Instruction for use: Myfortic

Dosage form: Enteric coated tablets

Active substance: Acidum mycophenolicum

ATX

L04AA06 Mycophenolic acid

Pharmacological group:

Immunodepressants

The nosological classification (ICD-10)

T86.1 Kidney transplant death and rejection: Reaction of acute rejection of a transplanted kidney; Refractory tissue rejection in patients after allogeneic kidney transplantation

Composition

Tablets, covered with a shell, soluble in the intestine 1 tab.

active substance: Sodium mycophenolate 192.4 mg; 384.8 mg

(Equivalent to mycophenolic acid 180 mg and 360 mg respectively)

Auxiliary substances: 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

Shell: 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 more - iron oxide red (No77491, E172) 0.167 mg

Description of dosage form

180 mg tablets: coated with enteric-coated shell, light green, round, with bevelled edges and marked "C" on one side.

360 mg tablets: coated with an enteric-soluble coat of grayish-pink color, oval in shape, marked "CT" on one side.

Pharmachologic effect

Mode of action - immunosuppressive.

Pharmacodynamics

The preparation of Myfortic ® inhibits the synthesis of guanosine nucleotides by selectively inhibiting the key enzyme of purine synthesis - inosine monophosphate dehydrogenase. Thanks 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.

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 during the resting phase of the cell cycle.

Pharmacokinetics

Suction. After ingestion, the sodium salt of mycophenolic acid (MPA) is intensively absorbed. Due to the presence of an enteric film coating of Cmax, the 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 IFC in an acidic medium similar to that of the stomach acid.

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 Myfortic® on an empty stomach did not differ from that when taken with a high-fat diet (55 g fat, 1000 calories). However, the Cmax of the MFC is reduced by 33%.

Distribution. The apparent volume of distribution (VSS) of the MPC in the equilibrium state is 50 liters. Both IFC and its phenol 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 a stable functioning kidney transplant who receive basic immunosuppressive therapy with cyclosporin in the form of a microemulsion, about 28% of the oral dose of the Myfortic® drug is metabolized to HMFC when it first passes through the liver.

Excretion. T1 / 2 MFC is 11.7 h, Cl is 8.6 l / h. The IFC is excreted mainly with urine in the form of HMFC, and very small amounts (<1%) are unchanged. T1 / 2 HMFC is 15.7 h, Cl is 0.45 l / h. GMPK is also secreted with bile into the intestine, where it is cleaved (by deconjugation) by the intestinal flora. The resulting IFC cleavage can then be reabsorbed. Six to eight hours after the administration of Myfortic®, the second peak of the concentration of MPA is observed, which corresponds to the re-absorption of the 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 the IFC after administration of the preparation Myfortic®. Values of the pharmacokinetic parameters of the preparation Myfortic® with single dose administration allow us to predict the possible values of these parameters for repeated and prolonged dosing. The mean values of AUC and Cmax of MFC, measured in the early post-transplant period, were approximately 50% of the values determined 6 months after transplantation.

Table

The mean values of the pharmacokinetic parameters of MFC after oral administration of the preparation Myfortic in patients who underwent kidney transplantation and received basic immunosuppressive therapy with cyclosporin in the form of a microemulsion

Renal insufficiency

The pharmacokinetics of IFC does not depend on the function of the kidneys. AUC of HMFC with a violation of kidney function, on the contrary, is increasing; Thus, in patients with anuria the AUC values of GMPA are approximately 8 times higher. Hemodialysis does not affect the clearance of IFC and GMPC. In renal insufficiency, the concentration of free MPC in the blood plasma can be significantly increased, which is probably due to a decrease in the binding of IFC to proteins under conditions of high urea concentration in the blood.

Liver failure

In patients with alcoholic cirrhosis of the liver, the effect of this disease on the IFC glucuronation reaction was not noted. The presence or absence of the effect of liver disease on the pharmacokinetics of IFC may depend on the nature of the disease (primary lesion of the parenchyma or bile duct system, or the like).

