Active ingredient: sodium mycophenolate;
Excipients: lactose anhydrous – 45/90 mg, crospovidone – 32,5 / 65 mg, povidone (K-30) – 20/40 mg, corn starch – 10.25 / 20.5 mg, silicon dioxide colloid – 6, 6 / 13.2 mg, magnesium stearate – 3.25 / 6.5 mg;
Sheath: hypromellose phthalate – 42/65 mg, titanium dioxide (No7789I, E171) – 2.883 / 4.666 mg, iron oxide yellow (No77492, E172) – 0.078 / 0.167 mg; for table. 180 mg additionally – indigocarmine (E132) – 0,039 mg; for table. 360 mg additionally – iron oxide red (No77491, E172) 0.167 mg;
The preparation of Myfortic ® inhibits the synthesis of guanosine nucleotides by selectively inhibiting the key enzyme of purine synthesis – inosine monophosphate dehydrogenase. Due to this mechanism it effectively suppresses the proliferation of T and B lymphocytes, and to a much greater extent than other cells, since the proliferation of lymphocytes depends mainly on the synthesis of purines de novo.
The suppression of the proliferation of T- and B-lymphocytes with the preparation of Myfortic ® supplements the action of inhibitors of calcineurin, which disrupt the production of cytokines and affect T-lymphocytes in the resting phase of the cell cycle.
Suction. After ingestion, the sodium salt of the mycophenolic acid (MPA) is intensively absorbed. Due to the presence of an enteric film coating, Cmax MPA is achieved after approximately 1.5-2 hours. In vitro studies, it has been shown that a particular composition of the enteric film coating of the Myfortic ® prevents the release of MPA in an acidic medium similar to that of the stomach.
In patients with a stable functioning kidney transplant receiving basic immunosuppressive therapy with cyclosporin in the form of a microemulsion, the degree of absorption of IFC from the gastrointestinal tract is 93%, and the bioavailability is 72%. In the dose range of 180 to 2160 mg, the pharmacokinetics of IFC are linearly dose-dependent. The AUC value when taking Mafractic ® on an empty stomach did not differ from that when taking the drug with a high-fat diet (55 g fat, 1000 calories). However, the C max of the MFC is reduced by 33%.
Distribution. The apparent volume of the distribution (V SS ) of the MPA in the equilibrium state is 50 liters. Both IFC and its phenolic glucuronide (HMFC) are highly binding to plasma proteins, 97%, and 82%, respectively. With a decrease in the number of binding sites with proteins (with uremia, hepatic insufficiency, hypoalbuminemia, simultaneous use of drugs with high binding to blood plasma proteins), an increase in the concentration of free MPA in plasma is possible.
Metabolism. IFC is predominantly metabolized with the participation of glucuronyltransferase to form the main pharmacologically inactive metabolite of HMFC. In patients with stable functioning renal transplant receiving basic immunosuppressive therapy with cyclosporin in the form of a microemulsion, about 28% of the oral dose of the Myfortic ® drug is metabolized into the HMFC when first passed through the liver.
Excretion. T 1/2 of the IFC is 11.7 h, Cl is 8.6 l / h. IFC is excreted mainly in urine in the form of GMPK, and very small amounts (1/2 of the GMPA is 15.7 hours, Cl is 0.45 L / h. GMPK is also secreted with bile into the intestine where it is cleaved (by deconjugation) by intestinal flora The IFC resulting from this cleavage can then be reabsorbed.After 6-8 hours after the preparation of Myfortic ®, the second peak of the concentration of MPA is observed, which corresponds to the re-absorption of deconjugated MPA.
Pharmacokinetics in patients who underwent kidney transplantation and are on basic immunosuppressive therapy with cyclosporin in the form of a microemulsion
The table presents the average values of the pharmacokinetic parameters of IFC after administration of the preparation Mayertics ® . The values of the pharmacokinetic parameters of the preparation Myfortic ® when taking a single dose allow us to predict the possible values of these parameters for repeated and prolonged dosing. The mean values of AUC and C max of MFC, measured in the early post-transplant period, were approximately 50% of the values determined 6 months after transplantation.
Prevention of acute graft rejection in patients with allogeneic kidney transplants receiving basic immunosuppressive therapy with cyclosporine in the form of a microemulsion and glucocorticosteroids.
