Mycophenolate Mofetil-TL - instructions for use, dose, side effects, contraindications

Active substance
Mycophenolate mofetil	0.500 grams
Excipients
Microcrystalline cellulose	0.130 g
Povidone-K90	0.028 g
Croscarmellose sodium	0.035 g
Magnesium stearate	0.007 grams
Film sheath of Opadrai II (white)	0.021 g
[polyvinyl alcohol - 46.9%, titanium dioxide - 12.1%, talc 17.4%, macroline 4000 - 23.6%]

Description:The tablets are round biconvex, covered with a white film membrane, two layers are visible on the cross section. The core of the tablet is white or almost white.

Pharmacotherapeutic group:Immunosuppressive remedy.

ATX: & nbsp

L.04.A.A Selective immunosuppressants

Pharmacodynamics:

Mycophenolate mofetil (MMF) is a 2-morpholinoethyl ester of mycophenolic acid (MPA). IFC is a potent selective noncompetitive and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDG), which suppresses the synthesis of guanosine nucleotides de novo. The mechanism by which IFC suppresses the enzyme activity of IMPDG appears to be due to the fact that the IFC structurally mimics both the cofactor of nicotinamide dinucleotide phosphate and the catalyzing water molecule. This prevents the oxidation of inosine monophosphate (IMP) into xanthose-5-monophosphate - the most important stage of the biosynthesis of guanosine nucleotides de novo. IFC has a more pronounced cytostatic effect on lymphocytes than on other cells, since the proliferation of T and B lymphocytes depends very strongly on purine synthesis de novo, while cells of other types can switch to metabolic bypasses.

To prevent rejection after kidney, heart and liver transplantation, MMF is used in combination with antitimocytic globulin, OKT3 (the orthoclone of mouse monoclonal antibodies), cyclosporine and glucocorticosteroids.

In kidney transplantation, the combination of MMF with glucocorticosteroids and cyclosporine reduces the incidence of ineffective use during the first 6 months after transplantation and histologically proven rejection during the use of the drug, at a dose of 2 g per day reduces the cumulative rate of graft death and mortality in 12 months after kidney transplantation, but in a dose of 3 g per day increases the frequency of premature dropout from the study for any reason.

According to the frequency of histologically proven rejection, lethality and repeated transplantations in cardiac transplantation, MMP exceeds azathioprine.

MMF in combination with glucocorticosteroids and cyclosporine is more effective than azathioprine, prevents acute rejection and provides similar survival with azathioprine in patients with primary liver transplantation.

The use of MMF reduced the frequency of graft death or deaths 6 months after the onset of use by 45% (p = 0.062) in patients who underwent kidney transplantation with refractory to the use of acute, cell-mediated rejection of the graft.

Pharmacokinetics:

Pharmacokinetic characteristics of MMP were studied in patients who underwent kidney, heart and liver transplantation. In general, in patients after kidney and heart transplantation, the pharmacokinetic profile of MMF is the same. In the early posttransplant period in patients who underwent liver transplant and received MMP at a dose of 1.5 g, the concentrations of MPA are the same as in patients after kidney transplantation receiving MMF at a dose of 1 g.

Suction

After oral administration, there is a rapid and complete absorption and complete presystemic metabolism of mycophenolate mofetil with the formation of an active metabolite - MPA. Bioavailability of mycophenolate mofetil for oral administration, in accordance with the value of AUC_IFC (area under the curve "concentration - time"), averages 94% of that for its intravenous administration. After oral administration, the concentrations of mycophenolate mofetil in plasma are not determined.

In the early post-transplant period (up to 40 days after kidney, heart or liver transplantation), the mean AUC_IFCwere approximately 30% lower, and maximum concentrations were about 40% lower than in the late post-transplant period (3-6 months after transplantation). Eating does not affect the degree of absorption of mycophenolate mofetil (AUC_IFC) at its application on 1,5 g twice a day in patients after kidney transplantation. However, the maximum concentration of IFC when taking the drug during meals is reduced by 40%.

Distribution

As a rule, approximately in 6-12 hours after taking the drug, a secondary increase in the concentration of MPA in the plasma is observed, which indicates a hepatic intestinal recirculation of the drug. With simultaneous application of colestyramine AUC_IFC is reduced by about 40%, indicating interruption of hepatic intestinal recirculation.

In clinically significant concentrations, the MPA is 97% bound to plasma albumin.

Metabolism

IFC is metabolized mainly under the action of glucuronyltransferase with the formation of pharmacologically inactive phenolic glucuronide MFC (IFPC). ln vivo IFPC is converted into a free IFC during hepatic intestinal recirculation.

