Sellsept: instructions for using the medicine, structure, Contraindications
Active material: Mycophenolate mofetil
When ATH: L04AA06
CCF: Immunosuppressive drugs
ICD-10 codes (testimony): Z94
When CSF: 14.02
Manufacturer: F.Hoffmann-La Roche Ltd. (Switzerland)
Sellsept: dosage form, composition and packaging
Capsules hard gelatin, size №1, with opaque blue cap and opaque body brown; the inscription on the lid “CellCept 250” black color, on the body – “Roche”; contents of capsules – the fine granular powder, partially skomkovavshiysya, from white to almost white.
| 1 caps. | |
| mycophenolic mofetil | 250 mg |
Excipients: pregelatinized corn starch, Croscarmellose sodium, povidone K90, magnesium stearate.
The composition of the shell capsules: gelatin, Titanium dioxide (E171), iron oxide red dye (E172), dye iron oxide yellow (E172).
The composition of the capsule caps: gelatin, Titanium dioxide (E171), dye indigo carmine (E132).
Ink composition: shellac, dye iron oxide black (E172), potassium hydroxide.
10 PC. – blisters (10) – packs cardboard.
Pills, coated Film pale purple, Engraved “CellCept 500” on one side and “Roche” – another.
| 1 tab. | |
| mycophenolic mofetil | 500 mg |
Excipients: microcrystalline cellulose, Croscarmellose sodium, povidone K90, magnesium stearate.
The composition of the shell: Лавандовый Opadry Y-5-10272-A (gipromelloza, giproloza, Titanium dioxide (E171), macrogol 400, dye indigo carmine (E132), iron oxide red dye (E172)).
10 PC. – blisters (5) – packs cardboard.
Sellsept: pharmachologic effect
Iimunodepressant, an inhibitor of inosine monophosphate dehydrogenase (IMFDG). Mycophenolic mofetil (IMF) It represents a 2-morpholinoethyl ester of mycophenolic acid (IFC). IFC – potent and selective non-competitive and reversible inhibitor of IMP DH, which inhibits the synthesis of guanosine nucleotides de novo. Mechanism, by IFC which inhibits the enzymatic activity of IMP DH, apparently, associated with the, IFC structurally mimics as a cofactor nikotinamiddinukleotidfosfata, and a catalytic water molecule. This prevents oxidation of IMP ksantozo-5-monophosphate – the most important stage guanosine nucleotide biosynthesis de novo. IFC has a more pronounced cytostatic effect on lymphocytes, than other cells, poskolyku proliferation T- and B-lymphocytes is highly dependent on the de novo purine synthesis, while other cell types can migrate to circuitous pathway.
To prevent rejection after kidney transplant, heart and liver, treatment of refractory rejection of the transplanted kidney MMF administered in combination with anti-thymocyte globulin, Muromonab-SD3, cyclosporine and corticosteroids.
When kidney transplantation MMF combination with cyclosporine and corticosteroids reduces the incidence of treatment failure in the first 6 months after transplantation and histologically proven rejection during therapy, dose 2 g / day reduces the cumulative incidence of death and mortality for transplant 12 months after kidney transplantation, but at a dose 3 g / day increases the rate of premature withdrawal from the study for any reason.
According to the frequency of histologically proven rejection, mortality and repeat heart transplants transplantation MMF exceeds azathioprine.
MMF in combination with corticosteroids and cyclosporin more effectively, than azathioprine, It prevents acute rejection and provides similar survival rates with azathioprine in patients with primary liver transplant.
MMF reduces the incidence of death or transplant deaths through 6 months after initiation of therapy 45% (p = 0.062) patients, Kidney transplant, with refractory acute therapy, cell-transplant oposredovannыm ottorzheniem.
Preclinical safety data
At doses 2-3 at times exceeding therapeutic kidney transplant, and in 1.3-2 times – compared with that of patients after heart transplant, mycophenolate mofetil did not have a carcinogenic effect, no effect on fertility of male rats. At doses, providing dramatic cytotoxic effect, in the two tests (determination of thymidine kinase in mouse lymphoma cells and mouse micronucleoli) mycophenolate mofetil has the potential to cause chromosomal instability.