Childhood

Experience with the use of the drug Myfortic® in children is limited. The table shows the average values of pharmacokinetic parameters in children with a stable kidney transplant receiving a microemulsion of cyclosporine as an immunosuppressive therapy. The Cmax and AUC values of IFC in children were more variable than in adult patients. With the use of the preparation Myfortic ® in children in a single dose of 450 mg / m2, the AUC MFC was higher than that in adults with the usual single dose of 720 mg. The average value of the IFC clearance was about 7.7 l / h / m2. It can be expected that with a dose of 200-300 mg / m 2 Myfortic®, the MUC AUC will be between 30 and 50 mkg / hr / ml.

Floor

Clinically significant differences in pharmacokinetic parameters were not found depending on the sex of patients.

Elderly age

Based on preliminary research data, it is assumed that the concentration of IFC does not change clinically with age.

Indications of the preparation Myfortic

Prevention of acute graft rejection in patients with allogeneic kidney transplants receiving basic immunosuppressive therapy with cyclosporin in the form of a microemulsion and glucocorticosteroids.

Contraindications

Hypersensitivity to mycophenolate sodium, mycophenolic acid, mycophenolate mofetil or any component of the drug.

Children's age (effectiveness and safety not studied)

Carefully:

Congenital insufficiency of hypoxanthine guanine phosphoribosyltransferase (including Lesch-Nayhan syndrome and Kelly-Sigmiller syndrome);

Gastrointestinal disease in the exacerbation phase.

Use in children

The efficacy and safety of the Myfortic® preparation in children have not been studied. There are limited data on the pharmacokinetics in children who underwent kidney transplantation. At the moment, there are no specific recommendations on the dosage regimen in children.

Application in pregnancy and breastfeeding

With the use of Myfortic ® 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 trials on the use of Myfortic® in pregnant women have not been conducted, according to NTPR, when using mycophenolate mofetil in combination with other immunosuppressants, an increased incidence of congenital malformations was noted during pregnancy-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 area, including clefts of the upper lip and palate, congenital diaphragmatic hernia and heart defects. When administered or IV the introduction of the conversion of mycophenolate mofetil into mycophenolic acid.

In experimental preclinical studies, the animals exhibited a teratogenic effect of mycophenolic acid.

The appointment of Myfortic ® during pregnancy is possible only if the expected effect of therapy exceeds the possible risk to the fetus.

It is not recommended to start therapy with Myfortic® before a negative pregnancy test result is obtained. In case of pregnancy, the patient should immediately consult a doctor.

Prior to the initiation of therapy with Myfortic®, effective contraceptive methods should be used throughout the therapy and for 6 weeks after its completion.

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 infant under the influence of sodium mycophenolate, it is necessary to resolve the issue either by stopping the use of Miforic®, or, given the importance of therapy with this drug for the mother, about stopping breastfeeding throughout the therapy And within 6 weeks after its termination.

Side effects

The following adverse events (AEs) were observed in two studies of the safety of the preparation Myfortic® and mycophenolate mofetil (MMF) in 423 patients with a recently transplanted kidney who had not received previous supportive therapy (patients with renal graft de novo) and 322 patients with a transplanted kidney , Previously received maintenance therapy. The incidence of adverse events was similar in both groups of patients. With the use of the preparation Myfortic® in combination with cyclosporine and GCS, very often (≥10%) observed such undesirable phenomena as leukopenia and diarrhea.

Malignant neoplasms. In patients receiving immunosuppressive therapy with several drugs, incl. IFC, the risk of developing lymphomas and other neoplasms, in particular, of the skin, is increased. In the course of studies, malignant neoplasms developed against the background of the preparation of Myfortic® with the following frequency:

Lymphoproliferative diseases or lymphomas developed in two patients with a renal transplant de novo (0.9%) and in two patients (1.3%) with a kidney who received therapy during the year;

Non-melanoma skin carcinomas developed in 0.9% with a de novo renal transplant and in 1.8% of patients with kidney transplant who had previously received maintenance therapy with Myfortic® for up to 1 year;

Other malignancies developed in 0.5% of patients with renal graft de novo and in 0.6% of patients with kidney transplants who received maintenance therapy.