Excretion

After oral administration of radiolabeled mycophenolate mofetil, 93% of the received dose is excreted in the urine, and 6% - with feces. Most (about 87%) of the administered dose is excreted in the urine in the form of MHCI. Minor quantities of the drug (<1% of the dose) are excreted in the urine in the form of an MFC.

Clinically determined concentrations of IFC and IFPC are not removed by hemodialysis. However, at higher concentrations of IFPC (> 100 μg / ml), some of it can be removed. Bile acid sequestrants such as colestyramine reduce AUC_IFC, interrupting hepatic intestinal recirculation.

Pharmacokinetics in special clinical groups

In a study with a single dose of the drug in patients with severe chronic renal failure (glomerular filtration rate <25 ml / min / 1.73 m²) AUC_IFC was 28-75% more than in healthy volunteers and patients with less severe renal involvement. After taking a single dose of AUC_IFCG in 3-6 times more in patients with severe renal failure, which is consistent with data on the renal excretion of IFH. Studies on the repeated administration of MMF in severe chronic renal failure have not been carried out.

Patients with delayed kidney transplant function after transplantation, the mean AUC_0-12 for IFC is comparable to that in patients in whom the graft began to function after a transplant without delay, and the mean AUC_0-12 for IFPC in the plasma was 2-3 times more.

Patients with liver damage. In volunteers with alcoholic cirrhosis of the liver after oral administration of MMF, no changes in the pharmacokinetics of IFC and IFPC have been revealed, indicating that damage to the liver parenchyma is not a contraindication for the use of MMF. The influence of hepatic pathology on this process probably depends on the specific disease. In the case of liver disease with predominance of lesions of the biliary tract (eg, primary biliary cirrhosis), the effect may be different.

In elderly and senile patients (≥65 years) pharmacokinetics has not been studied.

Indications:

In the combination therapy with cyclosporine and glucocorticosteroids.

Adults and children with a body surface area> 1.5 m² (approximate age of 14 years):

prevention of acute graft rejection in patients after allogeneic kidney transplantation.

Adults: prevention of acute graft rejection in patients after allogeneic heart transplant; prevention of acute graft rejection in patients after allogeneic liver transplantation.

Contraindications:

Hypersensitivity, pregnancy, breast-feeding (breastfeeding for the period of treatment stop), children with body surface area <1.5 m² (approximate age of 14 years), deficiency of hypoxanthine guanine phosphoribosyltransferase,

Carefully:

Diseases of the gastrointestinal tract (GIT) (in the phase of exacerbation), simultaneous reception with tacrolimus, sirolimus; with drugs that affect hepatic intestinal recirculation, along with azathioprine.

Simultaneous reception with azathioprine, severe chronic renal failure (glomerular filtration rate less than 25 ml / min / 1.73 m²) after allogeneic transplantation (AT) of the heart and liver (no data on efficacy and safety), severe hepatic failure after cardiac AT (no data on efficacy and safety).

Pregnancy and lactation:

Adequate and well-controlled studies in pregnant women have not been conducted.However, since the drug has a teratogenic effect in animals, it can adversely affect the human fetus.

The MMP should not be started until a negative pregnancy test result is obtained using the serum or urine analysis method with a sensitivity of at least 25 mIU / mL (no later than 1 week before the application begins). Prior to and during the application of MMF and within 6 weeks after the end, the use of effective methods of contraception is mandatory, even if the woman has a history of infertility (with the exception of the transferred hysterectomy). If abstinence from sexual intercourse is not possible, two reliable contraceptive methods should be used simultaneously. Simultaneous use of MMP does not affect the pharmacokinetics and pharmacodynamics of oral contraceptives, however, other methods of contraception should be used while taking MMP simultaneously with oral contraceptives. When pregnancy occurs during the course of the application, it is necessary to discuss the desirability of maintaining it with the doctor. If the patient uses the drug when planning a pregnancy or when a pregnancy occurs, she should be informed of the potential risk to the fetus.There is an increased risk of spontaneous abortion in the I trimester of pregnancy, as well as an increased risk of birth defects, including abnormalities of the ear, "cleft palate", "cleft lip", distal extremities, heart abnormalities, kidney and esophagus.

Whether the MMF is singled out with human milk is unknown. Since many drugs are excreted in human milk, as well as due to the possibility of serious adverse reactions to mycophenolate mofetil in infants, the choice between continuing breastfeeding or taking the drug is given the importance of the application for the mother.

Dosing and Administration:

For oral administration. The use of the MMP preparation should be started and carried out by transplant specialists having the appropriate qualifications. After kidney transplantation, heart or liver, the first dose of MMF formulation should be taken as quickly as possible - within 72 hours after renal transplantation, within 5 days after heart transplant surgery, for 4 days after allogeneic liver transplant.

