Mycophenolate Sandoz - instructions for use, dose, side effects, contraindications

1 tablet contains: active substance: mycophenolate mofetil 500 mg; Excipients: cellulose microcrystalline 281 mg, croscarmellose sodium 30 mg, povidone 22 mg, magnesium stearate 9 mg, talc 18 mg; film sheath: opedraj violet 20В50135 ** 25 mg.

** the composition of the precipitous violet 20B50135: hypromellose 3cP - 35.0%, hydroxypropylcellulose 30.0%, titanium dioxide 19.3%, macrogol-400-10.0%, hypromellose 50cP 5.0%, iron dye oxide black - 0.45%, iron dye oxide red - 0.25%.

Description:

Oval biconvex tablets, covered with a film coat of gray with a pinkish hue of color. On the cross section, the core of the tablet is white or almost white in color.

Pharmacotherapeutic group:Immunosuppressive remedy.

ATX: & nbsp

L.04.A.A Selective immunosuppressants

Pharmacodynamics:

Immunosuppressant, inhibitor of inosine monophosphate dehydrogenase

Mycophenolate mofetil (MMF) is a 2-morpholinoethyl ester of mycophenolic acid (MPA). IFC is a powerful selective noncompetitive and reversible inhibitor of inosine monophosphate dehydrogenase (IMPG), 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, fast and complete absorption and complete presystemic metabolism of MMP take place with the formation of an active metabolite - MPA. Bioavailability of MMF for oral administration, according to the area under the concentration-time curve (AUC for MPC), is, on the average, 94% of that for its intravenous administration. After oral administration, the concentrations of MMF 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 values for MPC were approximately 30% lower, and the maximum concentrations were about 40% lower than in the late post-transplant period (3-6 months after transplantation ). The intake of food does not affect the degree of absorption of MMF (AUC for MPC) when administered 1.5 g twice a day to patients after kidney transplantation. However, the maximum concentration of IFC when taking the drug during meals is reduced by 40%.

Distribution

As a rule, after about 6-12 hours after taking the drug, a secondary increase in the concentration of MPA in the blood plasma is observed, which indicates the hepatic-intestinal recirculation of the drug.With the simultaneous administration of colestyramine (4 g three times daily), the AUC for IFC decreases by about 40%, indicating a significant effect of intrahepatic recirculation.

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

Metabolism

IFC is metabolized, mainly, under the action of glucuronyltransferase with the formation of pharmacologically inactive phenolic glucuronide MFC (IFPC).

Excretion

After oral administration of radioactively labeled MMF, 93% of the dose obtained 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.

Within the limits of clinical concentrations, IFC and IFPC are not excreted by hemodialysis. Nevertheless, at high plasma concentrations of IFPC (> 100 microgram / ml), a small amount of IFPC is released.

Pharmacokinetics in special clinical cases

In a study with a single dose (in the group of 6 subjects) in patients with severe chronic renal failure (glomerular filtration rate <25 ml / min / 1.73 m²) the AUC value for IFC was 28-75% higher than in healthy volunteers and patients with less severe renal involvement. After receiving a single dose, the AUC for IFPC is 3-6 times greater in patients with severe renal failure than in healthy volunteers and patients with moderate renal involvement, consistent with the data on renal excretion of IFHC.

Studies on the repeated administration of MMF in severe chronic renal failure have not been carried out.

In patients with delayed kidney graft functionafter transplantation, the mean AUC_0-12for IFC is comparable to that in patients in whom the graft began to function after a transplant without delay. The average value of AUC_0-₁₂for IFHC was 2-3 times more than in patients after transplantation without delaying the function of the kidney transplant. In patients with delayed renal transplant function, a transient increase in the free fraction and in the concentration of MPC in the blood plasma can be observed. Probably the need for dose adjustment mycophenolate mofetil these patients do not.

Patients with liver damage. In volunteers with alcoholic liver damage, the presence of parenchymal liver disease relatively did not affect the glucuronization process of IFC in the liver.The effect of liver disease on this process probably depends on the specific disease. However, liver diseases with predominant bile duct damage, such as primary biliary cirrhosis, can demonstrate a different effect on IFC metabolism.

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 value for 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 for IFC did not differ between the age groups in the early and late transplantation period.

