SellSept - instructions for use, dose, side effects, contraindications

sheath: body - gelatin, titanium dioxide (E171), iron dye red oxide (E172), iron dye oxide yellow (E172); cap - gelatin, titanium dioxide (E171), dye indigo carmine (E132);

ink composition: shellac, iron dye oxide black (E172), potassium hydroxide.

Description:

Hard gelatin capsules No. 1, consisting of an opaque brown case and an opaque cap of blue color; on the body there is an inscription "Roche" black color, on the lid - "CellCept 250" black color; the contents of the capsules - a fine granular powder, partially crumpled, from white to almost white.

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 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 enzymatic activity of IMPDG appears to be due to the fact that IFC structurally imitates both the cofactor of nicotinamide dinucleotide phosphate and the catalyzing water molecule. This prevents the oxidation of IMP in xanthose-5-monophosphate - the most important stage of 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.

Efficiency

In clinical studies on the prevention of rejection after kidney, heart and liver transplants, Sellsept® was used in combination with the following preparations: immunoglobulin antitimocytic, OKTZ (orthoclone of mouse monoclonal antibodies), cyclosporine and glucocorticosteroids.

Prevention of transplant rejection

Adults

The safety and efficacy of Cellsept® in combination with glucocorticosteroids and cyclosporine were evaluated in patients after kidney, heart and liver transplantation.

Children

The safety, pharmacokinetics and efficacy of Sellsept® in combination with glucocorticosteroids and cyclosporine in children after kidney transplantation were evaluated in a study with the participation of 100 children aged 3 months to 18 years.

Kidney Transplantation

Adults

In combination with glucocorticosteroids and cyclosporin Cellsept® statistically significantly reduced the incidence of ineffective treatment in the first 6 months after transplantation and histologically proven rejection during therapy, at a dose of 2 g / day reduces the cumulative rate of graft death and mortality in 12 months after kidney transplantation, but at a dose of 3 g per day increases the frequency of premature dropout from the study for any reason.

Children

In children after kidney transplantation in all age groups, the reception of Sellsept® (powder for suspension) was administered at 600 mg / m twice a day (up to 1 g twice daily).

The overall incidence of histologically proven rejection at 6 months post-transplantation period was comparable to that in adults and was similar in different age groups. The total frequency of graft death (5%) and mortality (2%) for 12 months after transplantation was comparable with the values observed in adults who underwent kidney transplantation.

Heart transplantation

Rejection

Differences in the frequency of histologically proven rejection, leading to a violation of hemodynamics, in the groups Cellsept® and azathioprine were not.

Survival

In terms of mortality and repeated transplantations in cardiac transplantation, MMP is superior azathioprine.

Liver transplantation

The Selsept® preparation in combination with glucocorticosteroids and cyclosporine is more effective than azathioprine, prevented acute rejection and provided the same survival as azathioprine.

Preclinical safety data

In doses 2-3 times higher than therapeutic ones during kidney transplantation and 1.3-2 times compared to those in patients after heart transplantation, MMP did not stimulate the formation of tumors and did not affect the fertility of male rats.

Two genotoxicity tests indicated that in doses that have a serious toxic effect, MMF is potentially capable of causing chromosomal instability. In other genotoxicity tests, the presence of mutagenic activity in the preparation was not detected.

In experiments on the fertility and reproductive efficiency of female rats, oral administration of the drug caused malformations (including anophthalmia, agnathia and hydrocephalus) in the first generation of offspring without any toxic effect on the mother. In subsequent generations of offspring, there were no effects on fertility and reproductive performance.

In studies of teratogenicity in rats, resorption of the fetuses and congenital malformations in the offspring (including anophthalmia, agnathy and hydrocephalus in rats and malformations of the cardiovascular system, kidneys, ectopia of the heart and kidneys, diaphragmatic and umbilical hernias in the offspring of rabbits) the mother.

In toxicological studies of MMF on animals, the main lesions were localized in the hematopoietic and lymphoid organs and occurred at a level of system exposure of the drug that is equivalent to or less than the exposure level when taking a clinical dose of 2 g per day, recommended by patients after kidney transplantation. The profile of non-clinical toxicity of MMF coincides with the undesirable phenomena noted in clinical studies in humans, which allowed obtaining safety data that are more significant for the patient population (see section "Side effect").

Pharmacokinetics:

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

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 when administered orally, according to the area under the concentration-time curve (AUC_IFC), is, on average, 94% of that when administered intravenously. 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 values 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 MMF (AUC_IFC) when applied 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%.

When examining the bioequivalence of two oral forms of MMP release, it was shown that two 500 mg tablets are equivalent to four 250 mg capsules.