Prophylaxis of rejection of a kidney transplant. Patients with renal transplants are recommended to take 1 g twice daily (daily dose of 2 g). Although clinical studies have shown that a dose of 1.5 g twice daily (a daily dose of 3 g) is also safe and effective, its benefits in terms of effectiveness in patients after kidney transplantation are not established. In patients receiving 2 g MMF per day, the safety profile was generally better than those receiving a daily dose of 3 g.

Prevention of heart transplant rejection. The recommended dosing regimen is 1.5 g 2 times a day (daily dose 3 g).

Prevention of liver transplant rejection. The recommended dosing regimen is 1.5 g 2 times a day (daily dose 3 g).

Dosing in special cases

When neutropenia (absolute number of neutrophils <1300 in 1 μl of blood) it is necessary to interrupt the use of MMP or reduce its dose and carefully observe the patient.

Patients with severe chronic renal failure (glomerular filtration rate less than 25 ml / min / 1.73 m²) outside the nearest post-transplantation period or after application for acute or refractory rejection, doses above 1 g 2 times per day should be avoided.Data on patients with severe renal failure who underwent a heart or liver transplant are not available.

Dose adjustments for patients with delayed kidney graft function not required. Patients who underwent a kidney transplant and who had a severe parenchyma of the liver, dose adjustment is not required. Data on patients with severe lesions of the liver parenchyma, who underwent heart transplant, are absent.

In elderly and senile patients (> 65 years) who underwent kidney transplantation, the recommended dose is 1 g 2 times a day, and after heart or liver transplantation - 1.5 g 2 times a day (see "Special instructions").

Children: after allogeneic kidney transplantation to prevent rejection of the graft to patients of child age, the recommended dose is 1 g twice a day (daily dose of 2 g). Pharmacokinetic data obtained in children who underwent kidney transplantation are very limited, and in children after cardiac or liver transplantation - are absent.

Data on the safety and effectiveness of the drug in children after heart and liver transplantation are not available.

Side effects:

Profile of side effects,associated with the use of immunosuppressants, it is often difficult to establish due to the presence of the underlying disease and the simultaneous use of many other medicines.

Clinical Trials Data

The main side reactions associated with the use of MMF in combination with cyclosporine and glucocorticosteroids to prevent rejection of the renal, cardiac or hepatic graft are diarrhea, leukopenia, sepsis and vomiting; there are also data on the increase in the incidence of opportunistic infections. The safety profile of MMF in the prevention of refractory rejection of the kidney is similar to that in the prevention of kidney rejection when using the drug at a dose of 3 g per day. Diarrhea, leukopenia, anemia, nausea, vomiting, abdominal pain, sepsis were the predominant adverse reactions that occurred in patients on MMF more often than patients who received intravenous glucocorticosteroids.

Malignant neoplasms

In patients who underwent a kidney, heart or liver transplant and who had been observed for at least 1 year, lymphoproliferative diseases or lymphomas developed in 0.4-1.0% of patients receiving MMF (in doses of 2 or 3 g / day) in combination with other immunosuppressants .Skin cancer (excluding melanoma) was noted in 1.6-4.2% of patients, malignant neoplasms of other types - in 0.7-2.1% of patients. Three-year data on safety in patients after kidney or heart transplant did not reveal any unexpected changes in the incidence rate of malignant tumors, compared with annual indicators. After liver transplant patients were observed for at least 1 year, but less than 3 years.

Opportunistic infections

The risk of opportunistic infections is increased in all posttransplant patients and increases with an increase in the degree of immunosuppression (see section "Special instructions"). When MMF (2 or 3 g / day) was used in combination with other immunosuppressants in patients who had been observed for 1 year after kidney transplantation (at a dose of 2 g per day), heart and liver, the most frequent infections were candidiasis of the skin and mucous membranes, cytomegalovirus (CMV) infection: CMV viremia / CMV syndrome (13.5%) and infection caused by the herpes simplex virus.

The type of adverse reactions and the frequency of their occurrence with oral administration of 600 mg MMF 2 times a day in children aged 3 months to 18 years practically did not differ from those in adult patients who received the drug at a dose of 1 g 2 times a day.However, such adverse reactions as diarrhea, leukopenia, sepsis, infections, anemia were more common (≥10%) in children, especially under the age of 6 years. In elderly and senile patients (≥65 years) with MMF, the risk of certain infections (including tissue invasive forms of manifest cytomegalovirus infection), and possibly gastrointestinal bleeding and pulmonary edema is higher than in younger patients.