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

Indications:

Adults and children

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:

increased individual sensitivity to mycophenolate mofetil, mycophenolic acid and other components of the drug;
Children under 12 years of age (prevention of acute rejection of allogeneic kidney transplant), up to 18 years (according to other indications);
deficiency of hypoxanthine guanine phosphoribosyltransferase;
simultaneous administration with azathioprine;
severe chronic renal failure (glomerular filtration rate less than 25 ml / min / 1.73 m²) after allogeneic heart and liver transplantation (there is no data on efficacy and safety);
severe hepatic failure after allogeneic heart transplantation (no data on efficacy and safety).
lactation period.

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

Pregnancy and lactation:

An increased risk of spontaneous miscarriage in the first trimester of pregnancy, as well as an increased risk of congenital malformations, including anomalies of the external ear, "wolf mouth", "hare lip," distal extremities, heart, esophagus and kidney anomaly.

A patient planning a pregnancy should not take mycophenolate mofetil as long as other immunosuppressive drugs are effective. If the patient takes the drug when planning a pregnancy or when a pregnancy occurs, she should be informed of the potential harm to the fetus. MMF can be given to pregnant women only in cases where the potential benefit to the mother exceeds the possible risk to the fetus.

MMP therapy 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 start of therapy). Before the initiation of MMP therapy, during the treatment and for 6 weeks after the end of therapy, it is mandatory to use reliable contraceptive methods, 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 at the same time, since it is potentially possible to reduce the hormone concentration by oral intake of contraceptives against mycophenolate therapy with mycophenolate.

In rats, MMP is excreted in milk.Whether the MMF is singled out with human milk is unknown. Since many drugs are excreted with human milk, as well as in connection with the possibility of developing serious adverse reactions to MMF in infants, if it is necessary to use the drug during lactation it is necessary to stop breastfeeding.

Dosing and Administration:

Inside. Mycophenolate treatment with mycophenolate should be started and carried out by transplant specialists with appropriate qualifications.

Adult patients

Prophylaxis of kidney transplant rejection

The drug should be taken within 72 hours after the transplantation operation. Patients with renal transplants are recommended to take 1 g (2 tablets of 500 mg) 2 times a day (a daily dose of 2 g - 4 tablets of 500 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 (3 tablets of 500 mg) 2 times a day (daily dose of 3 g - 6 tablets of 500 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 (3 tablets of 500 mg) 2 times a day (daily dose of 3 g - 6 tablets of 250 mg).

Dosing in special cases

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

In patients with severe chronic renal failure (glomerular filtration rate less than 25 ml / min / 1.73 m²) beyond the nearest post-transplantation period or after therapy for acute or refractory rejection, doses above 1 g (2 tablets of 500 mg) should be avoided 2 times per day. 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 kidney transplantation and having severe lesion of the liver parenchyma,correction of the dose is not required. Data on patients with severe lesions of the liver parenchyma, who underwent heart transplant, are absent.

Patients old age (≥65 years) who underwent kidney transplantation, the recommended dose is 1 g (2 tablets of 500 mg) 2 times a day, and after heart or liver transplantation - 1,5 g (3 tablets of 500 mg) 2 times a day.

Children:

- prevention of kidney transplant rejection: patients aged over 12 years who underwent renal transplantation, with a surface area of more than 1.50 m² possible to assign the tablets of 1 g (2 500 mg tablets) twice a day (daily dose of 2 g - 4 tablets of 500 mg);

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

Side effects:

Profile of side effects associated with the immunosuppressive agents is often difficult to establish because of the underlying disease and simultaneous use of many other drugs.

Clinical Trials Data

The major adverse reactions associated with mycophenolate mofetil (MMF) in combination with cyclosporin and corticosteroids for preventing the rejection of kidney, heart or liver transplant 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 background of 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, the development of lymphoproliferative diseases or lymphomas was observed in 0.4-1% of patients receiving MMF in doses of 2-3 grams per day in combination with other immunosuppressive drugs. The development of skin cancer, with the exception of melanoma, was noted in 1.6-32% 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 of malignant growths, compared with the yearly indices. 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 2-3 g per day in combination with other immunosuppressants in patients,observed during 1 year after kidney transplantation (applied dose - 2 g per day), heart and liver, the most frequent infections were candidiasis of 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 patients 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 per day

Children aged 3 months to 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.

Patients over 65 years of age

In the treatment of MMF in a combination of immunosuppressive therapy, the risk of certain infections, including tissue invasive forms of manifest CMV infection,gastrointestinal bleeding and pulmonary edema are higher than in younger patients (see section "Special instructions").