In animal studies, the oral administration of the drug at a dose, in 0.5 times the systemic exposure dose 2 g / d after kidney transplantation, and about 0.3 systemic exposure times the clinical dose 3 g / day, recommended after heart transplantation, caused malformations (in t. no. anophthalmos, agnathy and hydrocephalus) in the first generation offspring, no toxic effects on the mother and fertility and reproductive future generations.
In teratogenicity studies in animals, receiving the drug in a dose of approximately systemic effects 0.5 times the dose 3 g / day, marked resorption of fruits and congenital malformations in rats (including anophthalmia, agnathy and hydrocephalus), in the offspring of rabbits were found malformations of the cardiovascular system, kidney, cardiac and renal ectopia, diaphragmatic hernia and umbilical, no signs of toxic effects on the mother's body.
In toxicological studies on animals MMF main lesions were located in the hematopoietic and lymphoid organs, And there is at this level of systemic exposure to the drug, which is equivalent to or less than the clinical dose exposure 2 g / day, recommended to patients after kidney transplantation. Nonclinical toxicity profile of mycophenolate mofetil, It coincides with adverse events, noted in clinical studies in humans, which provided data on safety, more meaningful to the patient population.
Sellsept: pharmacokinetics
The pharmacokinetic characteristics of MMF have been studied in patients, Kidney transplant, heart and liver. Generally, in patients after kidney transplantation and heart the same pharmacokinetic profile of MMF. In the early post-transplant patients, liver transplant and receiving MMF dose 1.5 g, IFC same concentration, both in patients after kidney transplantation, receiving MMF dose 1 g.
Absorption
Once inside there is a rapid and complete absorption and complete presystemic metabolism of MMF with the formation of the active metabolite – mycophenolic acid (IFC). The bioavailability of mycophenolate mofetil when administered, in accordance with the value of AUCIFC, is, average, 94% from that when on / in. Following oral administration of mycophenolate mofetil concentration in plasma was not determined.
In the early post-transplant period (to 40 days after kidney transplant, heart or liver) average AUC valuesIFC were approximately 30% below, a Cmax – about 40% below, than in the late post-transplant period (3-6 months after transplantation).
Food intake does not affect the extent of absorption of mycophenolate mofetil when administered at 1.5 g 2 times / day to patients after kidney transplantation. However, Cmax IFC while taking the drug during meals reduced by 40%.
Distribution
Usually, approximately 6-12 h after administration of the drug observed a secondary increase in the plasma concentration of IFC, indicating that liver-intestinal drug recycling. When concomitant administration kolectiramina AUCIFC reduced by about 40%, indicating that interrupting circulation hepatoenteric.
At clinically relevant concentrations of IFC 97% bound to plasma albumin.
Metabolism
IFC is metabolized, primarily, under the influence of glyukuroniltransferazy with a pharmacologically inactive phenolic glucuronide IFC (MFKG). In vivo MFKG turns into a free IFC in the intestinal and hepatic recirculation.
Deduction
After oral administration of radiolabelled mycophenolate mofetil 93% received a dose excreted in urine, and 6% – with feces. Most of (about 87%) of the administered dose is excreted in the urine as MFKG. Small amounts of the drug (<1% dose) excreted in the urine in the form of IFC.
Clinically defined concentration of IFC and MFKG not removed by hemodialysis. However, at higher concentrations MFKG (>100 ug / ml) some of it can be removed. Bile acid sequestrants such as cholestyramine reduce the AUCIFC, interrupting hepatoenteric recycling.
Bioequivalence
In the study of bioequivalence of two oral dosage forms of MMF has been shown, what 2 for tablets 500 mg equivalent of four capsules 250 mg.
Pharmacokinetics in special clinical situations
In a study of single dose of the drug in patients with chronic severe renal insufficiency (glomerular filtration rate < 25 ml / min / 1.73 m2) AUCIFC I was on 28-75% better, than in healthy volunteers and patients with less severe renal. After a single dose AUCmfkg in 3-6 times greater in patients with severe renal insufficiency, which is consistent with the known data on the renal excretion of MFKG.
Studies of multiple doses of mycophenolate mofetil in patients with chronic severe renal insufficiency has not been.