Undesirable effects when using MMP in combination with cyclosporine and glucocorticosteroids after kidney, heart and liver transplantation:

		Adverse events after transplantation kidneys	Adverse events after transplantation hearts	Adverse events after transplantation liver
Infectious and parasitic diseases	3-<10%	infection, sepsis	infection, sepsis	infection, sepsis
Violations of the blood and lymphatic system	≥10%	anemia (including hypochromic), leukocytosis, leukopenia, thrombocytopenia	anemia (including hypochromic), leukocytosis, leukopenia, thrombocytopenia, ecchymosis	anemia (including hypochromic), leukocytosis, leukopenia, thrombocytopenia
Violations of the blood and lymphatic system	3-<10%	ecchymosis, polycythemia, bleeding	petechiae, increased prothrombin and thromboplastin time, bleeding	ecchymosis, increased prothrombin time, pancytopenia, bleeding
Disorders from the endocrine system	3-<10%	diabetes mellitus, parathyroid gland disease (increased parathyroid hormone level)	diabetes, Cushing's syndrome, hypothyroidism	diabetes
Disorders from the metabolism and nutrition	≥10%		acidosis (metabolic or respiratory), hypervolemia, weight gain
Disorders from the metabolism and nutrition	3-<10%	acidosis (metabolic or respiratory), dehydration, hypervolemia, weight gain	alkalosis, dehydration, gout, hypovolemia, hypoxia, respiratory acidosis, thirst, weight loss, hypervolemia	acidosis (metabolic or respiratory), dehydration, hypervolemia, hypoxia, hypovolemia, weight gain, weight loss
Disturbances from the nervous system	≥10%	dizziness, insomnia, tremor, headache	agitation, anxiety, confusion, depression, dizziness, hypertonia, insomnia, paresthesia, drowsiness, tremor, agitation, headache	anxiety, confusion, depression, dizziness, insomnia, paresthesia, tremor, headache
Disturbances from the nervous system	3-<10%	anxiety, depression, hypertonia, paresthesia, drowsiness	convulsions, emotional lability, hallucinations, neuropathy, thinking disorders, vertigo, dizziness	agitation, convulsions, delirium, dry mouth, hypertonus, hypoesthesia, neuropathy, psychosis, drowsiness, thinking disorders, delirium, agitation
Disturbances on the part of the organ of sight	≥10%		amblyopia
Disturbances on the part of the organ of sight	3-<10%	amblyopia, cataract, conjunctivitis	visual disturbances, conjunctivitis, hemorrhages in the eye	visual impairment, amblyopia, conjunctivitis
Hearing disorders and labyrinthine disorders	3-<10%		deafness, earache, tinnitus	deafness
Heart Disease	≥10%		arrhythmia, bradycardia, heart failure, pericardial effusion	tachycardia
Heart Disease	3-<10%	Angina pectoris, atrial fibrillation, tachycardia, palpitations	angina, arrhythmias (supraventricular and ventricular extrasystoles, flutter and atrial fibrillation, supraventricular and ventricular tachycardias), cardiac arrest, congestive heart failure, syncope	Atrial fibrillation, arrhythmias, bradycardia, syncope
Vascular disorders	≥10%	increase in blood pressure	decrease and increase of arterial pressure	decrease and increase of arterial pressure
Vascular disorders	3-<10%	lowering of arterial pressure, orthostatic hypotension, thrombosis, vasodilation	orthostatic hypotension, pulmonary hypertension, vasospasm, increased venous pressure	arterial thrombosis, vasodilation
Disturbances from the respiratory system, chest and mediastinal organs	≥10%	cough, dyspnea, pharyngitis, pneumonia, bronchitis	asthma, coughing, dyspnea, pharyngitis, pleural effusion, pneumonia, rhinitis, sinusitis	cough, dyspnea, pharyngitis, pneumonia, pleural effusions, sinusitis, atelectasis
	3-<10%	asthma, pleural effusion, pulmonary edema, rhinitis, sinusitis	apnea, atelectasis, bronchitis, epistaxis, hemoptysis, hiccough, neoplasm, pneumothorax, pulmonary edema, increased sputum separation, voice change	asthma, bronchitis, epistaxis, hyperventilation, pneumothorax, pulmonary edema, candidiasis of the respiratory tract, rhinitis
Disorders from the gastrointestinal tract	≥10%	constipation, diarrhea, indigestion, nausea and vomiting, candidiasis of the oral mucosa, abdominal pain	constipation, diarrhea, indigestion, flatulence, nausea and vomiting, candidiasis of the oral mucosa, abdominal pain	anorexia, constipation, diarrhea, dyspepsia, flatulence, nausea and vomiting, candidiasis of the oral mucosa, hernia, peritonitis, ascites, abdominal pain, bloating
Disorders from the gastrointestinal tract	3-<10%	anorexia, flatulence, gastroenteritis, gastrointestinal bleeding, candidiasis of the gastrointestinal tract, gingivitis, gingival hyperplasia, intestinal obstruction, stomatitis, esophagitis, loss of appetite, gastritis, hernia, bloating	anorexia, dysphagia, gastroenteritis, gingivitis, gingival hyperplasia, melena, stomatitis, esophagitis, loss of appetite, hernia, bloating	dysphagia, gastritis, gastrointestinal bleeding, intestinal obstruction, melena, ulceration of the oral mucosa, esophagitis, rectal damage, gastric ulcer
