Composition, form of production and packaging
The tablets covered with an enteric-insoluble coat of light green color, round, with bevelled edges, on one side are stamped "C".
1 tab.
sodium mycophenolate 192.4 mg,
which corresponds to the content of mycophenolic acid 180 mg
Excipients: lactose anhydrous - 45 mg, crospovidone - 32.5 mg, povidone K30 - 20 mg, corn starch - 10.25 mg, silicon dioxide colloid - 6.6 mg, magnesium stearate - 3.25 mg.
The composition of the coating: hypromellose phthalate - 42 mg, titanium dioxide (в„–77891, E171) - 2.883 mg, iron oxide yellow (в„–77492, E172) - 78 Ојg, indigocarmine (E132) - 39 Ојg.
10 pieces. - blisters (5) - packs of cardboard.
10 pieces. - blisters (10) - packs of cardboard.
10 pieces. - blisters (12) - packs of cardboard.
10 pieces. - blisters (25) - packs of cardboard.
The tablets, covered with an enteric-insoluble coat of grayish-pink color, are oval in shape, on one side it is stamped "CT".
1 tab.
sodium mycophenolate 384.8 mg,
which corresponds to the content of mycophenolic acid 360 mg
Excipients: lactose anhydrous - 90 mg, crospovidone - 65 mg, povidone K30 - 40 mg, corn starch - 20.5 mg, silicon dioxide colloid - 13.2 mg, magnesium stearate - 6.5 mg.
The composition of the coating: hypromellose phthalate - 65 mg, titanium dioxide (в„–77891, E171) - 4.666 mg, iron oxide yellow (в„–77492, E172) - 167 Ојg, iron oxide red (в„–77491, E172) - 167 Ојg.
10 pieces. - blisters (5) - packs of cardboard.
10 pieces. - blisters (10) - packs of cardboard.
10 pieces. - blisters (12) - packs of cardboard.
10 pieces. - blisters (25) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
The product description was approved by the manufacturer for the 2009 print edition.
PHARMACHOLOGIC EFFECT
Immunodepressive drug. Mayfortik inhibits the synthesis of guanosine nucleotides by selectively inhibiting the key enzyme for the purine synthesis of 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.
Suppression of proliferation of T- and B-lymphocytes by Mayfortic supplements the action of inhibitors of calcineurin, which disrupt the production of cytokines and affect T-lymphocytes in the phase of rest of the cell cycle.
PHARMACOKINETICS
Suction
After ingestion, sodium mycophenolate (MPA) is intensively absorbed. Due to the presence of enteric film coating, Cmax MPA is achieved after approximately 1.5-2 hours. In vitro studies it was shown that a special composition of enteric film coating Mayfortika prevents the release of IFC in an acidic medium similar to the acidic environment 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 from 180 mg to 2160 mg, the pharmacokinetics of IFC are linearly dose-dependent. The AUC value for fasting was not different from that when taken with a high-fat diet (55 g fat, 1000 calories). However, the C max of the MFC is reduced by 33%.
Distribution
V d in the equilibrium state is 50 liters. Both IFC and GMPK have a high degree of 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 mainly metabolized with the participation of glucuronyltransferase to form the main pharmacologically inactive metabolite of phenol glucuronide MFC (HMFC). In patients with a stable functioning kidney transplant receiving basic immunosuppressive therapy with cyclosporin in the form of a microemulsion, about 28% of the oral dose of Mayfortics is metabolized into the HMFC when "first passed" through the liver.
Excretion
T 1/2 IFC is 11.7 hours, clearance is 8.6 l / h. IFC is excreted mainly with urine in the form of HMFC, and very small amounts (<1%) in unchanged form. T 1/2 HMFC is 15.7 h, clearance 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 Mayfortic, a second peak of the concentration of MPA is observed, which corresponds to the re-absorption of the deconjugated IFC.