In patients with delayed graft function after kidney transplant mean AUC0-12 IFC comparable to those of patients with, who started graft function after transplantation without delay, and the mean AUC0-12 for MFKG plasma was 2-3 times.
In volunteers with alcoholic cirrhosis of the liver after oral administration of MMF revealed no change in the pharmacokinetics of IFC and MFKG, which indicates, out, that the defeat of the liver parenchyma is not a contraindication for the purpose of MMF. Influence of hepatic pathology to this process, probably, It depends on the particular disease. In the case of liver disease with prevalence of lesions of the biliary tract (eg, primary biliary cirrhosis) effect may be different.
In children and adolescents 18 years and younger, Kidney transplant, after oral administration at a dose of MMF 600 mg / m2 2 times / day (a maximum of 1 g 2 times / day) AUC of the IFC is comparable to that in adult patients after kidney transplantation, receiving a drug dose 1 g 2 times / day in the early and late post-transplant period. AUC values for the IFC did not differ between age groups, and later transplant period.
Patients in elderly (≥65 years) pharmacokinetic not izuchalasy.
Sellsept: testimony
- Prevention of acute organ rejection and treatment of refractory to treatment of organ rejection in patients after allogeneic kidney transplant;
- Prevention of acute organ rejection and improved graft survival and patient survival after allogeneic heart transplant;
- Prevention of acute organ rejection in patients after allogeneic liver transplant.
Sellsept® administered as a combination therapy with cyclosporine and corticosteroids.
Sellsept: dosing regimen
To prevention of kidney transplant rejection patients with kidney transplant is recommended reception 1 g 2 times / day (daily dose 2 g). Although clinical studies have shown, that dose 1.5 g 2 times / day (daily dose 3 g) also is a safe and effective, advantages in terms of its effectiveness in patients after renal transplantation is not installed. Patients, MMF dose of 2 g / day, the safety profile was, generally, better, than those treated with 3 g / day.
To Prevention of graft rejection of the heart or liver recommended reception 1.5 g 2 times / day (daily dose 3 g).
To treatment of first or refractory rejection of kidney transplant recommended reception 1.5 g 2 times / day (daily dose 3 g).
After kidney transplantation, heart or liver first dose CellCept® should be taken as early as possible.
Dosage in special cases
At neutropenia (absolute neutrophil count <1300/l) drug treatment should be interrupted or the dose reduced and the patient carefully monitored.
In patients with chronic severe renal insufficiency (glomerular filtration rate of less than 25 ml / min / 1.73 m2) is the nearest post-transplant period or after treatment for acute rejection or refractory should avoid doses higher 1 g 2 times / day. Data for patients with severe renal insufficiency, suffered a heart transplant or a liver, no.
Dose adjustment in patients with delayed graft function in renal not required.
Patients, kidney transplant and having heavy defeat liver parenchyma, dose adjustment is not required. Data on patients with severe hepatic parenchyma, heart transplant, no.
In patients elderly (≥65 years), Kidney transplant, The recommended dose is 1 g 2 times / day, and after a heart transplant or a liver – 1.5 g 2 times / day.
Children over 12 years, Kidney transplant, for the prevention of kidney transplant rejection when the body surface area 1.25-1.5 m2 possible use of the drug in the form of capsules 750 mg 2 times / day (daily dose – 1.5 g); when a body surface area 1.5 m2 possible appointment in the form of tablets 1 g 2 times / day (daily dose 2 g).
Data on the efficacy and safety of the drug in children for treatment of first or refractory rejection of kidney transplant, and after a heart transplant or a liver no.
Terms of use of the drug
Because mycophenolate mofetil in experiments on rats and rabbits showed teratogenic, CellCept tablets® Do not crush and break the integrity of CellCept capsules®. It is necessary to avoid inhalation powder, contained in CellCept capsules®, or direct contact with skin or mucous membranes. If this happens, This should be thoroughly washed with soap and water, and the eyes – just water.
Sellsept: side effects
Profile side effects, associated with the use of immunosuppressive drugs, often difficult to establish because of the underlying disease and simultaneous use of many other drugs.
Data from clinical studies
The main adverse reactions, associated with the use of MMF in combination with cyclosporin and corticosteroids for preventing the rejection of kidney, a heart or liver transplant, are diarrhea, leukopenia, sepsis and vomiting; There is also evidence of increased frequency of opportunistic infections.