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 by glucuronyltransferase (the isoform of the UGT1A9 gene) with the formation of pharmacologically inactive phenolic glucuronide IFC (IFPC). ln vivo IFPC is converted back to free IFC during hepatic intestinal recirculation with the formation of acylglucuronide, which has pharmacological activity and is probably the cause of some of the side effects of IFC (diarrhea, leukopenia).

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.

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.

The distribution of IFC depends on several transporters: the transport polypeptide of organic anions (TPAA) and the protein associated with multiple drug resistance-2 (BAMLU-2). Isoforms of TPOA, BAMLU-2, as well as breast cancer resistance protein (BROM) are transports associated with excretion of glucuronide through bile. The protein of multiple drug resistance-1 can also participate in the transfer of IFC, but its involvement is limited by the absorption process. IFC and its metabolites can potentially react with organic anion transporters in the kidneys.

Pharmacokinetics in special clinical cases

In a study with a single dose of the drug in patients with severe chronic kidney failureinsufficiency (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 AUC_IFCG in 3-6 times more in patients with severe renal failure than in healthy volunteers and patients with moderate renal damage, which is consistent with data on renal excretion of IFH. Studies on the repeated administration of MMF in severe chronic renal failure have not been carried out.

In 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. 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 correction of the dose of Sellsept® in these patients is not (see the section "Dosing in special cases"). The mean AUC_0-12 for IFPC in plasma was 2-3 times greater than in patients in whom the graft began to function after a transplant without delay.

In patients with primary non-functioning graft after kidney transplantation, there was an increase in the concentration of IFPC in the blood plasma; the cumulation of IFC, if noted, is much less than in IFAC.

Patients with liver damage. In volunteers with alcoholic cirrhosis of the liver after oral administration of MMP, no changes in the pharmacokinetics of IFC and IFPC have been revealed. The influence of hepatic pathology on this process probably depends on the specific disease. In case of liver disease with a predominance of biliary tract lesions (eg, primary biliary cirrhosis), changes in the pharmacokinetics of IFC and IFPC can not be ruled out.

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

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

Indications:

Cellsept® is used as a combination therapy with cyclosporine and glucocorticosteroids.

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

Increased individual sensitivity to MMF, IFC and other components of the drug.

Deficiency of hypoxanthine guanine phosphoribosyltransferase (a rare genetic disease due to the hereditary deficiency of hypoxanthine guanine phosphoribosyltransferase - Lesch-Nyen syndrome and Kelly-Zygmiller syndrome).

Simultaneous reception with azathioprine (both drugs depress the bone marrow, their simultaneous administration has not been studied).

Children with body surface area <1.25 m² (approximate children's age to 12 years).

Pregnancy (use of Cellsept® is contraindicated during pregnancy due to its mutagenic and teratogenic potential).

Women of childbearing potential who do not use highly effective methods of contraception.

Breastfeeding period.

Carefully:

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

Pregnancy and lactation:

The use of Sellsept® is contraindicated during pregnancy and in women of childbearing potential, not using highly effective methods of contraception. Before starting treatment of patients with reproductive potential, both men and women, it is necessary to inform about the increased risk of fetal death and congenital malformations; should consult about measures to prevent pregnancy and its planning.

Before beginning therapy with Sellsept® in patients of childbearing potential, a negative result of two pregnancy tests should be obtained using the serum or urine analysis method with a sensitivity of at least 25 mIU / ml; The second test should be performed 8-10 days after the first test and immediately prior to the start of Selsept®.

Repeated pregnancy tests should be performed during routine follow-up visits. The results of all pregnancy tests should be discussed with the patient. Patients should be informed that in case of pregnancy they need to immediately consult with the attending physician.

Because of the mutagenic and teratogenic potential of Sellsept®, women of childbearing potential should use two reliable methods of contraception at the same time (since it is potentially possible to reduce the hormone concentration by oral contraceptive use against the background of Selsept® therapy), including at least one highly effective method, during therapy and for six weeks after discontinuing therapy with Sellsept® if abstinence from sexual activity is not possible. Leading an active sexual life, men are recommended to use condoms during treatment and for at least 90 days after discontinuation of treatment.

Condoms should be used by both men with normal reproductive function and men after vasectomy, since the risks associated with transmission of semen are also applicable to men who underwent a vasectomy.In addition, female partners of male patients are recommended to use highly effective methods of contraception during treatment and within 90 days after taking the last dose of Cellsept®.

When post-marketing use in children of patients treated with MMF in combination with other immunosuppressants during pregnancy, congenital malformations, including multiple malformations, were detected.

