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

Active substance
Mycophenolate mofetil	0.250 g
Excipients
Microcrystalline cellulose	0.0650 g
Povidone-K90	0.0140 g
Croscarmellose sodium	0.0175 g
Magnesium stearate	0.0035 grams
Capsule shell
Hard gelatin capsule
[body: iron oxide dye
black - 0.0224%, iron dye
oxide red - 0.0224%,
dye iron oxide yellow - 0.4343%,
titanium dioxide -	№0
0.5265%, gelatin - up to 100%;	0.100 g
lid: iron oxide dye
black - 0.07%, iron dye
oxide red - 0.07%,
dye iron oxide yellow - 0.5%,
titanium dioxide - 0.667%,
gelatin - up to 100%]

Description:Hard gelatin capsules №0 with a yellow body with a brownish hue and a light brown lid. The contents of capsules are powder from white to almost white.

Pharmacotherapeutic group:Immunosuppressive remedy.

ATX: & nbsp

L.04.A.A Selective immunosuppressants

Pharmacodynamics:Immunosuppressant, an inhibitor of inosine monophosphate dehydrogenase (IMPDG). Mycophenolate mofetil (MMF) is a 2-morpholinoethyl ester of mycophenolic acid (MPA). IFC is a powerful selective non-competitive and reversible inhibitor of IMPDG, which suppresses the initial cascade of reactions of guanosine nucleotide synthesis without introduction into DNA. Proliferation of T- and B-lymphocytes critically depends on the synthesis of purines de novo, while cells of other types can use different metabolic pathways. IFC has a more pronounced cytostatic effect on lymphocytes than on other cells.

Pharmacokinetics:

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 (below the detection threshold of 0.4 μg / ml).

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 cases

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 predominant damage to the bile duct, such as primary biliary cirrhosis,can demonstrate a different effect on the metabolism of IFC.

In patients of childhood (<18 years), who underwent kidney transplantation, after oral administration of MMF in a dose of 600 mg / m² twice a day (up to 1 g twice a day), the AUC_IFC is comparable to that in adult patients after kidney transplant receiving the drug at a dose of 1 g twice daily, in the early and late post-transplant period. The AUC values_IFC did not differ between age groups in the early and late transplantation period.

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

Indications:Adults and children with a body surface area> 1.25 m²(approximate age over 12 years):

prevention of acute rejection of allogeneic kidney transplant in the combination therapy with cyclosporine and glucocorticosteroids.

Adults:

prevention of acute rejection of allogeneic heart and liver transplant in combination therapy with cyclosporine and glucocorticosteroids.

Contraindications:

hypersensitivity to mycophenolate mofetil, mycophenolic acid and other components of the drug;
children with a body surface area <1.25 m² (approximate age of 12 years);
deficiency of hypoxanthine guanine phosphoribosyltransferase (a rare genetic disease due to a hereditary deficiency of hypoxanthyguanine phosphoribosyltransferase - Lesch-Mayen and Kelly-Zygmiller syndromes);
pregnancy;
simultaneous administration with azathioprine (both drugs depress the bone marrow, their simultaneous administration has not been studied);
severe chronic renal failure (glomerular filtration rate less than 25 ml / min / 1.73 m²) after allogeneic transplantation (AT) of the heart and liver (data on efficiency and safety are not);
severe hepatic failure after cardiac atherosclerosis (data but no efficacy and safety);
the period of breastfeeding.

Carefully:

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

Pregnancy and lactation:

Women of childbearing age

Use of MMF during pregnancy it is contraindicated.

Therapy MMP ns should begin before those pores until a negative result is obtained pregnancy tests with isnoanalysis of serum or urine with sensitivity of at least 25 mIU / mL (not later 1 week before the start of therapy).

Before starting MMP therapy, during treatment and in for 6 weeks after the end of therapy it is necessary to use reliable methods contraception, even if in a woman's historyThere is infertility (except for Persiansworn 1 hysterectomy).