The safety profile of MMF in the treatment of refractory renal rejection is similar to that for the prevention of kidney rejection when using the drug in doses 3 g / day. Diarrhea and leukopenia, then anemia, nausea, vomiting, stomach ache, sepsis were the predominant adverse reactions, occur in patients, MMF often, than in patients, receiving corticosteroids / in.
Malignancies. Patients, Kidney transplant, heart or liver and observed for at least 1 year, lymphoproliferative disease or lymphoma developed in 0.4-1% patients, MMF (doses 2 g / day or 3 g / day) in combination with other immunosuppressive. Skin cancer (excluding melanoma) I observed in 1.6-4.2% patients, other types of malignancy – in 0.7-2.1% patients. Three-year safety data in patients after kidney transplantation or heart did not reveal any unexpected changes in the incidence of malignant neoplasms, compared with growth rates. After a liver transplant patients were followed for at least 1 year, but less 3 years.
In the treatment of refractory renal rejection rate of lymphomas at a mean follow up 42 months was 3.9%.
Opportunistic infections. The risk of opportunistic infections increased in all post-transplant patients and increases with the degree of immunosuppression. In appointing the MMF (2 g / day or 3 g / day) in combination with other immunosuppressive drugs in patients, followed for 1 years after kidney transplant (at a dose 2 g / day), heart and liver, The most common infections were candidiasis of skin and mucous membranes, CMV viraemia / CMV syndrome (13.5%) and infection, Herpes simplex virus.
Type of adverse reactions and the frequency of their occurrence when administered at a dose of MMF 600 mg 2 times / day for children aged 3 months before 18 s did not differ from those of adults, receiving drug dose 1 g 2 times / day. However, such side effects as diarrhea, leukopenia, sepsis, infection, anemia occurred more frequently (≥ 10%) children, especially under 6 years.
Patients in elderly (≥65 years) MMF in the treatment as part of combination immunosuppressive therapy, the risk of certain infections (including tissue invasive forms of symptomatic CMV infection), and, perhaps, gastrointestinal haemorrhage and pulmonary edema above, than in younger patients.
Adverse Reactions, marked at ≥10% and ≥10% of patients, MMF in combination with cyclosporine and corticosteroids after kidney transplantation, heart and liver are listed below.
| The frequency of adverse reactions | After kidney transplantation | After a heart transplant | After Liver Transplant |
| From the body as a whole: | |||
| ≥10% | asthenia, fever, headache, infection, pain (in a stomach, loin, Chest), peripheral edema, sepsis | asthenia, fever, chills, headache, infection, pain (in a stomach, loin, Chest), peripheral edema, sepsis | ascites, asthenia, fever, chills, abdominal distention, headache, infection, pain (in a stomach, loin, Chest), peripheral edema, sepsis, Hernia, peritonitis |
| from 3% to < 10% | cyst (incl. lïmfocele and Hydrocele), facial swelling, flu-like symptoms, bleeding, Hernia, malaise, pelvic pain, abdominal distention | cellulitis, cyst (incl. lïmfocele and Hydrocele), facial swelling, flu-like symptoms, KRO votecheniya, Hernia, abdominal distention, malaise, pelvic pain, neck pain, pale skin | abscess, cellulitis, cyst (incl. lïmfocele and Hydrocele), flu-like symptoms, bleeding, malaise, neck pain |
| From the hematopoietic system: | |||
| ≥10% | anemia (incl. hypochromic), leukocytosis, leukopenia, thrombocytopenia | anemia (incl. hypochromic), leukocytosis, leukopenia, thrombocytopenia, ecchymosis | anemia (incl. hypochromic), leukocytosis, leukopenia, thrombocytopenia |
| from 3% to < 10% | ecchymosis, polycythemia | petechiae, increased prothrombin and thromboplastin time | ecchymosis, increased prothrombin time, pancytopenia |
| With the genitourinary system: | |||