Disturbances from the liver and bile ducts	≥10%		increased activity of lactate dehydrogenase (LDH), aspartate aminotransferase (ACT), alanine aminotransferase (ALT), bilirubinemia	bilirubinemia, cholangitis, cholestatic jaundice, hepatitis, increased activity of hepatic enzymes (including aspartate aminotransferase (ACT), alanine aminotransferase (ALT))
Disturbances from the liver and bile ducts	3-<10%	impaired liver function, increased concentrations of alkaline phosphatase, hepatitis, increased activity of hepatic enzymes (including aspartate aminotransferase (ACT), alanine aminotransferase (ALT))	impaired liver function, increased concentrations of alkaline phosphatase, jaundice, increased activity of hepatic enzymes (including aspartate aminotransferase (ACT), alanine aminotransferase (ALT))	jaundice
Disturbances from the skin and subcutaneous tissues	≥10%	acne, herpes simplex	acne, herpes simplex, shingles, rash	rash, itching, excessive sweating, hard-healing wounds
Disturbances from the skin and subcutaneous tissues	3- <10%	hair loss, benign neoplasms of the skin, fungal dermatitis, shingles, hirsutism, itching, skin cancer, skin hypertrophy (including actinic keratosis), excessive sweating, skin ulcers, rash	benign skin tumors, fungal dermatitis, hemorrhages, itching, skin cancer, skin hypertrophy, excessive sweating, skin ulcers, hard-healing wounds, cellulite	acne, fungal dermatitis, hemorrhages, herpes simplex, shingles, hirsutism, benign skin lesions, skin ulcers, vesicle-bullous rash, cellulitis, scrotal edema, abscesses
Disturbances from musculoskeletal and connective tissue	≥10%	back pain	cramps in the legs, muscle aches, muscle weakness, back pain	back pain
Disturbances from musculoskeletal and connective tissue	3-<10%	pain in the joints, leg cramps, muscle pain, muscle weakness	pain in the joints, pain in the neck	pain in the joints, leg cramps, muscle pain, muscle weakness, osteoporosis
Disorders from the kidneys and urinary tract	≥10%	hematuria, renal tubular necrosis, urinary tract infection	impaired renal function (decreased kidney function, increased serum creatinine concentration), oliguria, urinary tract infection	impaired renal function (decreased kidney function, increased serum creatinine concentration), oliguria, urinary tract infection
Disorders from the kidneys and urinary tract	3- <10%	albuminuria, dysuria, hydronephrosis, pyelonephritis, frequent urination	dysuria, hematuria, nocturia, renal failure, frequent urination, incontinence and urinary retention	acute renal failure, dysuria, hematuria, renal failure, frequent urination, incontinence
Violations of the genitals, mammary glands	3-<10%	impotence	impotence
General disorders and disorders at the site of administration	≥10%	asthenia, fever, infection, pain in the chest, swelling, sepsis	asthenia, fever, chills, infections, pain in the chest, swelling, sepsis	asthenia, fever, chills, infections, pain in the chest, swelling, sepsis
	3- <10%	cysts (including lymphocele and hydrocele), facial swelling, flu-like syndrome, malaise, pelvic pain	cysts (including lymphocele and hydrocele), facial swelling, flu-like syndrome, malaise, pelvic pain, pallor of the skin	cysts (including lymphocele and hydrocele), flu-like syndrome, malaise, pain in the neck
Laboratory and instrumental data	≥10%	hypercholesterolemia, hyperglycemia, hyperkalemia, hypokalemia, hypophosphataemia	hyperbilirubinemia, increased residual nitrogen, increased creatinine concentration, increased activity of enzymes (lactate dehydrogenase (LDH), aspartate aminotransferase (ACT), alanine aminotransferase (ALT)) in the blood serum, hypercholesterolemia, hyperglycemia, hyperkalemia, hyperlipidemia, hyperuricemia, hypokalemia, hyponatremia	hyperbilirubinemia, increased residual nitrogen, increased creatinine concentration, hyperglycemia, hyperkalemia, hypokalemia, hypocalcemia, hypoglycemia, hypomagnesemia, hypophosphatemia, hypoproteinemia
	3-<10%	increased activity of alkaline phosphatase,increase in the activity of enzymes (gamma glutamyltranspeptidase, lactate dehydrogenase (LDH), aspartate aminotransferase (ACT), alanine aminotransferase (ALT)) in serum, increased serum creatinine concentration, hypercalcemia, hyperlipidemia, hypocalcemia, hypoglycemia, hypoproteinemia, hyperuricemia	increased activity of alkaline phosphatase, hypocalcemia, hypochloraemia, hypoglycemia, hypoproteinemia, hypophosphataemia	increased activity of alkaline phosphatase, increased activity of enzymes (aspartate aminotransferase (ACT), alanine aminotransferase (ALT)) in the blood serum, hypercholesterolemia, hyperlipidemia, hyperphosphatemia, hyponatremia

