Selsept, 500 mg 50 pcs.

In combination therapy with cyclosporine and corticosteroids:

• Prevention of acute organ rejection and treatment of therapy-refractory organ rejection in patients after allogeneic kidney transplantation;
• Prevention of acute organ rejection in patients after allogeneic liver transplantation.

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Active ingredient

Composition

1 coated tablet contains:

the active ingredient:

mycophenolate mofetil 500 mg,

excipients:

MC;

croscarmellose sodium;

povidone (K-90);

magnesium stearate

coating:

Lavender Opadry Y-5-10272-A (hypromellose; hyprolose; titanium dioxide (E171); macrogol 400; indigo carmine dye (E132); iron oxide red dye (E172))

How to take, the dosage

Prevention of renal transplant rejection

Patients with renal transplants are recommended to take 1 g 2 times daily (daily dose is 2 g). Though in clinical trials it was shown that the dose of 1,5 g 2 times per day (daily dose – 3 g) is also safe and effective, its advantages in terms of efficacy in patients after kidney transplantation are not established. Patients who received 2 g of MMF per day had an overall better safety profile than those who received the daily dose of 3 g.

Prevention of heart transplant rejection

The recommended dosing regimen is 1.5 g twice daily (daily dose is 3 g).

Prophylaxis of liver transplant rejection

The recommended dosing regimen is 1.5 g 2 times daily (daily dose is 3 g).

Treatment of first or refractory renal transplant rejection

The recommended dosing regimen is 1.5 g 2 times daily (daily dose is 3 g). After a kidney, heart or liver transplant, the first dose of Selsept ® should be taken as soon as possible.

Dosing in special cases

In case of neutropenia (absolute neutrophil count <1300 in 1 µl of blood), MMF treatment should be discontinued or the dose reduced and the patient closely monitored.

In patients with severe chronic renal insufficiency (glomerular filtration rate less than 25 ml/min/1.73 m2) outside the immediate post-transplant period or after therapy for acute or refractory rejection, doses above 1 g 2 times daily should be avoided. No data are available for patients with severe renal failure who have undergone heart or liver transplantation.

Dose adjustment is not required in patients with delayed renal transplant function.

Patients who have undergone a kidney transplant and have severe liver parenchyma damage do not require dose adjustment. No data are available for patients with severe liver parenchyma damage who have undergone a heart transplant.

In elderly and elderly patients (≥65 years) who have undergone a kidney transplant, the recommended dose is 1 g 2 times daily and after a heart or liver transplant 1.5 g 2 times daily (see “Special Precautions”).

Children:

Interaction

Acyclovir. Concomitant use of mycophenolate mofetil and acyclovir increases plasma concentrations of both drugs in renal insufficiency, possibly due to competition with respect to tubular secretion, which may lead to further increases in concentrations of both drugs.

The antacids containing magnesium and aluminum hydroxide reduce absorption of MMF.

Colestyramine. After administration of a single dose of mycophenolate mofetil 1.5 g to healthy volunteers who had previously taken 4 g of colestiramine 3 times daily for 4 days, a 40% reduction in AUCMFC was observed. Caution should be exercised when concomitant administration of MMF and drugs affecting hepatic-intestinal recirculation.

Cyclosporine A. Mycophenolate mofetil does not affect the pharmacokinetics of cyclosporine A. When concomitantly administered, mycophenolate mofetil exposure is reduced by 30-50% compared to patients receiving MMF in combination with sirolimus.

Ganciclovir. According to the results of a study with single oral administration of the recommended doses of mycophenolate mofetil and intravenous administration of ganciclovir, no significant change in the pharmacokinetics of MMF is expected, so no adjustment of the MMF dose is necessary. If MMF and ganciclovir are administered to patients with renal impairment, patients should be closely monitored.

The oral contraceptives. MMF does not affect the pharmacokinetics of oral contraceptives. If concomitantly taken with combined oral contraceptives containing ethinylestradiol (0.02-0.04 mg) and levonorgestrel (0.05-0.2 mg), desogestrel (0.15 mg) or gestoden (0.05-0.1 mg), Selsept (1 g 2 times daily) has no clinically significant effect on progesterone, LH and FSH levels. Thus, Selsept has no effect on the suppression of ovulation by oral contraceptives.