| ≥10% | hematuria, renal tubular necrosis, urinary tract infection | impairment of renal function, oligurija, urinary tract infection | impairment of renal function, oligurija, urinary tract infection |
| from 3% to < 10% | albuminuria, dizurija, gidronefroz, impotence, pyelonephritis, frequent urination | dizurija, hematuria, impotence, nocturia, renal failure, frequent urination, incontinence and urinary retention | acute renal failure, dizurija, hematuria, renal failure, swelling of the scrotum, frequent urination, urinary incontinence |
| Cardio-vascular system: | |||
| ≥10% | increased blood pressure | arrhythmia, bradycardia, heart failure, rise and fall in blood pressure, pericardial effusion | rise and fall in blood pressure, tachycardia |
| from 3% to < 10% | angina, auricular fibrillation, low blood pressure, orthostatic hypotension, tachycardia, thrombosis, vasodilation | angina, Arrhythmia (supraventricular and ventricular premature beats, atrial flutter and atrial fibrillation, supraventricular and ventricular tachycardias and), cardiac arrest, congestive heart failure, orthostatic hypotension, pulmonary hypertension, swoon, vasospasm, increasing venous pressure | arteryalnыy thrombosis, auricular fibrillation, Arrhythmia, bradycardia, vasodilation, swoon |
| Metabolism: | |||
| ≥10% | Acidosis(metabolic or respiratory), gipervolemia, weight gain | wound healing complications | |
| from 3% to < 10% | Acidosis (metabolic or respiratory), degidratatsiya, gipervolemia, weight gain | wound healing complications, alkalosis, degidratatsiya, gout, gipovolemiя, gipoksiya, carbon dioxide acidosis, thirst, loss of flesh | Acidosis (metabolic or respiratory), degidratatsiya, gipervolemia, gipoksiya, gipovolemiя, weight gain, loss of flesh |
| From the laboratory parameters: | |||
| ≥10% | hypercholesterolemia, giperglikemiâ, hyperkalemia, giperfosfatemiя | giperʙiliruʙinemija, increase in residual nitrogen, creatinine increase, increase in liver enzymes (LDH, IS, GOLD) serum, hypercholesterolemia, giperglikemiâ, hyperkalemia, hyperlipidemia, hyperuricemia, kaliopenia, gipomagniemiya, giponatriemiya | giperʙiliruʙinemija, increase in residual nitrogen, creatinine increase, giperglikemiâ, hyperkalemia, kaliopenia, hypocalcemia, gipoglikemiâ, gipomagniemiya, gipofosfatemiя, hypoproteinemia |
| from 3% to < 10% | increased activity of alkaline phosphatase, increase in liver enzymes (GGT, LDH, ACT and ALT) serum, elevation of serum creatinine, hypercalcemia, hyperlipidemia, hypocalcemia, gipoglikemiâ, hypoproteinemia, hyperuricemia | increased activity of alkaline phosphatase, hypocalcemia, chloropenia, gipoglikemiâ, hypoproteinemia, gipofosfatemiя | increased activity of alkaline phosphatase, increase in liver enzymes (ACT and ALT) serum, hypercholesterolemia, hyperlipidemia, giperfosfatemiя, giponatriemiya |
| From the digestive system: | |||
| ≥10% | constipation, diarrhea, dyspepsia, nausea and vomiting, oral candidiasis | constipation, diarrhea, dyspepsia, flatulence, nausea and vomiting, oral candidiasis | anorexia, kholangit, cholestatic jaundice, constipation, diarrhea, dyspepsia, flatulence, hepatitis, nausea and vomiting, oral candidiasis |
| from 3% to < 10% | anorexia, flatulence, gastroenteritis, gastrointestinal bleeding, gastrointestinal candidiasis, gingivitis, giperplaziya right, ileus, stomatitis, esophagitis | anorexia, dysphagia, gastroenteritis, gingivitis, giperplaziya right, jaundice, ground, stomatitis, esophagitis | dysphagia, gastritis, gastrointestinal bleeding, ileus, jaundice, ground, ulceration of the mucous membranes of the mouth, esophagitis, defeat rectum, gastric ulcer |
| The respiratory system: | |||
| ≥10% | increased cough, breathlessness, pharyngitis, pneumonia, bronchitis | asthma, increased cough, breathlessness, pharyngitis, pleural effusion, pneumonia, rhinitis, sinusitis | increased cough, breathlessness, pharyngitis, pneumonia, pleural effusion, sinusitis, atelectasis |