Application in pregnancy and lactation
With the use of Mayertics ® during pregnancy, there was an increased risk of developing congenital anomalies. According to the American National Pregnancy Registry, National Transplant Pregnancy Registry (NTPR), the average incidence of congenital malformations in children born to women who undergo organ transplantation is 4-5%. Although controlled clinical studies on the use of medication Myfortic ® in pregnant women were not performed, according to NTPR when using mycophenolate mofetil in combination with other immunosuppressants during pregnancy, there was an increased incidence of congenital malformations – 22% (4 children from 18 newborns) compared with the average frequency. The most frequent use of mycophenolate mofetil during pregnancy in children was anomalies in the development of the inner ear, extremities, craniofacial region, including clefts of the upper lip and palate, congenital diaphragmatic hernia and heart defects. When ingestion or in / in the introduction of conversion mycophenolate mofetil to mycophenolic acid.
In experimental preclinical studies, the animals exhibited a teratogenic effect of mycophenolic acid.
The appointment of the drug Myfortic ® during pregnancy is possible only if the expected effect of therapy exceeds the possible risk to the fetus.
It is not recommended to begin therapy with Mafractic ® before a negative pregnancy test result is obtained. In case of pregnancy, the patient should immediately consult a doctor.
Before the start of therapy with Mafractic ® , throughout the entire therapy and for 6 weeks after it is completed, effective methods of contraception should be used.
It is not known whether IFC is excreted in breast milk. Since there is a potential risk of developing serious adverse events in a fed child under the influence of sodium mycophenolate, it is necessary to resolve the issue of either stopping the use of Mafractic ® , or, given the importance of therapy with this drug for the mother, to stop breastfeeding throughout the therapy and within 6 weeks after its termination.
Hypersensitivity to mycophenolate sodium, mycophenolic acid, mycophenolate mofetil or any component of the drug; children’s age (efficacy and safety not studied).
With caution: congenital insufficiency of hypoxanthine guanine phosphoribosyltransferase (including Lesha-Naikhan syndrome and Kelly-Sigmiller syndrome); Gastrointestinal disease in the phase of exacerbation.
Use in children: the effectiveness and safety of the Mafictic ® preparation in children have not been studied. There are limited data on the pharmacokinetics in children who underwent kidney transplantation. At the moment, no specific recommendations on the dosage regimen in children have been developed.
Infections and infestations: very often – viral, bacterial and fungal infections; often – infections of the upper respiratory tract; sometimes – wound infections, sepsis, osteomyelitis.
From the blood and lymphatic systems: very often – leukopenia; often – anemia, thrombocytopenia; sometimes – lymphocele, lymphopenia, neutropenia, lymphadenopathy.
Mental disturbances: sometimes – sleep disorders, delusional perception.
From the nervous system: often – headache; sometimes – tremor, insomnia.
From the respiratory system, chest and mediastinum: often – cough; sometimes – a “stagnant” lung, a stridor.
From the digestive system: very often – diarrhea; often – bloating, abdominal pain, constipation, dyspepsia, flatulence, gastritis, loosening of the stool, nausea, vomiting; sometimes – abdominal wall tension, pancreatitis, belching, halitosis (bad breath), intestinal obstruction, esophagitis, peptic ulcer, subillus, discoloration, gastrointestinal bleeding, dry mouth, ulceration of lips, occlusion of the excretory duct of the parotid salivary gland , gastroesophageal reflux disease, gingival hyperplasia, peritonitis.
General disorders and reactions at the injection site: often – fatigue, pyrexia; sometimes – influenza-like diseases, swelling of the lower extremities, pain, tremor, thirst, weakness.
On the part of the endocrine system and metabolism: sometimes – anorexia, hyperlipidemia, diabetes mellitus, hypercholesterolemia, hypophosphatemia.
From the skin and subcutaneous tissue: sometimes – alopecia, bruises.
On the part of the liver: often – abnormalities in the results of functional liver tests.
From the cardiovascular system: sometimes – tachycardia, pulmonary edema, ventricular extrasystoles.
On the part of the organs of vision: sometimes – conjunctivitis, “clouding” of vision.
From the musculoskeletal system and connective tissue: sometimes – arthritis, back pain, muscle cramps.
