase, an enzyme that participates in the conversion of inoinomonophosphate (IMP) to xanthosine monophosphate, which is a precursor of guanosine nucleotides. This results in a blockade in the synthesis of de novo guanosine nucleotides, which are indispensable substrates for the synthesis of DNA and RNA. Unlike other cells that can use guanosine synthesis bypasses, B- and T-lymphocytes depend on the synthesis of guanosines de novo.
PHARMACOKINETICS
Mycophenolate mofetil is rapidly absorbed from the digestive tract after ingestion and becomes an active metabolite of the IFC. IFC is further converted to gluconuride MFC (HMFC), which is pharmacologically inactive. After oral administration, the average relative bioavailability of MPA is 94%. C max in plasma is achieved approximately 2 hours after ingestion. The observed secondary peak plasma concentrations are due to enterohepatic recirculation of this drug. The food reduces the C max of the MPC by about 40%, but does not affect the AUC. The degree of binding of MPC to plasma albumin depends on its concentration. The binding of IFC to plasma proteins does not depend on the presence of widely used immunosuppressants, such as cyclosporine, prednisone and tacrolimus. The binding of IFC to proteins is also not affected by other widely used drugs, such as warfarin, digoxin and phenytoin. IFC is minimally bound to plasma lipoproteins, and this binding is independent of its concentration. IFC is converted into GMPA and three other inactive metabolites: N- (2-carboxymethyl) -morpholine, N- (2-hydroxyethyl) -morpholine and N-oxide of M- (2-hydroxyethyl) -morpholine. Alcoholic cirrhosis of the liver, in all likelihood, does not have a significant effect on the conversion of IFC into HMFC. IFC is eliminated mainly by the kidneys, and more than 90% of the dose is excreted in the urine in the form of HMFC. After oral administration, the average apparent T 1/2 and clearance from the plasma of mycophenolic acid are 17.9 hours and 11.6 l / h, respectively. After taking a single dose of mycophenolate mycophenolate mofetil AUC, IFC increased almost twice in patients with severe renal dysfunction.
Hemodialysis does not have a significant effect on plasma concentrations of IFC and HMFC. However, at higher concentrations of IFPC (> 100 Ојg / ml), some of it can be removed.
INDICATIONS
- allogeneic grafts: to prevent organ rejection in recipients of allogeneic grafts of the kidneys, liver or heart. Mycophenolate mofetil is used in combination with cyclosporine and corticosteroids.
DOSING MODE
Kidney transplantation: 1 g per day is given orally 2 times / day (daily dose of 2 g). In clinical studies, a dose of 1.5 g 2 times / day (daily dose of 3 g) was used which proved safe and effective, but in recipients of renal transplants such an increase dose was not accompanied by an increase in the effectiveness of immunosuppressive therapy. In general, in patients who received 2 g / day, the safety profile was better than those who received 3 g / day.
Heart transplantation: The recommended dose is 1.5 g orally 2 times / day (daily dose of 3 g).
Liver transplantation: the recommended dose is 1.5 g orally 2 times / day. The patient should be given the first oral dose as soon as possible after transplantation. It is shown that food reduces the experience of IFC by about 40%, and therefore it is recommended to take mycophenolate mofetil on an empty stomach.
In elderly and senile patients (? 65 years) who underwent kidney transplantation, the recommended dose is 1 g 2 times / day, and after heart or liver transplantation - 1.5 g 2 times / day.
SIDE EFFECT
The main side effects of mycophenolate mofetil are diarrhea, leukopenia, sepsis and vomiting, as well as an increased incidence of certain infections.
Rare cases of such serious life-threatening infections as meningitis and infective endocarditis are described, in addition, there was an increase in the incidence of such serious infections as tuberculosis and atypical mycobacterial infection.
Other side effects that occur? 3% of patients receiving combined mycophenolate therapy with mofetil, cyclosporine and corticosteroids include:
On the part of the body as a whole: pain, abdominal pain, fever, heart pain, infection.