| from 3% to < 10% | asthma, pleural effusion, pulmonary edema, rhinitis, sinusitis | apnea, atelectasis, bronchitis, nose bleed, hemoptysis, Ikotech, neoplasms, pneumothorax, pulmonary edema, strengthening of sputum, voice alteration | asthma, bronchitis, nose bleed, hyperventilation, pneumothorax, pulmonary edema, candidiasis of the respiratory tract, rhinitis |
| Dermatological reactions: | |||
| ≥10% | acne, herpes simplex | acne, herpes simplex, shingles, rash | rash, itch, increased sweating |
| from 3% to < 10% | hair loss, benign tumors of the skin, fungal dermatitis, shingles, girsutizm, itch, skin cancer, skin hypertrophy (incl. actinic keratosis), increased sweating, skin ulcers, rash | benign tumors of the skin, fungal dermatitis, gemorragii, itch, skin cancer, skin hypertrophy, increased sweating, skin ulcers | acne, fungal dermatitis, gemorragii, herpes simplex, shingles, girsutizm, benign tumors of the skin, skin ulcers, vesiculo- bullous rash |
| From the central and peripheral nervous system: | |||
| ≥10% | dizziness, insomnia, tremor | psychomotor agitation, alarm, confusion, depression, dizziness, gipertonus, insomnia, paresthesia, drowsiness, tremor | alarm, confusion, depression, dizziness, insomnia, paresthesia, tremor |
| from 3% to < 10% | alarm, depression, gipertonus, paresthesia, drowsiness | convulsions, emotional lability, hallucinations, Neuropathy, memory decline, vertigo | psychomotor agitation, convulsions, delirium, dry mouth, gipertonus, gipesteziya, Neuropathy, psychosis, drowsiness, memory decline |
| On the part of the musculoskeletal system: | |||
| ≥10% | leg cramps, muscle aches, muscular weakness | ||
| from 3% to < 10% | joint pain, leg cramps, muscle aches, muscular weakness | joint pain | joint pain, leg cramps, muscle aches, muscular weakness, osteoporosis |
| From the senses: | |||
| ≥10% | amblyopia | ||
| from 3% to < 10% | amblyopia, Cataract, conjunctivitis | visual impairment, conjunctivitis, deafness, earache, bleeding in the eye, noise in ears | visual impairment, amblyopia, conjunctivitis, deafness |
| On the part of the endocrine system: | |||
| ≥10% | |||
| from 3% to < 10% | diabetes, parathyroid disease (increase the level of parathyroid hormone) | diabetes, Cushing's syndrome, gipotireoz | diabetes |
The prevention of rejection in kidney transplant MMF safety profile in a daily dose 2 g was slightly better, than daily dosage 3 g.
Post-marketing use of the drug
From the digestive system: colitis (sometimes CMV etiology), pancreatitis; in some cases – atrophy of the intestinal villi.
On the part of the immune system: in some cases – heavy, life-threatening infections (meningitis, infective endocarditis), increased incidence of certain infections (tuberculosis and atypical mycobacterial infection).
Cases progressiruyushtey mulytifokalynoy leykoэntsefalopatii (PML), sometimes with fatal consequences, observed in patients, taking CellCept®. Reports of these cases, there is information about the presence of other patients risk factors for PML, including immunosuppressive therapy and the deterioration of the immune system.
Cases of partial red cell aplasia (PKKL) observed in patients, taking CellCept® in combination with other immunosuppressive drugs.
Reproductive system: reported cases of fetal anomalies (including the development of Rocky ear) patients, MMF pregnancy in combination with other immunosuppressive.
Other adverse reactions, observed during post-registration drug application, It does not differ from unwanted reactions, in clinical studies for the.
Sellsept: Contraindications
- increased individual sensitivity to mycophenolate mofetil, mycophenolic acid and other ingredients.
FROM caution should be prescribed the drug for gastrointestinal disorders in the acute phase.
Sellsept: Pregnancy and lactation
Category D drug. Revealed an increased risk of spontaneous abortion in the I trimester of pregnancy, as well as an increased risk of congenital malformations, including malformations of the external ear, “cleft palate”, “cleft lip”, distal extremities, heart abnormalities, esophagus, kidney.