In the prevention of rejection of the renal transplant, the safety profile of MMF in a daily dose of 2 g was slightly better than in a daily dose of 3 g.

Post-marketing application of the drug

From the gastrointestinal tract: colitis (sometimes cytomegalovirus etiology), pancreatitis, isolated cases of atrophy of intestinal villi.

Infectious and parasitic diseases: individual cases of severe life-threatening infections (meningitis, infective endocarditis), an increase in the incidence of certain infections such as tuberculosis and atypical mycobacterial infections.

Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal, were observed in patients taking MMF. In reports on these cases, there is information about the presence of additional risk factors for the development of PML in patients, including immunosuppressive therapy and impairment of immunity.

Cases of development of partial red cell aplasia (PKAA) were observed in patients taking MMP in combination with other immunosuppressive drugs.

Influence on the fetus: cases of fetal development anomalies (including malformations of the ear) in patients taking MMP during pregnancy in combination with other immunosuppressants have been reported.

Other undesirable reactions observed during the post-marketing use of the drug do not differ from the undesirable reactions recorded in controlled clinical trials.

If any of the side effects listed in the manual are aggravated, or if you notice any other side effects not listed in the instructions, inform the doctor about it.

Overdose:There is no data on an overdose of MMF in humans.In most cases, no undesirable events have been reported. Developed during an overdose, undesirable events coincided with the known safety profile of the drug. It is expected that an overdose of MMP is likely to lead to immunosuppression (as a consequence, to an increased sensitivity to infections) and bone marrow suppression. In the case of neutropenia, MMP should be stopped or the dose of the drug reduced. IFC can not be removed from the body by hemodialysis. However, at high concentrations of IFPC in plasma (> 100 μg / ml), small amounts are still output. Preparations that bind bile acids, for example, colestramine, can help eliminate IFC from the body, increasing its excretion.

Interaction:

Acyclovir: higher plasma concentrations of acyclovir were noted with the use of mycophenolate mofetil with acyclovir, compared with the administration of acyclovir alone. Changes in the pharmacokinetics of the phenolic glucononide IFC (IFPC) were minimal (an increase in IFPC by 8%) and is not considered clinically significant. Due to the fact that the plasma concentrations of IFCG are increased by violationfunctions of the kidneys, as well as the concentration of acyclovir, there is the possibility that mycophenolate mofetil and acyclovir or a prodrug thereof, for example valaciclovir, will compete for tubular secretion, and further concentrations of both substances may occur.

Antacids containing magnesium hydroxide and aluminum: with simultaneous application of mycophenolate mofetil and antacids (magnesium hydroxide and aluminum hydroxide) or proton pump inhibitors (including lansoprazole and pantoprazole) there was a decrease in the exposure of the IFC. Significant differences in the incidence of transplant rejection between patients taking mycophenolate mofetil and STIs, and patients taking only mycophenolate mofetil (without IPP), was not observed.

Kolestyramine: after applying a single dose of 1.5 g of mycophenolate mofetil to healthy volunteers who previously took 4 g of colestyramine 3 times a day for 4 days, a decrease in AUC_IFC on 40%. It should be used with caution both MMF and colestramine, considering the potential ability to reduce the effectiveness of mycophenolate mofetil.

Azathioprine: It is not recommended to use MMF simultaneously with azathioprine, since their simultaneous use has not been studied.

Medicines that disrupt enterohepatic recycling: it is necessary to use with caution the drugs that disrupt enterohepatic recycling, given their potential ability to reduce the effectiveness of mycophenolate mofetil.

Cyclosporine: the pharmacokinetics of cyclosporine (CsA) did not change with simultaneous use with MMF. Conversely, when discontinuation of concomitant use with cyclosporin, an increase in AUC_IFC by about 30%.