However, other contraceptive methods should be used in addition to oral contraceptives while taking Selseptic.

Trimethoprim/sulfamethoxazole, norfloxacin, metronidazole. Do not affect the bioavailability of MFC when prescribed with one of the antibacterial drugs. But concomitant administration of Selsept in combination with norfloxacin and metronidazole reduces the AUC0-48 of MFC by 30% after a single dose of Selsept.

Tacrolimus. No effect on the AUC and Cmax of MFC in patients after liver and kidney transplantation was found when concomitantly administered. In patients after renal transplantation, administration of Selsept had no effect on tacrolimus concentrations. In patients with stable hepatic transplantation, the AUC of tacrolimus increased by approximately 20% after repeated administration of MMF at a dose of 1.5 g 2 times per day.

Rifampicin. After dose adjustment, a 70% reduction in mycophenolic acid exposure (AUC0-12) has been noted in patients after a single-step heart and lung transplant; it is recommended that MMF exposure be controlled and the dose of Selsept adjusted to maintain the clinical effect when co-administered.

Ciprofloxacin and amoxicillin in combination with clavulanic acid. In patients after renal transplantation in the days immediately following oral administration of ciprofloxacin or amoxicillin in combination with clavulanic acid, a 54% reduction in Cmin IFC was observed. This effect decreases with continuation of antibiotic therapy 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 total IFC exposure.

Other interactions. Blockers of tubular secretion (probenecid) increase concentrations of MFKG.

The concomitant use of svelamer and MFC in adults and children reduces the Cmax and AUC0-12 of MFC by 30 and 25%, respectively. Sevelamer and other calcium-free phosphate-binding drugs should be administered 2 h after administration of Selsept to reduce the effect on MFC absorption.

Live vaccines. Should not be administered to patients who are immunosuppressed. Antibody formation in response to other vaccines may be reduced.

Special Instructions

At the same time as with combined immunosuppression in general, there is an increased risk of lymphoma and other malignancies, especially of the skin, when MMF is prescribed as a component of an immunosuppressive regimen (see “Side Effects”). This risk appears to be related not to the use of any drug per se, but to the intensity and duration of immunosuppression.

As in all patients with an increased risk of skin cancer, exposure to the sun and UV rays should be limited by wearing appropriate covered clothing and using sunscreens with a high protective factor.

Patients receiving MMF should be informed to report any signs of infection, bleeding, bleeding or other signs of bone marrow suppression to their physician immediately.

Excessive suppression of the immune system may also increase susceptibility to infections, including opportunistic infections, sepsis, and other fatal infections.

Cases of PML, sometimes fatal, have been observed in patients taking Selsept®. These cases have been reported as having additional risk factors for PML, including immunosuppressive therapy and immune impairment. In immunosuppressed patients with neurologic symptoms, a differential diagnosis of PML should be made and a consultation with a neurologist should be recommended.

Cases of PKKA have been observed in patients taking Selsept in combination with other immunosuppressive drugs. The mechanism of PKCA with administration of Selsept, as well as other immunosuppressive drugs and their combinations, is unknown. In some cases, PCKA has been reversible after reduction of the dose of Selsept or withdrawal. However, in transplant patients, decreased immunosuppression may compromise the graft.

In the course of MMF treatment, vaccination may be less effective; live, attenuated vaccines should be avoided. Anti-influenza vaccination can be given according to national guidelines.

Because MMF administration may be accompanied by gastrointestinal adverse reactions (mucosal ulceration, gastrointestinal bleeding, perforations), care should be taken when prescribing MMF to patients with acute digestive tract conditions.

Because MMF is an IMFDH inhibitor, in theory, it should not be prescribed to patients with rare genetically determined hereditary hypoxanthine anguanine phosphoribosyltransferase deficiency (Lesh-Naikhan and Kelly-Seegmiller syndromes).

MMF is not recommended for concomitant administration with azathioprine because both drugs depress bone marrow, and their concomitant administration has not been studied.

Cautions must be taken when concomitantly prescribing MMF with drugs that affect hepatic circulation because they may decrease the effectiveness of MMF (see “Interactions”).