The patient, planning a pregnancy, It should not take CellCept® until, is more effective than other immunosuppressive drugs. If the patient receives the drug when the planned or stepped pregnancy, the doctor should be informed of the potential harm to the fetus.
MMF may be administered during pregnancy only in cases, the potential benefit to the mother outweighs the potential risk to the fetus.
MMF should not begin until, until a negative result is screening for pregnancy using the method of analysis of serum or urine samples with a sensitivity of at least 25 mIU / ml. Before initiation of therapy with MMF, during treatment and over 6 weeks after it mandatory to use effective contraceptive methods, even if a woman has a history of infertility (except transferred hysterectomy). If abstinence from sexual intercourse is impossible, you need to use two reliable methods of contraception at the same time, because CellCept® may reduce the level of hormones in the oral contraceptive drugs, which reduces their effectiveness.
In rats, mycophenolate mofetil is excreted in milk. Provided there MMF breast milk in humans, unknown. Because breast milk many drugs are excreted, as well as due to the possibility of serious adverse reactions to MMF in infants, the choice between continuation of breast-feeding, or taking medication do given the importance of the treatment to the mother.
Sellsept: Special instructions
In the appointment of MMF as a component of immunosuppressive schemes have an increased risk of developing lymphomas and other malignancies, particularly of the skin. This risk, apparently, not associated with any of the drug as such, and with the intensity and duration of immunosuppression.
As with all patients with an increased risk of skin cancer, should limit exposure to the sun and UV rays by wearing appropriate clothing and closed using sunscreen with a high protection factor.
Patients, MMF, You should be informed about the need to immediately tell your doctor about any signs of infection, bleeding, bleeding or other signs of suppression of bone marrow hematopoiesis.
Excessive suppression of the immune system can also increase susceptibility to infection, incl. Opportunistic, sepsis and other infections with a fatal outcome.
In patients with immunosuppression in the presence of neurological symptoms should make a differential diagnosis of PML and recommend consulting a neurologist.
Cases of PKKA observed in patients, taking CellCept® in combination with other immunosuppressive drugs. The mechanism of the appointment of CellCept PKKA® Unknown, as well as the role of other immunosuppressants, and combinations thereof. In some cases, PKKA was reversible upon dose reduction CellCept® or cancel. However, patients, transplant, reduction of immunosuppression may increase the risk of graft rejection.
During treatment with MMF vaccination may be less effective; you must avoid the use of live attenuated vaccines. You can spend influenza vaccination in line with national guidelines.
Since receiving MMF may be accompanied by side effects from the digestive system (ulceration of the gastrointestinal mucosa, gastrointestinal bleeding, perforation of the gastrointestinal tract), must be used with caution in patients with MMF gastrointestinal diseases in acute phase.
Since the MMF is an inhibitor of IMP DH, then, from a theoretical point of view, it should not be administered to patients with rare hereditary deficiency of genetically caused hypoxanthine (syndrome Lesch-Nayena and Kelly Zigmillera).
MMF is not recommended in conjunction with azathioprine, because both drugs inhibit the bone marrow, and their simultaneous reception has not been studied.
Caution should be exercised with concomitant administration of MMF with drugs, affecting the intestinal and hepatic circulation, because they can reduce the effectiveness of MMF.
In patients with chronic severe renal insufficiency should be avoided at doses more 1 g 2 times / day.
Dose adjustment in patients with delayed graft function in renal not required, however, they should be carefully monitored. Data for patients, suffered a heart transplant or a liver and have severe renal insufficiency, no.
In elderly patients the risk of adverse events may be higher, than in younger patients.
Monitoring of laboratory parameters
In the treatment of MMF is necessary to determine complete blood count during the first month – weekly, during the second and third months of treatment – 2 once a month, and then during the first year – monthly. Neutropenia may be associated with both the MMF, and using other drugs, viral infections, or a combination of these reasons. In the event of neutropenia (absolute neutrophil count less than 1,300 cells / mm) need to interrupt treatment or reduce the dose of MMF, This involves careful monitoring of these patients.