Pharmacokinetics in special clinical cases
The table shows the average values ​​of the pharmacokinetic parameters of the IFC after taking Mayforth. The values ​​of the pharmacokinetic parameters of Mayforth when administered with a single dose allow us to predict the possible values ​​of these parameters during 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.
Mean values ​​of pharmacokinetic parameters of MFC after oral administration of Maisfort in patients who underwent kidney transplantation and received basic immunosuppressive therapy with cyclosporin in the form of a microemulsion
Patient category Dose for oral administration T max (h) C max (Ојg / ml) AUC (Ојg x h / ml)
Adults
Single dose (n = 24) 720 mg 2 26.1 (12) AUC 0-? 66.5 (22.6)
Adults
Repeated doses 6 days 2 times / day (n = 12) 720 mg 2 37 (13.3) AUC 0-12 67.9 (20.3)
Adults
Repeated doses 28 days 2 times / day (n = 36) 720 mg 2.5 31.2 (18.1) AUC 0-12 71.2 (26.3)
Adults
Long-term therapy (2 times / day) (n = 48)
14 days after transplantation 720 mg 2 13.9 (8.6) AUC 0-12 29.1 (10.4)
3 months after transplantation 720 mg 2 24.6 (13.2) AUC 0-12 50.7 (17.3)
6 months after transplantation 720 mg 2 23 (10.1) AUC 0-12 55.7 (14.6)
Children
Single dose (n = 10) 450 mg / m 2 2-2.5 31.9 (18.2) AUC 0-? 76.2 (25.2)
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; so 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 failure, the concentration of free MPA 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.
In patients with alcoholic cirrhosis of the liver, no effect of this disease on the IFC glucuronation reaction was observed. 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).
Experience with the use of Mayfortics in children is limited. The table shows the average values ​​of pharmacokinetic parameters in children with stable kidney transplant receiving a microemulsion of cyclosporine as an immunosuppressive therapy. The C max and AUC values ​​of IFC in children were more variable than in adult patients. In the application of Mayforth in children in a single dose of 450 mg / m 2, the AUC of the IFC was higher than that in adults with a usual single dose of 720 mg. The average value of the IFC clearance was about 7.7 l / h / m 2 . It can be expected that at a dose of Mayfortik, equal to 200-300 mg / m 2 , the MUC AUC will be from 30 to 50 μg? h / ml.
Clinically significant differences in pharmacokinetic parameters were not found depending on the sex of patients.
Based on preliminary research data, it is assumed that the concentration of IFC does not change clinically with age.
INDICATIONS
- 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.
DOSING MODE
The drug is taken orally, the tablets should be swallowed whole, not chewing and not breaking. Mayforth can be taken on an empty stomach or together with a meal.
Mayercotics therapy in patients who did not receive it before, begin in the first 48 hours after transplantation. The recommended dose is 720 mg (4 tablets of 180 mg or 2 tablets of 360 mg) 2 times / day, daily dose of 1440 mg. In patients receiving mycophenolate mycophenolate mofetil at a dose of 2 g / day, MMP can be replaced with Mayfortik in a dose of 720 mg 2 times / day.
Correction of the dosing regimen in elderly patients is not required.
In patients with delayed recovery of renal transplant function, a change in the dose of Mayforth is not required.
Careful observation of patients with severe renal dysfunction is necessary (QC less than 25 ml / min / 1.73 m 2 ) .
In patients with severe liver disease associated with the primary lesion of the parenchyma, there is no need for dose adjustment Mayfortika.
The rejection reaction of the transplant does not lead to a change in the pharmacokinetics of the IFC. In these cases, changes in the dosing regimen are not required.
SIDE EFFECT
The following adverse events were observed in two Mifortic and MMF safety studies in 423 patients with recently transplanted kidney who were not receiving previous maintenance therapy (patients with renal graft de novo) and 322 patients with kidney transplant receiving previous maintenance therapy. The incidence of adverse events was similar in both groups of patients.