In patients with severe chronic renal insufficiency, doses greater than 1 g 2 times daily should be avoided.

Dose adjustment is not necessary in patients with delayed renal transplant function, but they should be closely monitored. No data are available for heart or liver transplant patients with severe renal insufficiency.

The risk of adverse events may be higher in elderly patients than in younger patients.

Laboratory monitoring: during treatment with MMF it is necessary to determine the detailed blood count during the first month weekly, during the second and third months of treatment – twice a month, and then during the first year – monthly. Neutropenia may be caused by taking MMF as well as by other drugs, viral infections or a combination of these reasons. In case of neutropenia (absolute number of neutrophils less than 1300 per 1 µl) it is necessary to interrupt MMF treatment or reduce the dose, while closely monitoring these patients.

Handling of the drug. Because MMF has shown teratogenic effects in rats and rabbits in experiments, the tablets of Selsept should not be crushed and the integrity of the capsules should not be compromised. Avoid inhalation of the powder contained in Sellsept capsules or direct contact with skin or mucous membranes. If this happens, you should rinse the area thoroughly with soap and water, and the eyes with just water.

Contraindications

Hypersensitivity to mofetil mycophenolate or mycophenolic acid and other components of the drug.
With caution – gastrointestinal diseases (in the acute phase).

Side effects

The profile of adverse events associated with the use of immunosuppressants is often difficult to establish because of the underlying disease and the simultaneous use of many other medications.

The data from clinical trials. The main adverse reactions associated with the use of MMF in combination with cyclosporine and corticosteroids to prevent renal, cardiac or hepatic transplant rejection are diarrhea, leukopenia, sepsis and vomiting; there is also evidence of an increased incidence of opportunistic infections.

The safety profile of MMF in the treatment of refractory kidney rejection is similar to that for the prevention of kidney rejection when the drug is used at a dose of 3 g per day. Diarrhea and leukopenia, followed by anemia, nausea, vomiting, abdominal pain, and sepsis were the predominant adverse reactions seen in patients receiving MMF more often than in patients receiving corticosteroids w/v.

Malignant neoplasms. Lymphoproliferative disease or lymphoma developed in 0.4-1% of kidney, heart, or liver transplant patients followed for at least 1 year who received MMF (in doses of 2 or 3 g daily) in combination with other immunosuppressants. Skin carcinoma (excluding melanoma) was observed in 1.6-4.2% of patients, malignant neoplasms of other types in 0.7-2.1% of patients. Three-year safety data in patients after kidney or heart transplantation showed no unexpected changes in the incidence of malignant neoplasms compared with one-year rates. After liver transplantation, patients were followed for at least 1 year but less than 3 years.

In the treatment of refractory kidney rejection, the incidence of lymphoma was 3.9% with a mean follow-up period of up to 42 months.

Opportunistic infections. The risk of opportunistic infections is increased in all post-transplant patients and increases with the degree of immunosuppression. When MMF (2 or 3 g per day) was administered in combination with other immunosuppressants in patients followed for 1 year after kidney transplantation (at a dose of 2 g per day), heart and liver, the most frequent infections were candidiasis of the skin and mucous membranes, CMV viremia/CMV syndrome (13.5%) and infection caused by herpes simplex virus.

The type and incidence of adverse reactions with oral administration of 600 mg of MMF 2 times daily in children aged 3 months to 18 years was virtually the same as in adult patients receiving the drug in a dose of 1 g 2 times daily. However, adverse reactions such as diarrhea, leukopenia, sepsis, infections, and anemia were more common (≥10%) in children, especially those under 6 years of age.

The risk of certain infections (including tissue invasive forms of manifest WVD infection) and possibly gastrointestinal bleeding and pulmonary edema is higher in elderly and elderly patients (≥65 years) when treated with MMF as part of combined immunosuppressive therapy than in younger patients.