If abstinence from sexual activity is not possibleyou can use two reliablecontraceptive method at the same time, hormonal concentrations with oral administrationof contraception onRapid mycophenolate with mofetil.

The increased risk is revealed spontaneouslyth miscarriage in the first trimesteras well as an increased risk of congenital developmental anomalies, including developmental anomalies external ear, "wolf mouth", "hare lip", distal limbs, anomalies heart, esophagus and kidneys.

A patient planning a pregnancy is not should take mycophenolate mofetil before those holes, while other immunodeficides are effectivePressed preparations. If the patient isdrug when planning a pregnancyor when a pregnancy occurs, she should be informed about thethe potential harm to the fetus.

Breast-feeding

In rats, MMP is excreted in milk. SelectWhether MMF is available with human milk is unknown. Since it is excreted with human milkmany drugs, as well as in connection with thethe development of serious adverseshares in MMF in infants, if necessarythe use of the drug during the lacquer periodYou must stop breastfeedingcasting.

Dosing and Administration:For oral administration. Treatment with the drug Mycophenolate Mofetil-TL should be initiated and conducted by specialists in transplantology, with the appropriate qualifications.

Adult patients

Prophylaxis of kidney transplant rejection

The drug should be taken within 72 hours after the transplant operation. Patients with renal transplants are recommended to take 1 g (4 250 mg capsules) twice a day (a daily dose of 2 g - 8 capsules of 250 mg).

Prevention of heart transplant rejection

The drug should be taken within 5 days after the transplant operation.The recommended dosage regimen is 1.5 g (6 250 mg capsules) 2 times a day (daily dose of 3 g - 12 capsules of 250 mg).

Prevention of liver transplant rejection

The drug should be taken as early as possible after the transplant operation (depending on the patient's ability to transfer the drug). The recommended dosage regimen is 1.5 g (6 capsules 250 mg) twice a day (daily dose of 3 g - 12 capsules of 250 mg).

Dosing in special cases

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

In patients with severe chronic renal insufficiency (glomerular filtration rate less than 25 ml / min / 1.73 m²) after the AT heart and liver MMF is contraindicated. However, in special cases in patients with severe chronic renal insufficiency after AT heart and liver outside the nearest post-transplantation period or after therapy for acute or refractory rejection with MMF, doses above 1 g (4 250 mg capsules) should be avoided 2 times a day. Data on patients with severe renal failure who underwent a heart or liver transplant are not available (see section "Special instructions").

Correction of the dose to patients with delayed kidney graft function not required. Patients who underwent kidney transplantation and having a heavy 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 patients elderly and senile age (> 65 years) who underwent a kidney transplant, the recommended dose is 1 g (4 250 mg capsules) 2 times a day, and after a heart or liver transplant - 1.5 g (6 capsules 250 mg each) twice a day.

Children

- prevention of kidney transplant rejection: patients aged over 12 years (at a surface area of 1.25-1.50 m²⁾ who underwent renal transplantation, it is possible to use capsules in a single dose 750 mg (3 250 mg capsules) twice daily (daily dose of 1.5 g - 6 capsules but 250 mg);

- with a surface area of more than 1.50 m² it is possible to use capsules of 1 g (4 capsulesly 250 mg) twice a day (daily dose of 2 g - 8 capsules of 250 mg each);

- data on the safety and efficacy of the drug in patients of childhood after heart or liver transplantation are absent.

Side effects:

The 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 drugs.

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 certain types of infections, for example, opportunistic infections (see section "Special instructions").

Malignant neoplasms

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"). In controlled clinical trials, 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 (at doses of 2 or 3 g / day) in combination with other immunosuppressants.Skin cancer (excluding melanoma) was noted in 1.6-3.2% 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"). In controlled clinical trials using MMF (2 or 3 g / day) in combination with other immunosuppressants in patients who were 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. After kidney transplantation, sepsis (usually associated with CMV) was more likely to occur in patients receiving MMF than in the control group.In patients receiving MMF at a dose of 3 g, the incidence of sepsis was higher than in patients receiving MMF at a dose of 2 g.