The most common malformations were:

malformations of the face, such as split lip, split sky, micrognathia and hypertelorism of the eye sockets;
anomalies of ear development (eg, an anomaly of the shape or absence of the outer / middle ear) and eyes (eg, coloboma, microphthalmus);
malformations of the fingers (eg, polydactyly, syndactyly, brachydactyly);
heart abnormalities such as atrial and interventricular septal defect;
malformations of the esophagus (eg, esophageal atresia);
malformations of the nervous system (such as the non-vertebral arches).

In the medical literature, 23-27% of live births affected by mycophenolate mofetil during intrauterine development were reported to develop.For comparison, the risk of malformations in live births is approximately 2% in the general population and approximately 4-5% in patients undergoing transplantation of solid organs receiving treatment with other immunosuppressants other than mycophenolate mofetil.

Patients who received mycophenolate mofetil, an increased risk of spontaneous miscarriage, mainly in the first trimester of pregnancy.

According to the medical literature, the risk in patients who received mycophenolate mofetil, was 45-49% compared with the frequency of 12-33% in patients treated with other immunosuppressants after organ transplantation.

Studies in animals have shown the presence of reproductive toxicity.

The drug Selsept® is contraindicated in the period of breastfeeding due to the possibility of serious adverse reactions in children who are breastfeeding.

In rats, MMP is excreted in milk. Whether the MMF is singled out with human milk is unknown.

Dosing and Administration:

Inside.

Adults

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 twice a day (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 advantages 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 drug should be taken within 5 days after the transplant operation. The recommended dosing regimen is 1.5 g 2 times a day (daily dose 3 g).

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 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 treatment of MMF or to reduce its dose and carefully observe the patient (see Fig.section "Special instructions").

In patients with severe chronic renal failure (glomerular filtration rate less than 25 ml / min / 1.73 m²) outside the nearest post-transplant period, 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 (see section "Special instructions").

Correction of the dose to patients with delayed kidney graft function is not required (see section "Pharmacokinetics in special clinical cases").

Patients who underwent a kidney transplant and who had a severe parenchyma of the liver, dose adjustment is not required (see section "Pharmacokinetics in special clinical cases"). Data on patients with severe lesions of the liver parenchyma, who underwent heart transplant, are absent.

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

Children:

- prevention of kidney transplant rejection: in patients older than 12 years who underwent renal transplantation, at a surface area of 1.25-1.50 m²it is possible to use capsules 750 mg twice a day (daily dose 1.5 g), with a surface area of more than 1.50 m² it is possible to apply capsules 1 g twice a day (daily dose of 2 g);

- data on the safety and efficacy of the drug in patients of childhood 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 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% 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 a kidney transplant (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.

Have 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), as well as, possibly, gastrointestinal bleeding and pulmonary edema is higher than in younger patients (see Fig.section "Special instructions").

Undesirable effects noted in ≥10% and 3-10% of patients who received MMP 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 study for a liver transplant.

		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,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)

Post-marketing application of the drug
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.

Infections: 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 Sellsept®. 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 Sellsept®, 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.

From the side of the blood and the immune system: cases of development of partial red cell aplasia (PKAA) and hypogammaglobulinemia were observed in patients taking Cellsept® in combination with other immunosuppressive drugs.

Developmental anomalies: in the post-registration period, cases of congenital malformations in children of patients taking Sellsept® during pregnancy in combination with other immunosuppressants have been reported.

Pregnancy, postpartum and perinatal conditions: in patients receiving mycophenolate mofetil, there were registered cases of spontaneous miscarriage, mainly in the first trimester of pregnancy.

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

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:

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 below described, it is not revealed.

It is expected that an overdose of MMF is likely to lead to excessive immunosuppression (as a consequence, to an increased sensitivity to infections) and bone marrow suppression (see section "Special instructions"). In the case of development of neutropenia, the use of Sellsept® the dose of the drug should be discontinued or reduced (see section "Special instructions"). 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 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 and proton pump inhibitors (IPN)

In the joint use of the drug Sellsept® with antacids (aluminum and magnesium hydroxide) and with proton pump inhibitors (lansoprazole and pantoprazole) there was a decrease in the concentration of MPA. However, there was no significant difference between the rates of graft rejection in patients taking Sellsept® simultaneously with and without PTS preparations.This conclusion theoretically extends to antacids, as when taken concomitantly with Cellsept®, the concentration of MPA is reduced to a much lesser degree than with the simultaneous administration of Sellsept® with IPN.