With the use of Mafortika in combination with cyclosporine and glucocorticosteroids, very often (? 10%) such undesirable phenomena as leukopenia and diarrhea were observed.
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. Lymphoproliferative diseases or lymphomas developed in two patients with a renal transplant de novo (0.9%) and in two patients (1.3%) with a transplanted kidney receiving maintenance therapy for up to 1 year; non-melanoma skin carcinomas developed in 0.9% with a de novo renal transplant and in 1.8% of patients with kidney transplants who received previous supportive therapy with Mayfortic for up to 1 year; Other malignancies developed in 0.5% of patients with renal transplant de novo and 0.6% of patients with kidney transplant receiving maintenance therapy.
Infectious diseases (opportunistic infections). In patients with a recently transplanted kidney who received Miffortik as part of complex immunosuppressive therapy for 1 year, the most frequent infection was cytomegalovirus (CMV), candidiasis and infection caused by the herpes simplex virus. CMV infection (confirmed serologically, viremia or clinical data) was noted in 21.6% of patients with recently transplanted kidney and in 1.9% of patients with a stable graft on prolonged maintenance therapy.
Below are the undesirable events detected with the use of Mayforth at a dose of 1440 mg / day for 12 months in combination with a microemulsion of cyclosporine and corticosteroids in two clinical studies in patients with renal graft de novo and in patients with kidney transplant who received previous maintenance therapy . These phenomena had a possible or probable cause-and-effect relationship with the reception of Mayforth.
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 infestations: very often - viral, bacterial and fungal infections; often - infections of the upper respiratory tract; sometimes - wound infections, sepsis, osteomyelitis *.
On the part of the hematopoiesis system: very often - leukopenia; often - anemia, thrombocytopenia; sometimes - lymphocele *, lymphopenia *, neutropenia, lymphadenopathy *.
From the nervous system: often - headache; sometimes - a violation of sleep *, delusional perception *, tremor, insomnia *.
From the respiratory system: often - cough; sometimes - "stagnant" lung *, stridor.
From the digestive system: very often - diarrhea; often - bloating, abdominal pain, constipation, indigestion, flatulence, gastritis, loosening of the stool, nausea, vomiting, abnormalities in the results of functional liver tests; sometimes anorexia, abdominal wall tension, pancreatitis, belching, halitosis (bad breath), intestinal obstruction, esophagitis *, peptic ulcer *, subillus *, discoloration of tongue, gastrointestinal bleeding, dry mouth, ulceration of lips, occlusion excretory duct of the parotid salivary gland *, gastro-oesophageal reflux disease, gingival hyperplasia, peritonitis.
Common disorders: 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 - hyperlipidemia, diabetes mellitus *, hypercholesterolemia, hypophosphatemia *.
From the skin and subcutaneous tissue: sometimes - alopecia, bruises *.
From the cardiovascular system: sometimes - tachycardia, pulmonary edema *, ventricular extrasystole *.
From the side of the organ of vision: sometimes - conjunctivitis *, "clouding" of vision *.
From the musculoskeletal system: sometimes - arthritis *, back pain *, muscle cramps *.
Benign and malignant tumors: sometimes - skin papilloma *, basal cell carcinoma *, Kaposi's sarcoma *, lymphoproliferative disorders, squamous 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.
* - 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 receiving previous 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"):
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.
Phenomena associated with immunosuppression: infectious diseases of severe course, sometimes life-threatening, incl. meningitis, infective endocarditis, tuberculosis; atypical infections caused by mycobacteria.
When using mycophenolate mofetil (a derivative of mycophenolic acid - active substance Maisfortika), it was reported about the development of progressive multifocal leukoencephalopathy (in some cases, with lethal outcomes).
On the part of the hematopoiesis system: neutropenia, pancytopenia.
CONTRAINDICATIONS
- hypersensitivity to mycophenolate sodium, mycophenolic acid, mycophenolate mofetil or any other component of the drug.