Children (3 months - 18 years)

The type of adverse reactions and the frequency of their occurrence in a clinical trial with oral administration of 600 mg / m²MMF 2 times a day in children aged 3 months to 18 years (N = 100) 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) in the treatment of MMF in a combination of immunosuppressive therapy, the risk of certain infections (including tissue invasive forms of manifest cytomegalovirus infection), and possibly also gastrointestinal bleeding and pulmonary edema is higher than in younger patients (see section "Special instructions").

Adverse events noted in ≥10% and in 3-10% of patients receiving MMF in combination with cyclosporine and glucocorticosteroids in controlled studies on the prevention of kidney transplant rejection (3 studies, data for a daily dose of 2 and 3 mg),in a controlled heart transplantation study and in a controlled liver transplantation study.

		Adverse events after kidney transplantation (n = 991) *	Adverse events after cardiac transplantation (n = 289) **	Adverse events after liver transplantation (n = 277) ***
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, increase serum creatinine concentration, increasing the activity of enzymes (lactate dehydrogenase (LDH), aspartate aminotransferase (ACT), alanine aminotransferase (ALT) levels) 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, increased 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

* (total n = 1483), ** (total n = 578), *** (total n = 564)

In three controlled studies on the prevention of kidney transplant rejection, 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

On the part of the digestive system: colitis (sometimes cytomegalovirus etiology), pancreatitis, isolated cases of atrophy of intestinal villi.

From the immune system: 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.

In patients taking MMF, there were cases of development of nephropathy associated with VC virus (VC virus-associated nephropathy). This infection can lead to serious consequences, sometimes to the death of a kidney transplant.

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

Developmental anomalies: cases of fetal development anomalies (including malformations of the ear) in patients, who took MMP during pregnancy in combination with other immunosuppressants.

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

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 increase in susceptibility to infections) andoppression of the bone marrow. 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. With the simultaneous use of MMP and acyclovir, higher concentrations of phenolic glucuronide IFC (IFPC) and acyclovir in plasma were observed than with each drug alone. Since plasma concentrations of IFPC, like acyclovir, increase with renal insufficiency, it is likely that these two drugs compete for tubular secretion, which may lead to a further increase in the concentration of both drugs.

Antacids (aluminum hydroxide and magnesium hydroxide) and proton pump inhibitors (PPIs). With the simultaneous use of MMP 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. However, there was no significant difference between the frequencies of graft rejection in patients taking MMP concomitantly with and without PPI preparations. This conclusion theoretically extends to antacids, as when they were taken simultaneously with MMF, the level of MPC decreased to a much lesser degree than with the simultaneous administration of MMF with PPI.

Kolestyramine. After applying a single dose of MMF, 1.5 g to healthy volunteers, previously taking 4 grams of colestyramine 3 times a day for 4 days, there was a decrease in AUC for MPC by 40%. Caution should be exercised while using MMF and preparations that affect hepatic intestinal recirculation.

Cyclosporine. Mycophenolate mofetil does not affect the pharmacokinetics of cyclosporine. However, when ciclosporin is discontinued, an increase in AUC for MPA can be expected by about 30%.

Ganciclovir. Based on the results of the study with a single oral intake of the recommended doses of MMF and intravenous administration of ganciclovir, taking into account the known effect of renal failure on the pharmacokinetics of MMF and ganciclovir,it can be assumed that the simultaneous use of these two drugs will lead to an increase in the concentrations of IFPC and ganciclovir. There is no significant change in the pharmacokinetics of IFC, therefore, it is not necessary to adjust the dose of MMF.