Infectious diseases (opportunistic infections). In patients with a recently transplanted kidney who received Myfortic® as part of complex immunosuppressive therapy for 1 year, CMV infection, candidiasis and infection caused by the herpes simplex virus were most frequently observed. In the course of the studies, it was shown that CMV infection (confirmed serologically, by viremia or clinical data) was noted with a frequency of 21.6% in patients with recently transplanted kidney and in 1.9% of patients with a stable graft functioning with prolonged maintenance therapy.

Other undesirable phenomena

Below are the AEs detected against the background of taking Myfortic® at a dose of 1440 mg / day for 12 months in combination with a cyclosporine microemulsion and corticosteroids in two clinical studies in patients with renal transplant de novo and in patients with kidney transplant who received a previous supporting Therapy. These phenomena had an eventual or probable cause-and-effect relationship with the use of the Myfortic® preparation.

Adverse events are given in accordance with the classification of organs and systems by MedDRA (medical dictionary of regulatory activity) and are listed according to frequency. The frequency of unwanted reactions is estimated as follows: very often (≥10%); Often (≥1 and <10%); Sometimes (≥0.1 and <1%); Rarely (≥0.01 and <0.1%); Very rarely (<0.01%), including individual messages.

Infections and invasions: 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 disturbances *, delusional perception *.

From the nervous system: often - headache; Sometimes - tremor, insomnia *.

From the respiratory system, chest and mediastinum: often - cough; Sometimes - "stagnant" lung *, 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 of the tongue, gastrointestinal bleeding, dry mouth, ulceration of the lips, occlusion of the excretory duct Parotid salivary gland *, gastroesophageal reflux disease, gingival hyperplasia, peritonitis.

General disorders and reactions at the injection site: often - fatigue, pyrexia; Sometimes - influenza-like diseases, edema of the lower extremities *, pain, tremor *, thirst *, weakness *.

From 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 - an increase in the level 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.

* This undesirable phenomenon was registered only in one patient out of 372.

The profile of adverse events was not different in patients with kidney transplantation de novo and in patients who had previously received maintenance therapy, but the incidence of adverse events was lower in the second group.

The following side effects were observed against the background of taking medications containing as my active substance mycophenolic acid ("class-effects"):

Infections and infestations: severe course, sometimes life-threatening infectious diseases (in some cases, fatal), incl. Meningitis, infective endocarditis, tuberculosis, atypical infections caused by mycobacteria. The development of polyomavirus nephropathy (especially associated with VC virus) has been reported.

When using mycophenolate mofetil (a derivative of mycophenolic acid - the active substance of the preparation Myfortic ®), it was reported about the development of progressive multifocal leukoencephalopathy, in some cases - with a lethal outcome.

From the hemopoietic system: neutropenia, pancytopenia. With 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.

From the digestive system: colitis, esophagitis (including CMV-colitis and CMV-esophagitis), CMV gastritis, pancreatitis, perforation of the intestinal wall, gastrointestinal bleeding, stomach and / or duodenal ulcer, intestinal obstruction.

Interaction

Azathioprine. Since no special studies have been conducted on the interaction between the preparation of Myfortic® 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. Perhaps, both drugs compete when excreted from the body (a similar way of excretion - 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 Cmax decreases by 25%. Caution should be exercised when combined with Myfortic® with antacid preparations containing magnesium hydroxide and aluminum.

Kolestyramin and drugs that affect 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 Myfortic®, 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 MPA is reached, the clearance of ganciclovir does not change. However, with the combined administration of Myfortic® 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. In patients with stable kidney transplant in a cross-sectional study, the pharmacokinetics of the Mafractic® preparation in the equilibrium state was studied with simultaneous application to the preparation of Sandimmun® Neoral® and tacrolimus. The mean values of the AUC of the IFC with the co-administration of the preparation of Myfortic® and tacrolimus were 19% higher than when Myfortic® and Sandimmune® Neoral® were co-administered, and the Cmax value of MFC was 20% lower. For HMPA, the values of AUC and Cmax were 30% lower when taking MaborTic® with tacrolimus than with Mabopict® with the Sandimmun® Neoral® preparation.