Ganciclovir: based on the results of the study with a single oral intake of the recommended doses of mycophenolate mofetil and the administration of ganciclovir, given the known effect of renal failure on the pharmacokinetics of mycophenolate mofetil and ganciclovir, it can be expected that the simultaneous use of these agents (competing in renal tubular secretion) will lead to an increase in the concentration of IFPC and ganciclovir. A significant change in the pharmacokinetics of IFC is not expected, so adjust the dose of mycophenolate mofetil is not required.Patients with renal insufficiency who simultaneously use mycophenolate mofetil and ganciclovir or a prodrug thereof, for example valganciclovir, it is necessary to adhere to the recommended dosing regimen for ganciclovir and to establish constant monitoring of the patient.

Oral contraceptives: simultaneous application of mycophenolate mofetil does not affect the pharmacokinetics and pharmacodynamics of oral contraceptives.

Rifampicin: simultaneous application of mycophenolate mofetil and rifampicin leads to a decrease in exposure to IFC (AUC_0-12) from 18 to 70%. It is recommended to monitor the exposure concentration of the IFC and adjust the dose of MMF accordingly to maintain clinical efficacy while being used with rifampicin.

Sirolimus: in patients with kidney transplant, the simultaneous use of mycophenolate mofetil and cyclosporin A reduced the exposure of MFC by 30-50% compared with patients receiving a combination of sirolimus and similar doses of mycophenolate mofetil.

Sevelamer: decrease in IFC C_max and AUC_0-12 at 30 and 25%, respectively, with simultaneous use of mycophenolate mofetil with sevelamer without any clinical consequences (i.e., transplant rejection).However, it is recommended to use MMF at least 1 hour before or 3 hours after taking sevelamer, in order to minimize the effect on IFC absorption. There are no data on the interaction of mycophenolate mofetil with other substances that bind phosphate, except for sevelamer.

Trimethoprim / sulfamethoxazole: no influence on the bioavailability of IFC was detected.

Ciprofloxacin and amoxicillin in combination with clavulanic acid: for several days immediately after the onset of oral administration of ciprofloxacin or amoxicillin with clavulanic acid, a reduction in the preset (minimum) IFC value by approximately 50% was reported in patients with renal transplants. With the onset of antibiotic therapy, this effect tended to decrease and disappeared within a few days after their cessation. Changes in the preset value can not accurately indicate changes in the overall exposure of the IFC. Accordingly, there is no need to change the dose of MMF in the absence of clinical signs of graft dysfunction. However, it is necessary to carry out thorough clinical monitoring during combined treatment and shortly after antibiotic treatment.

Norfloxacin and metronidazole: in healthy volunteers, no significant interaction was noted when mycophenolate mofetil used simultaneously with norfloxacin and metronidazole separately. However, the combination of norfloxacin and metronidazole reduced the exposure of the IFC by about 30% after a single dose of mycophenolate mofetil.

Tacrolimus: in liver transplant recipients who started taking mycophenolate mofetil and tacrolimus, AUC and C_max IFC has not been significantly affected by the minimum concentration of tacrolimus. In patients with a kidney transplant, obviously, the concentration of tacrolimus is not affected by mycophenolate mofetil. However, in patients with liver transplant who took the tacrolimus, an increase in the Tacrolimus AUC was observed by approximately 20% after multiple administration of mycophenolate mofetil (1.5 g 2 times a day, morning and evening).

Other interactions: while simultaneous application of probenecid and mycophenolate mofetil in animals, an increase in AUC_IFC in blood plasma in 3 times. Thus, other drugs exposed to renal tubular secretion can compete with IFCG,which leads to an increase in the concentration in the blood plasma of the IFPC or other agent, which is also subjected to tubular secretion.

Live vaccines: Live vaccines should not be administered to patients who are immunosuppressed. Antibody formation in response to other vaccines can be reduced.

Special instructions:As against the combined immunosuppression in general, and with the use of MMF as a component of the immunosuppressive regimen, there is an increased risk of developing lymphomas and other malignant tumors, especially the skin (see section "Side effect"). This risk appears to be associated not with the use of any drug per se, but with the intensity and duration of immunosuppression.

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. Patients receiving MMF should be informed of the need to report immediately to the doctor any signs of infection, bleeding, bleeding, or other signs of bone marrow depression.Excessive suppression of the immune system can also increase susceptibility to infections, including opportunistic, sepsis and other fatal infections.