Benign and malignant tumors: sometimes – skin papilloma, basal cell carcinoma, Kaposi’s sarcoma, lymphoproliferative disorders, scaly-cell carcinoma.
From the urinary system: often – increased levels of creatinine in the blood; sometimes – hematuria, necrosis of the renal tubules, stricture of the urethra.
From the side of the reproductive system: sometimes – impotence.
Azathioprine. Since there have been no special studies of the interaction between the preparation Mayertics ® and azathioprine, they should not be prescribed simultaneously.
Live vaccines. Do not use live vaccines in patients with a compromised immune response. With the use of other vaccines, the production of antibodies can be reduced.
Acyclovir. In patients with impaired renal function, blood concentrations of both HMFC and acyclovir may increase. It is possible that both drugs compete when removed from the body (a similar pathway is tubular secretion). Such patients require careful observation.
Antacid preparations containing magnesium hydroxide and aluminum. With simultaneous administration with antacids, the absorption of sodium mycophenolate is reduced, as a result of which the AUC of the MPA decreases by 37% and the C max by 25%. Caution should be exercised when combined with Mafractic ® with antacid preparations containing magnesium hydroxide and aluminum.
Kolestiramin and drugs that affect the hepatic-intestinal circulation. Due to its ability to bind bile acids in the intestine, colestyramine can reduce the concentration of IFC in the blood and AUC. In connection with a possible decrease in the effectiveness of the preparation Mayertics ® , caution should be exercised when it is combined with colestyramine and preparations affecting the hepatic intestinal circulation.
Ganciclovir. The addition of ganciclovir does not affect the pharmacokinetics of IFC and HMFC. When the therapeutic concentration of MFC is reached, the clearance of ganciclovir does not change. However, with the combined administration of Mafractic ® and ganciclovir to patients with impaired renal function, correction of the ganciclovir dosage regimen may be required, and careful monitoring must be made for such patients.
Tacrolimus. Patients with stable renal transplant study with cross-over design was studied pharmacokinetics Myfortic ® in equilibrium with its simultaneous use with the drug Sandimmun ® Neoral ® and tacrolimus. Mean AUC values IFC by sharing a drug Myfortic ® and tacrolimus were 19% higher than when co-administered drugs Myfortic ® and Sandimmune ® Neoral ® , and znacheniyaC max IFC – 20% lower. For HMPA, the values of AUC and C max were 30% lower when taking Mayertics ® with tacrolimus than with Mayertics® with the preparation of Sandimmun ® Neoral ® .
Oral contraceptives. Metabolized by oxidation reactions, while the preparation of Mafractic ® – through glucuronation. The effect of oral contraceptives on the pharmacokinetics of the preparation Mafractic ® is unlikely, and therefore, it is unlikely that any clinically relevant interactions can be expected. On the other hand, if we take into account the fact that the influence of prolonged therapy with Mafractic ® on the pharmacokinetics of oral contraceptives has not yet been studied, the probability of a decrease in the effectiveness of contraceptives cannot be ruled out.
Cyclosporine. In studies in patients with stable renal transplant, it was shown that the pharmacokinetics of cyclosporine remained unchanged against the background of equilibrium concentrations of the Myfortic ®preparation .
How to take, intake and dosage
Inside, swallowing whole, without chewing, not breaking, on an empty stomach or together with food.
Therapy with Mafractic ® in patients who did not receive it before, begin in the first 48 hours after transplantation. The recommended dose is 720 mg (4 tablets in an enteric coating of 180 mg or 2 tablets of 360 mg) twice a day (daily dose of 1440 mg). In patients receiving mycophenolate mofetil (MMF) in a dose of 2 mg, MMP can be replaced by the preparation Myfortic ® at a dose of 720 mg 2 times a day.
Use in elderly patients. Correction of the dosing regimen in elderly patients is not required.
Use in patients with impaired renal function. In patients with delayed recovery of renal transplant function, a change in the dose of Myfortic not required. Careful observation of patients with chronic severe renal dysfunction is necessary (glomerular filtration rate is less than 25 ml × min -1 × 1.73 m 2 ).
Use in patients with impaired liver function. Patients with severe liver disease associated with primary lesion of the parenchyma do not need a dose adjustment for Mafractic ® .