Oral contraceptives. Metabolized by oxidation reactions, while the preparation of Myfortic® - through glucuronation. Influence of oral contraceptives on the pharmacokinetics of the preparation Myfortic® is unlikely, and, therefore, it is unlikely that any clinically significant interactions can be expected. On the other hand, if one takes into account the fact that the influence of prolonged therapy with Myforctic® 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.

Dosing and Administration

Inside, swallowing whole, without chewing, not breaking, on an empty stomach or together with food.

Therapy with Myfortic® 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 the enteric membrane for 180 mg or 2 tablets for 360 mg) 2 times a day (daily dose - 1440 mg). In patients receiving mycophenolate mofetil (MMF) at 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® is 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 m2).

Use in patients with impaired liver function. Patients with severe liver disease associated with primary parenchymal involvement do not need a dose adjustment for Myfortic®.

Episodes of rejection reaction. The rejection reaction of the transplant does not lead to a change in the pharmacokinetics of mycophenolic acid. In these cases, a change in the dosing regimen is not required.

Overdose

With the use of the drug Myfortic ® cases of overdose were not observed. Although the inactive metabolite of HMFC is excreted by hemodialysis, it should not be expected that this method will effectively excrete clinically significant amounts of the 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.

Special instructions

Therapy with Myfortic® should be performed only by qualified transplant doctors. In patients receiving combined immunosuppressive therapy, including t. And the preparation of Myfortic®, increased the 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 Myfortic® should be instructed to immediately notify the doctor of all cases of infection, sudden appearance of bruising, bleeding, and any other manifestations of bone marrow depression.

Excess immunosuppression increases the likelihood of developing infections, incl. Opportunistic, as well as sepsis and fatal infections.

The cases of development of progressive multifocal leukoencephalopathy (PML) against mycophenolate mofetil was 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 either by the influence of the IFC itself, or concomitant medications, viral infections or a combination of these factors, is not excluded. In patients receiving Myfortic®, 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. Whenever neutropenia develops (the absolute number of neutrophils is <1.5 × 103 / mm3), therapy with Mayfortic® should be discontinued or discontinued. With 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 ingredient 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 reduction in the dose or discontinuation of MMP therapy, there was a normalization of the patients' condition. However, in patients with transplantation, a decrease in immunosuppression may increase the risk of graft rejection.

The change in the dosage regimen of Myfortic® should only be carried out under proper control of the patient's condition in order to reduce the risk of rejection of the transplant.

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: antimonocitic globulin, basiliximab, cyclosporine (in the form of microemulsion) and GCS. Efficacy and safety in its use with immunosuppressive drugs have not been studied.

Influence on the ability to drive vehicles and work with mechanisms. The effect of taking Myfortic® on the ability to drive vehicles and mechanisms has not been established. The mechanism of action of the preparation Myfortic®, its pharmacodynamic effects and registered AEs 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 careful in work that requires concentration.

Release form

Tablets, coated with enteric coating, 180 mg. 10 tablets in a blister pack. 5,10,12 or 25 blisters are placed in a cardboard box.

Tablets, covered with enteric coating, 360 mg. 10 tablets in a blister pack. 5, 10, 12 or 25 blisters are placed in a cardboard box

Manufacturer

Novartis Pharma AG.

Produced by Novartis Pharma Stein AG, Switzerland.

Lichtstraße, 35, 4056 Basel, Switzerland.

Novartis Pharma AG.

Manufactured by Novartis Pharma Stein AG, Switzerland.

Lichtstrasse, 35, 4056 Basel, Swtzerland.

Conditions of supply of pharmacies

On prescription.

Storage conditions of the drug Myfortic

At a temperature of no higher than 30 ° C.

Keep out of the reach of children.

Shelf life of the drug Myfortic

2,5 years.

Do not use after the expiry date printed on the package.