Adverse events noted in ≥10% and in 3-10% of patients receiving MMP in combination with cyclosporine and glucocorticosteroids in controlled studies on the prevention of kidney transplant rejection (3 studies, data on the use of the drug at a daily dose of 2 and 3 mg), in 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, 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

* (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: isolated 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 taking MMP during pregnancy in combination with other immunosuppressants have been reported.

Other undesirable reactions observed with post-marketing use of the drug are not different from undesirable reactions recorded in controlled clinical trials of MMF.

Overdose:

Data on the overdose of MMF were obtained in clinical trials and post-marketing applications. In most cases, no undesirable events have been reported. In case of an overdose of undesirable phenomena, in addition to the above, it was not revealed.

It is expected that an overdose of MMF will likely lead to excessive immunosuppression (as a consequence, to an increased sensitivity to infections) and bone marrow suppression. In the case of neutropenia, the use of mycophenolate mofetil should be discontinued, or the dose of the drug should be 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:

Interaction with other drugs was studied only in adult patients.

Acyclovir. With the simultaneous use of MMP and acyclovir, higher concentrations of IFPC and acyclovir in plasma were observed than with the administration of 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 (PPI). With the simultaneous use 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 the appointment of a single dose of MMF, 1.5 g to healthy volunteers who previously took 4 g of colestyramine 3 times a day for 4 days, a decrease in the AUC for MPC was observed by 40%. Caution should be exercised while using MMF and preparations that affect hepatic intestinal recirculation.

Cyclosporin. 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. According to the study with a single oral administration of the recommended doses of MMF and intravenous ganciclovir, given remarkable influence on the pharmacokinetics of renal failure MMF and ganciclovir, it can be assumed that the concurrent use of the two drugs will result in increased concentrations MFKG and ganciclovir. A significant change in the pharmacokinetics of IFC is not expected, so adjust the dose of mycophenolate mofetil is not necessary. If MMF and ganciclovir (or a prodrug thereof, for example, valganciclovir) are prescribed to 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), desogestrel (0.15 mg) or Gestodene (0.05-0.1 mg), mycophenolate mofetil (1 g 2 times a day) does not have a clinically significant effect on the concentration of progesterone,luteinizing hormone (LH) and follicle-stimulating hormone (FSH). In this way, mycophenolate mofetil does not affect the suppression of ovulation under the influence of oral contraceptives. However, during the reception of mycophenolate mofetil in addition to oral contraceptives, it is necessary to use other methods of contraception.

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

Tacrolimus. With simultaneous application, no effect on AUC and maximum concentration (C_max) IFC in patients after liver and kidney transplant. In patients after kidney transplantation, the administration of mycophenolate mofetil 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 transplantationsimultaneous administration of mycophenolate mofetil and cyclosporine resulted in a decrease in the exposure of MPA by 30-50% compared with patients receiving a combination of sirolimus and mycophenolate mofetil.

Rifampicin. After dose correction, a decrease in MFK exposure by 70% (AUC_0-12) in patients after simultaneous transplantation of the heart and lungs, it is recommended to monitor the exposure of IFC and dose correction of mycophenolate mofetil to maintain clinical effect in a joint appointment.

Ciprofloxacin and amoxicillin in combination with clavulanic 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, due to the potential decrease in the effectiveness of mycophenolate mofetil.

Sevelamer. Simultaneous application of sevelamer and IFC in adults and children reduced C_max and AUC_0-12for the IFC 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:

Neoplasms

Patients receiving immunosuppressive drugs, including combination therapy with mycophenolate mofetil, 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.

Infections

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 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 with a neurologist.

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

Kidney Transplantation

In patients who underwent kidney transplantation and who received mycophenolate mofetil, 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. The status of patients taking MMF should be monitored to identify patients at risk of developing nephropathy associated with BV virus. When developing symptoms of nephropathy associated with VC-virus, it is necessary to consider the issue of dose adjustment for immunosuppressive therapy.

PACA

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 underwent transplantation,a decrease in the dose of immunosuppressants may jeopardize the transplant, so the change in the treatment of such patients should be carefully monitored.