Cardiovascular system: angina pectoris, atrial fibrillation, arterial hypotension, peripheral vascular injury, postural hypotension, tachycardia, thrombosis, vasodilation, ventricular extrasystoles, congestive heart failure, supraventricular tachycardia, ventricular tachycardia, atrial flutter, pulmonary arterial hypertension, cardiac arrest, increased venous pressure, fainting, supraventricular extrasystoles, pallor, vasospasm.
From the side of the central nervous system: anxiety, depression, hypertension, paresthesia, drowsiness, emotional lability, neuropathy, convulsions, hallucinations, dizziness, tremor, insomnia.
From the skin: alopecia, fungal dermatitis, hirsutism, itching, benign skin tumors, skin hypertrophy, skin ulcers, sweating, bruising and skin cancer.
On the part of the endocrine system: diabetes, impaired parathyroid function, Cushing's syndrome, hypothyroidism.
Metabolic and nutritional disorders: edema, hypercholesterolemia, hyperproteinemia, increased ALT.
From the digestive system: anorexia, esophagitis, flatulence, gastritis, gastroenteritis, bleeding, gingivitis, gingival hyperplasia, hepatitis, intestinal obstruction, infections, ulceration of the oral mucosa, rectal pathology, enlargement of the liver, dysphagia, jaundice, stomatitis, thirst, pain in stomach, nausea, constipation, diarrhea.
From the genitourinary system: albuminuria, dysuria, hydronephrosis, impotence, pain, pyelonephritis, frequent urination, nocturia, renal failure, hematuria, urinary incontinence, prostate pathology, urinary retention, herpetic and CMV infections, hyperuricemia, nephronecrosis, infectious lesions of the lower urogenital ways.
From the musculoskeletal system: arthralgia, joint damage, spasms of the calf muscles, myasthenia gravis.
On the part of the respiratory system: asthma, pulmonary edema, pleural effusion, rhinitis, sinusitis, lung atelectasis, hiccough, pneumothorax, increased sputum, nosebleeds, apnea, voice change, pain, hemoptysis, tumors, cough, infections.
From the sense organs: amblyopia, cataracts, conjunctivitis, pain in the ears, deafness, eye phytology, tinnitus, visual disturbances, lacrimal gland disorders, eye hemorrhages.
Other: increased abdomen, chills and fever, facial swelling, flu-like syndrome, bleeding, hernia, fatigue, pelvic pain, ecchymosis, erythrocytosis, neck pain, cellulitis, petechiae, phlebitis, thrombosis, increased or decreased body weight, impaired healing wounds, dehydration, anemia, leukopenia, leukocytosis, thrombocytopenia.
CONTRAINDICATIONS
- hypersensitivity to mycophenolate mofetilumikofenolovoy acid or to any other ingredient of the drug.
With caution
Monitoring: A complete blood count is done weekly during the first month of treatment, every two weeks during the second and third months of treatment, and then once a month during the first year of therapy.
Gastrointestinal bleeding: Mycophenolate treatment with mycophenolate is accompanied by an increased incidence of gastrointestinal side effects, including infrequent gastrointestinal ulceration, bleeding and perforation, and should therefore be used with caution in patients suffering from active serious gastrointestinal diseases.
Delayed recovery of renal allograft function: these patients do not need to reduce the dose of mycophenolate mofetil, but it is necessary to closely monitor their condition.
Since MMF is an inhibitor of IMPDG, from the theoretical point of view, it should not be prescribed to patients with a rare, genetically determined hereditary deficiency of hypoxanthine guanine phosphoribosyltransferase (Lesch-Nienen syndrome and Kelly-Zygmiller syndrome). It is not recommended to combine the use of mycophenolate mofetil with aziotioprine, as they both cause bone marrow suppression. Their joint application has not been studied.