If MMF and ganciclovir (or a prodrug thereof, for example, valganciclovir) are prescribed for patients with renal insufficiency, patients should be carefully monitored.

Oral contraceptives. MMF does not affect the pharmacokinetics of oral contraceptives. When taken concomitantly with combined oral contraceptives containing ethinyl estradiol (0.02-0.04 mg) and levonorgestrel (0.05-0.2 mg), desogesterl (0.15 mg) or gestodene (0.05-0.1 mg), MMF (1 g twice daily) does not have a clinically significant effect on the concentrations of progesterone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Thus, MMF does not affect the suppression of ovulation under the influence of oral contraceptives. However, during the MMP intake, in addition to oral contraceptives, other methods of contraception should be used.

Trimethoprim / sulfamethoxazole, norfloxacin, metronidazole. Simultaneous use with one of the antibacterial drugs does not affect the systemic exposure of IFC. But the simultaneous use of MMF in combination with norfloxacin and mstronidazole reduces AUC_0-48 IFC by 30% after a single intake of MMF.

Tacrolimus. With simultaneous application, no effect on AUC and maximum concentration (FROM_max) IFC in patients after liver and kidney transplant. In patients after kidney transplantation, the use of MMF did not affect the concentration of tacrolimus. In patients with stable hepatic transplant, the value of Tacrolimus AUC after multiple MMP intake in a dose of 1.5 g twice a day increased by about 20%.

Sirolimus. In patients after kidney transplantation, simultaneous administration of MMP and cyclosporine resulted in a 30-50% decrease in MPC exposure compared to patients receiving a combination of sirolimus and MMF.

Rifampicin. After correction of the dose, a decrease in the exposure of MFK by 70%AUC_0-12) in patients after single-stage heart and lung transplantation, it is recommended to monitor the exposure of IFC and dose correction of mycophenolate mofetil to maintain clinical effect when combined.

Ciprofloxacin and amoxicillin in combination with clavulonic acid. In patients after kidney transplantation, on the day immediately after oral administration of ciprofloxacin or amoxicillin in combination with clavulanic acid, the minimum concentration of MPA is reduced by 50%. With the continuation of antibacterial therapy, this effect is reduced, and after discontinuation of therapy disappears. The clinical significance of this phenomenon is not known, since a change in the minimum concentration may inadequately reflect the change in the total exposure of the IFC.

Drugs that interfere with hepatic intestinal recirculation: caution should be used to prevent hepatic intestinal recirculation, but the potential for a decrease in the effectiveness of MMF.

Sevelamer. Simultaneous use of sevelamer and IFC in adults and children reduced FROM_max and AUC_0-12 for MFK by 30% and 25%, respectively. Sevelamer and other phosphate-binding drugs that do not contain calcium should be administered 2 hours after taking mycophenolate mofetil in order to reduce the effect on IFA absorption.

Other interactions. With the simultaneous use of probenecid and MMF, there was an increase in the AUC of IFPC in plasma. Thus, other drugs undergoing tubular secretion can compete with IFPC, which leads to an increase in the concentration of IFPC or another drug in the plasma, which is also subjected to tubular secretion.

Live attenuated vaccines. Should not be administered to patients in a state of immunosuppression. Antibody formation in response to other vaccines can be reduced.

Special instructions:

Patients receiving immunosuppressive drugs, including combination therapy with MMF, are at increased risk of developing lymphomas and other malignant tumors, especially skin cancer. Apparently, this risk is associated not with the use of any particular drug, but with the intensity and duration of therapy.

There are general guidelines for minimizing the risk of skin cancer: it is necessary to limit exposure to sunlight and ultraviolet rays with appropriate closed clothing and the use of sunscreens with a high protective factor.

Patients taking MMF should be informed of the need to promptly tell the doctor about any signs of infection, bleeding, sudden appearance of bruising 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. Cases of PML development, 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, neurologic symptoms should be advised by a neurologist to exclude PML.