Sellsept: overdose
Data on overdose of MMF have been obtained in clinical trials and post-registration application. In most cases undesirable reactions data registered. Developing an overdose undesirable effects coincides with the known safety profile of the drug. Expected, overdose of MMF, probably, lead to immunosuppression (consequently – to increased susceptibility to infections) and inhibition of bone marrow hematopoiesis. In case of neutropenia receiving CellCept® discontinue or reduce the dose of the drug.
IFC can not be removed from the body by hemodialysis. However, at high concentrations in plasma MFKG (>100 ug / ml) a small amount is still displayed. Preparations, binding bile acids, eg, cholestyramine, can help remove the body of the IFC, increasing its excretion.
Sellsept: drug interaction
With simultaneous use of MMF and increases the concentration of acyclovir in plasma of both drugs in renal failure, perhaps, as a result of competition for tubular secretion, which may lead to a further increase in the concentration of both drugs.
Antacids, containing magnesium hydroxide and aluminum reduce the absorption of MMF.
Following the appointment of a single dose of MMF 1.5 g in healthy volunteers, previously accepted by 4 Mr. kolestiramina 3 times / day for 4 days, observed a decrease in AUCIFC on 40%. Caution should be exercised with concomitant administration of MMF and preparations, affecting the liver-intestinal recycling.
MMF has no effect on cyclosporine pharmacokinetics. When concomitant administration is reduced by the impact of the IFC 30-50% compared to patients, MMF in combination with sirolimus.
According to the study with a one-time oral administration of MMF in the recommended doses and / in the introduction of ganciclovir, significant changes in the pharmacokinetics are not expected to IFC, therefore, adjust the dose of MMF is not required. If the MMF and ganciclovir used in patients with renal insufficiency, requires careful clinical monitoring.
MMF does not affect the pharmacokinetics of oral contraceptives. At the same time taking a combined oral contraceptive, containing ethinylestradiol (20-40 g) and levonorgestrel (50-200 g), desogestrel (150 g) or gestodene (50-100 g), Sellsept® (1 g 2 times / day) no clinically significant effect on the level of progesterone, LG, FSH. Thus, Sellsept® no effect on the inhibition of ovulation by the action of oral contraceptives. However, while receiving CellCept® in addition to oral contraceptives need to use other methods of contraception.
Trimethoprim / sulfamethoxazole, norfloxacin, Metronidazole not affect the bioavailability of the IFC. But single dose CellCept® in combination with norfloxacin and metronidazole reduces AUC0-48 IFC 30%.
While the use of tacrolimus revealed no effect on the AUC and Cmax IFC in patients after liver and kidney transplants. In patients after renal transplantation CellCept appointment® It did not affect the concentration of tacrolimus.
In patients with stable liver transplant tacrolimus AUC after multiple dose MMF dose 1.5 g 2 times / day increased by about 20%.
In an application with rifampicin, after dose adjustment decreased the impact of IFC 70% (AUC0-12) patients after simultaneous Heart and Lung Transplantation. It is recommended to control the concentration of the regular IFC in plasma and CellCept dose adjustment® to maintain clinical benefit with a joint appointment.
Patients after kidney transplantation in the bottom immediately after oral ciprofloxacin or amoxicillin in combination with clavulanic acid, a decrease in Cmin IFC blood plasma 54%. With extended antibiotic therapy, this effect is reduced, and disappears after discontinuation of therapy. The clinical significance of this phenomenon is unknown, since the change in Cmin may not adequately reflect the change in the total exposure to the IFC.
Blockers tubular secretion (probenecid) increase the concentration MFKG.
The simultaneous use of sevelamer and IFC in adults and children reduces Cmax и AUC0-12 IFC 30% and 25% respectively. Sevelamer and other phosphate binders, not containing calcium, should be appointed through 2 h after administration of CellCept®, to reduce the effect on the absorption IFC.
Live vaccines should not be given to immunosuppressed patients.. Antibody production in response to the other vaccine may be reduced.
Sellsept: terms of dispensing from pharmacies
The drug is released under the prescription.
Sellsept: terms and conditions of storage
List B. The drug should be stored out of reach of children, dry, protected from light, at a temperature no higher than 30 ° C. Shelf life – 3 year.