PREGNANCY AND LACTATION
Pregnant women did not undergo adequate and well-controlled studies of mycophenolate mofetil. This drug can be given to a pregnant woman only if the potential benefit to a future mother outweighs the possible risks to the fetus. For 1 week or less before the start of treatment for mycophenolate mofetil in women capable of childbearing, the result of a urine test for pregnancy with a sensitivity of at least 50 mIU / ml should be negative. Mycophenolate therapy with mycophenolate can not be started until a negative pregnancy test result is obtained. It is necessary to use effective contraception before the treatment of mycophenolate mofetil, during treatment and for 6 weeks after the end of treatment. This rule extends even for women suffering from infertility, except when the latter is due to hysterectomy. In the absence of abstinence from sexual activity, two effective methods of preventing pregnancy should be used simultaneously. In case of pregnancy during treatment with mycophenolate mofetil, the patient should discuss with the doctor the advisability of maintaining a pregnancy.
Studies in rats treated with mycophenolate mofetil showed that mycophenolic acid penetrates into the milk. It is not known whether this substance is capable of penetrating the breast milk of women. Feeding infants with mothers who receive mycophenolate mofetil may in principle cause serious side effects, and therefore in such situations, the dilemma of abandoning breastfeeding or eliminating mycophenolate mofetil should be addressed, taking into account the importance of treating a woman with this drug.
APPLICATION FOR FUNCTIONS OF THE LIVER
It should avoid the use of mycophenolate mofetil in doses more than 1 g 2 times / day, you should also carefully monitor the patient's condition.
APPLICATION FOR CHILDREN
At present, there is no data on the safety and efficacy of mycophenolate mofetil in children.
APPLICATION IN ELDERLY PATIENTS
In elderly and senile patients (? 65 years) who underwent kidney transplantation, the recommended dose is 1 g 2 times / day, and after heart or liver transplantation - 1.5 g 2 times / day.
SPECIAL INSTRUCTIONS
Children
At present, there is no data on the safety and efficacy of mycophenolate mofetil in children.
Allophoma and malignant neoplasm
In patients receiving immunosuppressive therapy, in particular combinations of mycophenolate mofetil with other immunosuppressors, the risk of developing lymphomas and other malignant tumors, particularly cutaneous ones, is increased. This risk appears to depend on the intensity and duration of immunosuppression, and not on the use of a particular immunosuppressant. In addition, hypersuppression of the immune system increases the susceptibility of patients to various infections.
As with all patients with an increased risk of skin cancer, exposure to sunlight and ultraviolet rays should be limited by wearing appropriate closed clothing and using sunscreens with a high protective factor.
Neutropenia
In patients receiving mycophenolate mofetil, regular blood tests should be done to monitor neutropenia. Neutropenia can be caused by mycophenolate mofetil itself, concomitant medications, viral infections and various combinations of these factors.
Impaired renal function
It should avoid the use of mycophenolate mofetil in doses more than 1 g 2 times / day, you should also carefully monitor the patient's condition.
In elderly patients, the risk of adverse events may be higher than in younger patients.
To prevent rejection after kidney, heart and liver transplantation, treatment of refractory rejection of the transplanted kidney, MMF is prescribed in combination with antitimocytic globulin, OKTZ (orthoclone of mouse monoclonal antibodies), cyclosporine and corticosteroids.
Abnormal laboratory indicators
Increased levels of alkaline phosphatase, creatinine, gamma-glutamyl transpeptidase, lactate dehydrogenase, ACT and ALT, hypercalcemia, hyperlipidemia, hyperuricemia, hypervolemia, hypocalcemia, hypoproteinemia, acidosis, hypoxia, hypophosphatemia, alkalosis and hypochloremia.
Treatment with the drug
Since mycophenolate mofetil in a rat and rabbit experiment showed teratogenic effects, Maiscept should not be broken and violated the integrity of the capsule or tablet. It is necessary to avoid inhaling the powder contained in capsules / Mayscept tablets or direct exposure to the skin or mucous membranes. If this happens, you need to thoroughly rinse this area with soap and water, and your eyes - just water.