Episodes of rejection reaction. Reaction rejection of the graft does not lead to a change in the pharmacokinetics of mycophenolic acid. In these cases, the dosage regimen is not required.
With the use of Mayertics ®, cases of overdose were not observed. Although the inactive metabolite of GMPA is excreted by hemodialysis, it should not be expected that this method will effectively excrete clinically significant amounts of active IFC. This is largely due to a high degree (97%) of binding of MPC to plasma proteins. Kolestyramin and other bile acid sequestrants disrupt the absorption of IFC from the intestine and, therefore, can lead to a decrease in its concentration in the blood.
Therapy with Mafictic ® should be performed only by qualified transplant doctors. In patients receiving combined immunosuppressive therapy, including including. and the preparation Myfortic ® , increased risk of developing lymphomas and other malignant tumors, especially the skin. This risk is most likely associated not with the use of the drug, but with the intensity and duration of immunosuppressive therapy. To reduce exposure to sunlight and UV radiation in order to reduce the risk of skin cancer, it is recommended to protect the skin with clothing and use sunscreens with a high protective factor. Patients receiving therapy with Mafractic ®, should be instructed about the need to immediately inform the doctor of all cases of infection, the sudden appearance of bruising, bleeding and any other manifestations of oppression of bone marrow function.
Excess immunosuppression increases the likelihood of developing infections, including opportunistic infections, as well as sepsis and fatal infections.
The cases of development of progressive multifocal leukoencephalopathy (PML) against mycophenolate mofetil were noted mainly in patients with risk factors for PML, including therapy with immunosuppressive drugs and immune disorders. Doctors should consider the possibility of developing PML on the background of drug therapy in patients with reduced immunity and, if necessary, refer patients with neurologic disorders to a consultation with a neurologist. The development of polyomavirus nephropathy, especially associated with VC virus, should be taken into account in the differential diagnosis of the causes of liver dysfunction in patients receiving immunosuppressive therapy. With the development of PML or polyomavirus nephropathy, a doctor should consider the possibility of reducing the intensity of immunosuppressive therapy. However, in patients after transplantation, a decrease in immunosuppression may increase the risk of graft rejection. In patients receiving therapy with Myfortic® , the development of neutropenia, caused by the influence of the IFC itself, and concomitant drugs, viral infections or a combination of these factors, is not excluded. In patients receiving the preparation Mifractic ® , the number of leukocytes and the blood formula should be regularly determined: during the first month of therapy – weekly, during 2- and 3 months – 2 times a month, then, during the first year – 1 time per month. With the development of neutropenia (absolute number of neutrophils – 3 / mm 3 ) therapy with Myfortic ® it is advisable to interrupt or terminate. In the use of mycophenolate mofetil in combination with other immunosuppressants, there have been cases of development of partial red cell aplasia of the bone marrow. MMF is metabolized in the body with the formation of MPA, which has strong immunosuppressive properties.
The active substance of the preparation Myfortic ® is mycophenolic acid in the form of sodium salt. At present, there is no known mechanism for the development of partial red cell aplasia of the bone marrow against the background of MMF therapy, as well as the role of other immunosuppressants and their combinations. In a number of cases, with a decrease in the dose or discontinuation of MMP therapy, there was a normalization of the patients’ condition. However, in patients after transplantation, a decrease in immunosuppression may increase the risk of graft rejection.
The change in the dosage regimen of Mafractic ® should be carried out only under proper control of the patient’s condition in order to reduce the risk of graft rejection.
Patients should be warned that vaccination may be less effective during therapy, and that live attenuated vaccines should be avoided. Vaccination against influenza can be beneficial for patients, so the recommendations of local health authorities regarding vaccination against influenza should guide this issue. Myfortic ® was used in combination with the following drugs: antimonastic globulin, basiliximab, cyclosporine (in the form of a microemulsion) and GCS. Efficacy and safety in its use with immunosuppressive drugs has not been studied.
Influence on ability to drive vehicles and work with mechanisms. The effect of taking Mifortic ® on the ability to drive vehicles and mechanisms is not established. The mechanism of action of the preparation Myfortic ® , its pharmacodynamic effects and registered AE indicate a low probability of such an effect. Nevertheless, patients should be warned about possible undesirable effects of the drug and the need to be cautious in works that require concentration.