Kolestyramine

After applying a single dose of MMF 1.5 g in healthy volunteers, previously taking 4 grams of colestyramine 3 times a day for 4 days, there was a decrease AUC_IFC on 40%. Caution should be exercised while using MMF and preparations that affect hepatic intestinal recirculation (see section "Special instructions").

Cyclosporin

MMF does not affect the pharmacokinetics of cyclosporine. but ciclosporin influences hepatic intestinal recirculation of the IFC, which can lead to an increase AUC_IFC by about 30% with discontinuation of cyclosporine in patients after kidney transplantation receiving Sellsept® and ciclosporin (compared with patients receiving sirolimus or belatacept with similar doses of Cellsept®). In contrast, when patients transition from cyclosporine therapy to therapy with immunosuppressants that do not affect hepatic intestinal recirculation of IFC, a change in the exposure of IFC should be expected.

Telmisartan

Simultaneous application with Sellsept® results in a decrease in the concentration of MPA by approximately 30%. Telmisartan has an effect on the excretion of IFC by increasing the expression of a gamma receptor activated by peroxisome proliferators, which in turn increases the expression and activity of the UGT1A9 gene. There were no clinical manifestations of drug interaction when comparing the incidence of graft rejection and adverse event profiles in patients receiving Sellsept® with or without concomitant telmisartan therapy.

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 (see the sections "Pharmacokinetics in Special Clinical Cases" and "Specific Guidance") and ganciclovir, it can be assumed that simultaneous application of these two drugs (competing in the process of tubular secretion) 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 giciclovir (or its prodrugs, for example, valganciclovir) are used in patients with renal insufficiency, it is necessary to carefully observe patients.

Oral contraceptives

In a study involving 18 women with psoriasis, while taking Selsept® (1 g 2 times a day) for 3 menstrual cycles 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), no clinically significant effect of Sellsept® on the concentration of progesterone, luteinizing hormone (LH) and follicle stimulating hormone (FSH) was found. Thus, Cellsept® had no effect on the suppression of ovulation by oral contraceptives. The pharmacokinetics of oral contraceptives did not change to a clinically significant extent when combined with Sellsept®.

However, other methods of contraception should be used in addition to oral contraceptives when taking Selsept® (see the section on "Application during pregnancy and during breastfeeding").

Tacrolimus

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

Sirolimus

In patients after kidney transplantation, simultaneous administration of Cellsept® and cyclosporine resulted in a 30-50% reduction in MFC exposure compared to patients receiving a combination of sirolimus and Cellsept®.

Rifampicin

After correction of the dose, a decrease in the exposure of MFC 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 adjustment of Sellsept® to maintain clinical effect when combined.

Antibiotics, leading to the death of bacteria that produce β-glucuronidase in the intestine (for example, antibiotics from the group of aminoglycosides, cephalosporins, fluoroquinolones and penicillins), can disrupt the hepatic intestinal recirculation of IFPC / IFC, which in turn can lead to a decrease in the systemic exposure of IFC.

Information on the following antibiotics is available.

Ciprofloxacin or amoxicillin in combination with clavulanic acid

In patients after kidney transplantation, on days immediately after oral administration of ciprofloxacin or amoxicillin in combination with clavulanic acid, the minimum concentration of MPA is reduced by 54%. 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.

Norfloxacin and metronidazole

The use of norfloxacin in combination with metronidazole reduces AUC_0-48 IFC by 30% after a single dose of Cellsept®. With the separate use of one of these antibiotics, such an effect on the systemic exposure of IFC is absent.

Trimethoprim / sulfamethoxazole

When combined with trimethoprim / sulfamethoxazole, the effect on the systemic exposure of IFC (AUC, FROM_max) was not observed.

Other interactions

With simultaneous application probenecid and MMF monkeys there was an increase AUC IFPC in the plasma 3 times. 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.

Sevelamer

Simultaneous application of sevelamer and IFC in adults and children reduced C_max and AUC_0-12 IFC by 30% and 25%, respectively. Sevelamer and other phosphate-binding drugs that do not contain calcium should be used 2 hours after taking Sellsept® to reduce the effect on suction of the MPC.

Live attenuated vaccines

Should not be administered to patients in a state of immunosuppression. Antibody formation in response to other vaccines can be reduced (see section "Special instructions").

Special instructions:

Neoplasms

As against the combined immunosuppression in general, and when MMF is used 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.

Infections

Excessive suppression of the immune system can also increase susceptibility to infections, including opportunistic, sepsis and other fatal infections (see "Side effect" section). Such cases include the reactivation of a latent viral infection, for example, hepatitis B or C, or an infection caused by polyomaviruses. Hepatitis has been reported as a result of the reactivation of hepatitis B or C viruses in patients with hepatitis B or C viruses receiving immunosuppressive therapy. The cases of development of PML, associated with JCvirus, sometimes fatal, were observed in patients taking Sellsept®. 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.