OVERDOSE
Symptoms: when taking 4-5 g of mycophenolate mofetil per day, the frequency of gastrointestinal side effects (nausea, vomiting, diarrhea), as well as hematologic disorders, in particular neutropenia, increases, in comparison with the intake of 3 g / day or less.
Treatment: IFC and HMFC are usually not removed from the body by hemodialysis. It should be noted, however, that at high concentrations of HMFC in the plasma (more than 100 mg / ml), small amounts of this substance are still excreted by hemodialysis. Elimination of IFC can be accelerated with the help of sequestrants of bile acids, such as cholestyramine.
DRUG INTERACTION
Interactions were studied only in adults.
Acyclovir: in the administration of mycophenolate mofetil together with acyclovir, higher concentrations of IFPC and acyclovir in plasma were observed than with the administration of each drug alone. Since plasma concentrations of IFNP, acyclovir or its homologues, such as valacyclovir, increase with renal failure, it is likely that these two drugs compete for tubular secretion, which may lead to a further increase in the concentration of both drugs.
Antacids containing magnesium hydroxide and aluminum: when taken together with antacids, the absorption of mycophenolate mofetil decreases.
Kolestyramine: after the appointment of a single dose of mycophenolate mofetil in 1.5 g of healthy volunteers, previously taking 4 g of cholestyramine 3 times a day for 4 days, there was a decrease in AUC, C max by 40%.
Drugs acting on the intrahepatic circulation: when combined with mycophenolate mycophenolate mofetil noted a decrease in the effect of the latter.
Ganciclovir: Based on the results of a study with a single oral intake of recommended doses of mycophenolate mofetil and intravenous administration of ganciclovir, given the known effect of renal failure on the pharmacokinetics of mycophenolate mofetil and ganciclovir, it can be assumed that the simultaneous use of these two drugs (competing in tubular secretion) concentrations of IFPC and ganciclovir. A significant change in the pharmacokinetics of IFC is not expected, so adjust the dose of mycophenolate mofetil is not necessary. If mycophenolate mofetil, ganciclovir and its analogues, such as valganciclovir, are prescribed to patients with renal insufficiency, it is necessary to adhere to the recommended dosing regimen for ganciclovir and carefully monitor patients.
Ciclosporin A: Mycophenolate mofetil does not affect the pharmacokinetics of cyclosporin A. Observations have shown that the use of cyclosporin A reduces AUC by 19-38%, probably because of inhibition of bile secretion, which reduces intrahepatic circulation.
Tacrolimus: in patients with kidney transplantation: when combined with cyclosporine and mycophenolate mofetil, AUC is increased by 30%, but when cyclosporin is replaced with tacrolimus, the maximum concentration of IFC does not change, and IFPC decreases by 20%. In part, this may be due to increased biliary secretion of IFPC in combination with increased hepatic intestinal recirculation of MPA, as the increase in MPC concentrations after tacrolimus administration was more pronounced near the end of the AUC (4-12 hours after administration). In patients taking tacrolimus, the dose of MMF should not exceed 1 g 2 times / day.
In patients with transplanted liver: the interaction of mycophenolate mofetil and tacrolimus is not enough. When studying the pharmacokinetics of mycophenolate mofetil together with tacrolimus in stable patients with transplanted liver, an increase in AUC of tacrolimus by 20% is observed, after prolonged use of mycophenolate mofetil 1.5 g 2 times / day.
Other interactions: with simultaneous administration of probenecid and mycophenolate mofetil monkeys, an increase in plasma AUC in plasma was observed 3-fold.Thus, other drugs undergoing tubular secretion may compete with MFKG, resulting in increased plasma concentrations MFKG or another drug which is also subjected to tubular secretion.
Live vaccines: should not be administered to patients in a state of immunosuppression. Antibody production in response to other vaccine may be reduced.
TERMS OF RELEASE FROM PHARMACY
Conditions of leave from pharmacies
TERMS AND CONDITIONS OF STORAGE
List B. Store the drug in a dry, dark place at a temperature not higher than 30 В° C. Keep out of the reach of children. Shelf life - of the year. Do not use after expiry date.