With caution should prescribe the drug with congenital insufficiency of hypoxanthine-guanine-phosphoribosyl transferase (including Lesch-Nichena syndrome and Kelly-Sigmiller syndrome), gastrointestinal diseases in the phase of exacerbation.
PREGNANCY AND LACTATION
The use of the drug during pregnancy is possible only if the intended benefit for the mother exceeds the potential risk to the fetus.
With the use of Mayforth during pregnancy, there was an increased risk of developing congenital anomalies. According to the American National Pregnancy Pregnancy Registry (NTPR), the average incidence of congenital malformations in children born to women who undergo organ transplantation is 4-5%.
Although controlled studies on the use of Mayforth 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 registered in pregnancy - 22% (4 children from 18 newborns) compared with the average frequency. Most often, when using mycophenolate mofetil in pregnancy, anomalies in the development of the inner ear, limbs, craniofacial region (including cleft of the upper lip and palate), congenital diaphragmatic hernia and heart defects were noted in pregnancy. When administered or in / in the introduction of the conversion of mycophenolate mofetil to mycophenolic acid.
In experimental preclinical studies , the animals exhibited a teratogenic effect of mycophenolic acid.
It is not recommended to begin therapy with Mayfortic before a negative pregnancy test result is obtained. In case of pregnancy, the patient should immediately consult a doctor.
Before the start of Mayertics therapy, effective methods of contraception 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 decide whether to stop using Mayforth, or, given the importance of therapy with this drug for the mother, to stop breastfeeding throughout the therapy and for 6 weeks after its termination.
APPLICATION FOR FUNCTIONS OF THE LIVER
Careful observation of patients with severe renal dysfunction is necessary (QC less than 25 ml / min / 1.73 m 2 ) .
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
In patients with severe liver disease associated with the primary lesion of the parenchyma, there is no need for dose adjustment Mayfortika.
APPLICATION IN ELDERLY PATIENTS
Correction of the dosing regimen in elderly patients is not required
SPECIAL INSTRUCTIONS
Therapy Mifortikom should be conducted only by qualified transplant doctors.
In patients receiving combination immunosuppressive therapy including including , and Myfortic are at increased risk of developing lymphomas and other malignancies, particularly of the skin. This risk is likely not associated with the use of the drug, and with the intensity and duration of immunosuppressive therapy. To reduce exposure to sunlight and UV light to reduce the risk of skin cancer, it is recommended to protect the skin clothing and use a sunscreen with a high protection factor.
Patients receiving Myfortic therapy should be informed of the need to immediately tell your doctor about all the cases of infection, unexpected bruising, bleeding, and any other forms of oppression of bone marrow function.
Excessive immunosuppression increases the likelihood of infection, including opportunistic, as well as sepsis and infections with a fatal outcome.
Cases of progressive multfokalnoy leukoencephalopathy (PML) during treatment with mycophenolate mofetil have been reported primarily in patients with risk factors for PML, including treatment with immunosuppressive drugs, and immune disorders. The physician should consider the possibility of PML on the background of Myfortic therapy in patients with reduced immunity and, if necessary, to refer patients with neurological disorders to consult a neurologist. With the development of PML physician should consider the possibility of reducing the intensity of immunosuppressive therapy. However, transplant patients while reducing immunosuppression may increase the risk of graft rejection.
Patients receiving Myfortic therapy, it is possible the development of neutropenia associated with both the influence of the most IFC and concomitant medications, viral infections, or a combination of these factors. Patients receiving Myfortic should be regularly carried out to determine the number of white blood cells and blood cell counts: in the first month of therapy - weekly, during the second and third months - 2 times a month, and then, in the first year - 1 time per month. With the development of neutropenia (absolute neutrophil count <1500 / L) Myfortic therapy should interrupt or terminate.
Patients should be advised that during treatment drugs IFC vaccination may be less effective, and that we should avoid the use of live attenuated vaccines. Influenza vaccination may be useful for patients, so this issue should be guided by the recommendations of the local health authorities regarding the influenza vaccination.