Genetic diseases

Because the mycophenolate mofetil is an inhibitor of IMPDG, then, from the theoretical point of view, it should not be administered to patients with a rare genetically determined hereditary deficiency of hypoxanthine guanine phosphoribosyltransferase (Leschy-Naikhan syndrome and Kelly-Zygmiller syndrome).

Vaccination

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.

Diseases of the digestive tract

Since the use of the drug may be associated with an increased risk of gastrointestinal side effects (ulceration of the gastrointestinal mucosa, gastrointestinal bleeding, gastrointestinal perforation), MMP should be administered with caution to patients with gastrointestinal diseases at the acute stage.

Special interactions

MMF is not recommended to be administered simultaneously with azathioprine, since both drugs depress the bone marrow, their simultaneous administration has not been studied.

Care should be taken when switching from combination therapy, including immunosuppressants, that have an effect on hepatic intestinal recirculation of mycophenolic acid (for example, ciclosporin), on therapy with drugs that are devoid of this effect (for example, sirolimus and belatacept), and vice versa. This transition can lead to a change in the exposure of mycophenolic acid. Care must be taken when using other classes of drugs that affect hepatic enteric mycofenolic acid (for example, colestramine) due to their ability to lower the plasma concentration and the effectiveness of MMF.

The ratio of risk and benefit of simultaneous use of MMF and tacrolimus or sirolimus is not established.

Impaired renal function

Patients with severe chronic renal failure should avoid dosing more than 1 g 2 times a day. Correction of MMF dose in patients with delayed renal transplant function is not required, but careful monitoring is necessary.Data are not available for patients who undergo heart or liver transplant or who have severe renal failure.

Laboratory testing

Patients receiving MMF should be monitored for the appearance of neutropenia, which may be due to the use of MMF itself, and concomitant medications, viral infections, or some combination of these causes. Patients receiving mycophenolate mofetil, it is necessary to conduct a complete blood test weekly during the first month, twice a month during the second and third months of treatment, then monthly until the end of the first year of treatment. With the development of neutropenia (absolute number of neutrophils <1300 / μL), it is necessary to interrupt the treatment of MMF or reduce the dose with careful observation. In elderly patients, the risk of adverse events may be higher than in younger patients.

Hypogammaglobulinemia

There are reports of the development of hypogammaglobulinemia, leading to the development of recurrent infections in patients receiving mycophenolate mofetil in combination with other immunosuppressants.In some cases, the replacement of mycophenolate mofetil with an alternative drug led to a normalization of the plasma IgG concentration. In patients with recurrent infections, the plasma concentration of IgG should be assessed. The management of patients with clinically significant hypogammaglobulinemia should be selected taking into account the pronounced cytostatic effect of mycophenolate with mycophenolate mofetil on T and B lymphocytes.

Bronchoectasia

There have been reports of the development of bronchiectasis in adults and children receiving treatment with the drug in combination with other immunosuppressants. Sometimes the replacement of mycophenolate mofetil with an alternative drug resulted in relief of symptoms from the respiratory system. The risk of developing bronchiectasis can be associated with both hypogammaglobulinemia and direct effects on lung tissue. There are also reports of cases of interstitial lung disease and pulmonary fibrosis, sometimes fatal. It is recommended to conduct a thorough examination of patients with persistent symptoms on the part of the respiratory system, such as coughing and shortness of breath.

When using the drug Mycophenolate Sandoz®, cases of congenital malformations were noted.

Treatment with the drug

Since MMF in the experiment on rats and rabbits showed teratogenic effect, it should not be violated to break the tablets Mycophenolate Sandoz®.

Effect on the ability to drive transp. cf. and fur:During treatment with mycophenolate, mycophenolate should take into account the potential for the development of side effects such as dizziness, convulsions and drowsiness. 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 PVC / A1 blister. For 5 or 10 blisters are placed in a cardboard box together with instructions for medical use.

Storage conditions:

Store at a temperature not exceeding 30 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

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

Terms of leave from pharmacies:On prescription

Registration number:LP-001816

Date of registration:29.08.2012 / 29.05.2014

Expiration Date:29.08.2017

Date of cancellation:2018-04-02

The owner of the registration certificate:Sandoz d.Sandoz d. Slovenia

Manufacturer: & nbsp

SANDOZ PRIVATE, Limited India

Representation: & nbspSANDOZ SANDOZ Switzerland

Information update date: & nbsp02.04.2018

Illustrated instructions

Instructions

Mycophenolate Sandoz® (Mycophenolate Sandoz)