In patients taking MMP, a latent viral infection, such as hepatitis B or C, or an infection caused by polyomavirus can be reactivated. Cases of PML development associated with JC virus, sometimes fatal, were observed in patients taking MMF. In reports on these cases, there is information about the presence of additional risk factors for the development of PML in patients, including immunosuppressive therapy and impairment of immunity. In patients with immunosuppression in the presence of neurologic symptoms should conduct differential diagnosis of PML and recommend a consultation of a neurologist.

The incidence of PKA was observed in patients taking MMP in combination with other immunosuppressive drugs. The mechanism of development of PKA in the use of MMF is not known, as well as the contribution of other immunosuppressants and their combination. In some cases, the PKA was reversible after a decrease in the dose of MMF or cancellation.However, in patients who undergone transplantation, a decrease in immunosuppression may compromise the graft. During the MMP application, vaccination may be less effective; It is necessary to avoid the use of live attenuated vaccines. It is possible to carry out influenza vaccination in accordance with national recommendations. Because MMF may be accompanied by adverse reactions from the gastrointestinal tract (gastrointestinal ulceration of the gastrointestinal tract, gastrointestinal bleeding, gastrointestinal perforation), care should be taken when MMF is used for patients with digestive tract diseases in the acute stage. Since MMF is an inhibitor of IMPDG, it should not, theoretically, be applied to patients with a rare genetically determined hereditary deficiency of hypoxanthine guanine phosphoribosyltransferase (Lesch-Nienen syndrome and Kelly-Zygmiller syndrome). MMF is not recommended to be used simultaneously with azathioprine, since both drugs depress the bone marrow, and their simultaneous administration has not been studied. Caution should be exercised while using MMF with drugs that affect hepatic intestinal recirculation,since they can reduce the effectiveness of MMF (see "Interaction with other drugs"),

In patients with severe chronic renal failure, doses greater than 1 g 2 times per day should be avoided. Correction of the dose to patients with delayed renal transplant function is not required, but they must be carefully observed. There are reports of the development of nephropathy associated with VC virus. Nephropathy is manifested by a progressive decrease in the function of the transplant. The period of onset of nephropathy associated with VC virus is from 1 to 15 months (an average of 9 months after transplantation). This infection can lead to serious consequences, sometimes to the death of a kidney transplant. The status of patients taking MMF should be monitored to identify patients at risk of developing nephropathy associated with BV virus. With the development of symptoms of nephropathy associated with BV-virus, it is necessary to consider the question of reducing immunosuppression.

Data on patients who underwent a heart or liver transplant and who have severe renal failure are not available.

In elderly and elderly patients, the risk of adverse events may be higher than in younger patients.

Laboratory testing: when using MMF it is necessary to determine the developed blood formula during the first month weekly, during the second and third months of treatment - twice a month, and then during the first year - every month. Neutropenia can be associated with both MMF intake and other medications, viral infections, or a combination of these causes. If neutropenia occurs (the absolute number of neutrophils is less than 1300 in 1 μl), it is necessary to interrupt the use of MMP or reduce the dose, while carefully monitoring these patients.

Treatment with the drug

Do not break the MMP tablet. It is necessary to avoid direct contact of the ground tablets on the skin or mucous membranes. If this happens, you need to thoroughly rinse this area with soap and water, and your eyes - just water.

Effect on the ability to drive transp. cf. and fur:

Taking into account the profile of the revealed adverse reactions when taking MMP such as dizziness, psychomotor agitation, insomnia, tremor, drowsiness, confusion,to drive vehicles, operate machinery or engage in other potentially hazardous activities that require a high concentration of attention and speed of psychomotor reactions, it is necessary taking into account the profile of side effects. When these undesirable phenomena appear, one should refrain from performing these activities.

Form release / dosage:

Tablets, film-coated, 500 mg.

Packaging:

For 10 tablets in a contour mesh box made of polyvinylchloride film and aluminum foil printed lacquered. For 50, 100 or 150 tablets in a jar (bottle) polymer for medicines or in a jar (bottle) for medicines made of plastic. A jar (bottle), 5, 10 or 15 contour squares, together with instructions for use, is placed in a pack of cardboard boxes.

Storage conditions:

In the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:2 years.

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

Terms of leave from pharmacies:On prescription

Registration number:LP-001706

Date of registration:10.05.2012 / 15.12.2014

Expiration Date:10.05.2017

The owner of the registration certificate:TECHNOLOGY OF DRUGS, LTD. TECHNOLOGY OF DRUGS, LTD. Russia

Manufacturer: & nbsp

TECHNOLOGY OF DRUGS, LTD. Russia

R-PHARM, JSC Russia

Information update date: & nbsp25.09.16

Illustrated instructions

Instructions

Mycophenolate Mofetil-TL (Mycophenolate mofetil-TL)