Myfortic used in combination with the following drugs: antithymocyte globulin, basiliximab, cyclosporine (in the form of a microemulsion) and glucocorticoids. The efficacy and safety of Myfortic when used with other immunosuppressive agents has not been studied.
Use in Pediatrics
The efficacy and safety of Myfortic in children have not been studied. There are limited data on the pharmacokinetics in children who have undergone a kidney transplant. At present specific recommendations on dosing regimen is not designed for children.
Impact on the ability to drive vehicles and manage mechanisms
Effect receiving Myfortic the ability to drive a car, and operate the mechanisms is not established. The mechanism of action of Myfortic, its pharmacodynamic effects and recorded adverse events indicate low probability of influence. However, patients should be warned about possible adverse events and drug caution during activities requiring concentration.
OVERDOSE
Cases of overdose when using Myfortic have not been observed. Although inactive metabolite GMFK appear in hemodialysis, do not expect that this method will effectively remove clinically significant amounts of the active IFC. This is largely due to the high degree (97%) IFC binding to plasma proteins. Cholestyramine and other bile acid sequestrants violate IFC absorption from the intestine and therefore may lead to decrease in its concentration in the blood.
DRUG INTERACTION
As special studies of the interaction Myfortic and azathioprine has been conducted, these drugs should not be administered simultaneously.
Do not use live vaccines in patients with impaired immune response. The use of other vaccines antibody production can be reduced.
With simultaneous use of Myfortic and acyclovir in patients with impaired renal function may increase the concentration in the blood as GMFK and acyclovir. Perhaps both drugs compete with the excretion of (similar route of elimination - kanaltsievaya secretion). These patients require careful monitoring.
Joining ganciclovir has no effect on the pharmacokinetics of IFC and GMFK. Upon reaching therapeutic concentrations of ganciclovir IFC clearance does not change. However, when combined appointment Myfortic ganciclovir and patients with impaired renal function may require correction dosing regimen ganciclovir, and for such patients should be carefully monitored set.
When concomitant administration of Myfortic with antacids containing magnesium and aluminum hydroxide, absorption of mycophenolate sodium is reduced, whereby the AUC IFC reduced by 37% and C max - 25%. Care must be taken in the combined use with Myfortic antacid preparations containing magnesium hydroxide and aluminum.
In connection with its ability to bind bile acids in the intestine may reduce colestyramine IFC blood concentration and AUC. In connection with a possible reduction in the efficiency Myfortic caution during concomitant use of cholestyramine preparations and breaking circulation of bile acids.
In studies in patients with stable renal graft it has been shown that against the equilibrium concentrations Myfortic pharmacokinetics cyclosporin A did not change.
Oral contraceptives are metabolized via oxidation reactions while Myfortic - by glyukuronirovaniya. Effect of oral contraceptives on the pharmacokinetics of Myfortic is unlikely, and therefore, one can hardly expect any clinically significant interactions. On the other hand, if we take into account the fact that the impact of long-term treatment Myfortic pharmacokinetics of oral contraceptives has not been studied, we can not exclude the possibility of reducing the contraceptive effectiveness.
In patients with stable kidney transplant in the study with a crossover design was studied the pharmacokinetics of Myfortic in equilibrium with its simultaneous application with Sandimmun Neoralom and tacrolimus. Mean AUC values IFC by sharing a Myfortic and tacrolimus were 19% higher than with a joint reception Myfortic and Sandimmun Neoral, and the values of C max IFC - 20% lower. GMFK values for AUC and C max is reached 30% lower when receiving Myfortic with tacrolimus than when Myfortic with Sandimmune Neoralom.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
List B. The drug should be stored out of reach of children at or above 30 В° C, in their original packaging. Protect from moisture. Shelf life - 2.5 years. The drug should not be used after the expiration date.