In patients who underwent transplantation of the night and who received MMP. There were cases of development of nephropathy associated with VC virus (VK virus-associated nephropathy). This infection can lead to serious consequences, sometimes to the death of a kidney transplant. Monitor the status of patients taking MMF.to identify patients at risk of developing nephropathy associated with BV virus. With the development of symptoms of nephropathy associated with VC virus. it is necessary to consider the issue of dose adjustment for immunosuppressive therapy.

In patients taking MMF, it is possible to reactivate a latent viral infection, such as hepatitis B or C.

In patients who took MMP in combination with other immunosuppressive drugs, there were cases of development of PKA. In some cases, the PKA was reversible after a decrease in the dose of MMF or cancellation. However, in patients who undergo transplantation, lowering the dose of immunosuppressants may endanger the transplant, so the treatment change of such patients should be closely monitored.

Because MMF is an inhibitor of IMPDG, then, from the theory's point of view, it should not be administered to patients with a rare genetically determined hereditary deficiency of hyooxanthyguanium phosphoribosyltransferase (Leschy-Nyen and Kelly-Sigmillers syndromes).

Patients should be informed that during the MMP treatment, vaccination may be less effective and the use of live attenuated vaccines should be avoided.If necessary, influenza vaccination should be guided by national recommendations.

Since the use of the drug may be associated with an increased risk of adverse events on the part of the gastrointestinal tract, MMP should be administered with caution to patients with gastrointestinal tract diseases in the acute stage.

MMF is not recommended to be administered simultaneously with azathioprine, since both drugs depress the bone marrow, their simultaneous administration has not been studied. Caution should be exercised when using MMF together with drugs that affect hepatic intestinal circulation, as they may reduce its effectiveness.

In patients with severe chronic renal failure, doses greater than 1 g 2 times per day should be avoided. Correction of MMF dose in patients with delayed renal transplant function is not required, but careful monitoring is necessary. For patients who underwent a heart or liver transplant, or who have severe renal failure, no data.

Laboratory testing

Patients receiving MMF, it is necessary to determine the developed blood formula for the first month of the week,during the second and third months of treatment - twice a month, and then during the first year - every month. Particular attention should be paid to the possibility of developing neutropenia. Neutropenia can be associated with both MMF intake and other medications, viral infections, or a combination of these causes (see section "Dosage in special cases"). If neutropenia occurs (the absolute number of neutrophils is less than 1300 in 1 μl), it is necessary to interrupt the treatment of MMF or reduce the dose, while carefully monitoring these patients.

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

Special precautions when handling the drug and when destroying an unused medicinal product

Since the MMF in the experiments showed a teratogenic effect, the integrity of capsules of the drug Mycophenolate Mofetil-TL should not be violated. It is necessary to avoid inhaling the powder contained in the capsules of the preparation, as well as direct exposure to the skin or mucous membranes. If this happens, you need to thoroughly rinse this area with soap and water, and your eyes - just water.

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

Given the profile of identified adverse eventsshares when receiving MMF, such as dizzinesspsychomotor agitation, sleeplessnesstsza, tremor, drowsiness, confusion, carry out driving vehicles, manage mechanisms or deal with otherspotentially dangerous specieswhich require increased concentration attention and speed of psychomotor reactionstions, it is necessary, taking into account the profile of the side effects. When these undesirable phenomena appear, one should refrain from performing these activities.

Form release / dosage:Capsules 250 mg.

Packaging:

10 capsules per contour melt packaging from polyvinylchloride film and aluminum foil printed lacquered.

For 30, 100 capsules in a jar (bottle) polymer for drugs or a jar (bottle) for medicines from plastic. Free space in the bank (vial) is filled with cotton wool hygroscopic. Each jar (bottle), 3 or 10 contour packages together with instructions for use are a pack of cardboard box.

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-001950

Date of registration:25.12.2012 / 24.04.2015

Expiration Date:25.12.2017

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)