In patients who underwent kidney transplantation and who received Sellsept®, cases of development of nephropathy associated with VC virus (VC virus - associated nephropathy) have been observed. This infection can lead to serious consequences, sometimes to the death of a kidney transplant. It is necessary to monitor the status of patients taking MMF to identify patients at risk of developing nephropathy associated with VC virus. With the development of symptoms of nephropathy associated with BV-virus, it is necessary to consider the question of reducing immunosuppression.

The blood system and the immune system

Cases of PACA development were observed in patients taking Sellsept® in combination with other immunosuppressive drugs. Mechanism of development PKKA Sellsept® when applying the drug is unknown, as well as the contribution of other immunosuppressants, and combinations thereof. In some cases, the PKA was reversible after a decrease in the Selsept® dose or withdrawal. However, in patients who undergone transplantation, a decrease in immunosuppression may compromise the graft.

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.

In the treatment of 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 - monthly. 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"). When neutropenia occurs (the absolute number of neutrophils is <1.3 × 10³/ μl), it is necessary to interrupt the treatment of MMF or reduce the dose, while carefully monitoring these patients.

In the course of MMP treatment, vaccination may be less effective; It is necessary to avoid the use of live attenuated vaccines (see section "Interaction with other drugs"). It is possible to carry out influenza vaccination in accordance with national recommendations.

Gastrointestinal tract

Admission MMF can be accompanied by adverse reactions from the gastrointestinal tract (ulceration of the mucous membrane of the gastrointestinal tract, gastrointestinal bleeding, perforation of the gastrointestinal tract).Care should be taken when using MMF in patients with diseases of the digestive tract at the stage of exacerbation.

MMP is an inhibitor of IMPDG, therefore, from the theoretical point of view, it should not be used in patients with a rare genetically determined hereditary deficiency of hypoxanthine guanine phosphoribosyltransferase (Lesch-Nienen syndrome and Kelly-Zygmiller syndrome).

Interaction

Care must be taken when switching from combination therapy, including immunosuppressants, that have an effect on the hepatic intestinal recirculation of the IFC, (for example, ciclosporin), on therapy with drugs devoid of this effect (for example, sirolimus and belatacept) and vice versa. This transition can lead to a change in the exposure of the IFC. Care should be taken when using drugs that affect the IFH hepatic-intestinal cycle (for example, colestramine, antibiotics) due to their ability to lower the plasma concentration and effectiveness of Cellsept®.

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

Special patient groups

The drug Selsept® is contraindicated during pregnancy and during breastfeeding.

In patients with severe chronic renal failure, doses of more than 1 g 2 times per day should be avoided (see sections "Pharmacokinetics in special clinical cases" and "Dosing in special cases").

Correction of dose to patients with delayed renal transplant function is not required, but they should be carefully observed (see sections "Pharmacokinetics in special clinical cases" and "Dosing in special cases"). Data on patients who have undergone heart or liver transplant and who have severe renal failure are absent.

In elderly patients, the risk of adverse events may be higher than in younger patients (see section "Side effect").

Treatment with the drug

Since MMF in the experiment on rats and rabbits showed a teratogenic effect, the integrity of the Cellsept® capsules should not be violated.It is necessary to avoid inhaling the powder contained in the capsules of the Sellsept® preparation or 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:

When driving vehicles, working with machinery and engaging in other potentially hazardous activities, it is necessary to take into account that the drug can cause dizziness and other side effects that can affect the concentration of attention and the speed of psychomotor reactions. When these undesirable phenomena appear, one should refrain from performing these activities.

Form release / dosage:

Capsules 250 mg.

Packaging:

10 capsules per blister of polyvinylchloride film and aluminum foil.

10 blisters together with instructions for use are placed in a cardboard box.

Storage conditions:

Store at a temperature of no higher than 30 ° C in a dry, dark place.

Keep out of the reach of children.

Shelf life:

3 years. Do not use after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:П N015393 / 01

Date of registration:12.08.2009 / 09.04.2012

The owner of the registration certificate:Hoffmann-La Roche Ltd.Hoffmann-La Roche Ltd. Switzerland

Manufacturer: & nbsp

Roche, S.p.A. Italy

Representation: & nbspF.Hoffmann-La Roche Ltd. F.Hoffmann-La Roche Ltd. Switzerland

Information update date: & nbsp22.09.16

Illustrated instructions

Instructions

SellSept® (CellCept®)