The adverse events noted in ≥10 and 3-10% of patients treated with MMF in combination with cyclosporine and corticosteroids after kidney, heart, and liver transplantation

An adverse event noted in patients who received MMF in combination with cyclosporine and corticosteroids/p> Organs and body systems Frequency, % Undesirable phenomena after kidney transplantation Undesirable phenomena after heart transplantation Adverse events after liver transplantation Body as a whole ≥10 Asthenia, fever, headache, infections, pain (abdomen, lower back, chest), peripheral edema, sepsis Asthenia, fever, chills, headache, infections, pain (abdomen, lower back, chest), peripheral edema, sepsis Ascites, asthenia, fever, chills, abdominal bloating, headache, infections, pain (abdomen, lower back, chest), peripheral edema, sepsis, hernias, peritonitis 3-< 10 Cysts (incl.including lymphocele and hydrocele), facial edema, flu-like syndrome, bleeding, hernia, malaise, pelvic pain, abdominal bloating Subcutaneous inflammation, cysts (including lymphocele and hydrocele), facial edema, flu-like syndrome, bleeding, hernias, abdominal distension, malaise, pelvic pain, neck pain, pale skin Abscess, inflammation of subcutaneous tissue, cysts (incl.ч. lymphocele and hydrocele), flu-like syndrome, bleeding, malaise, neck pain Blood and lymphatic system ≥10 Anemia (includingincluding hypochromic), leukocytosis, leukopenia, thrombocytopenia Anemia (including hypochromic), leukocytosis, leukopenia, thrombocytopenia, ecchymosis Anemia (including Hypochromic), leukocytosis, leukopenia, thrombocytopenia 3-< 10 Echymosis, polycythemia Petechiae, increased prothrombin and thromboplastin time Echymoses, increased prothrombin time, pancytopenia Genitourinary tract ≥10 Hematuria, renal tubule necrosis, urinary tract infections Renal dysfunction, oliguria, urinary tract infections Renal impairment, oliguria, urinary tract infections 3-< 10 Albuminuria, dysuria, hydronephrosis, impotence, pyelonephritis, frequent urination Dysuria, hematuria, impotence, nycturia, renal failure, frequent urination, incontinence and urinary retention Acute renal failure, dysuria, hematuria, renal failure, scrotal edema, frequent urination, urinary incontinence /td> Cardiovascular system ≥10 Increased blood pressure Arrhythmia, bradycardia, heart failure, decreased or increased BP, pericardial effusion Decreased or increased BP, tachycardia 3-< 10 Stenocardia, atrial fibrillation, decreased BP, orthostatic hypotension, tachycardia, thrombosis, vasodilation Angina, arrhythmias (supraventricular and ventricular extrasystoles, atrial flutter and fibrillation, supraventricular and ventricular tachycardia), cardiac arrest, congestive heart failure, orthostatic hypotension, pulmonary hypertension, syncope, vasospasm, increased venous pressure/td> Arterial thrombosis, atrial fibrillation, arrhythmias, bradycardia, vasodilation, syncope Metabolism ≥10 – Acidosis (metabolic or respiratory), hypervolemia, weight gain td> Wound healing disorder 3-< 10 Acidosis (metabolic or respiratory), dehydration, hypervolemia, weight gain Laboratory values ≥10 Hypercholesterolemia, hyperglycemia, hyperkalemia, hypokalemia, hypophosphatemia Hyperbilirubinemia, increased residual nitrogen, increased creatinine, increased serum enzyme activity (LDH, AST, ALT), hypercholesterolemia, hyperglycemia, hyperkalemia, hyperlipidemia, hyperuricemia, hypokalemia, hypomagnesemia, hyponatremia Hyperbilirubinemia/td> Hyperbilirubinemia, increased residual nitrogen, increased creatinine, hyperglycemia, hyperkalemia, hypokalcemia, hypoglycemia, hypomagnesemia, hypophosphatemia, hypoproteinemia 3-< 10 Increase in alkaline phosphatase activity, increase in enzyme activity (gamma-glutamyl transpeptidase, LDH, AST and ALT) in serum, increase in serum creatinine, hypercalcemia, hyperlipidemia, hypocalcemia, hypoglycemia, hypoproteinemia, hyperuricemia ; 10/td> Increased ALP activity, hypocalcemia, hypochloremia, hypoglycemia, hypoproteinemia, hypophosphatemia

Overdose

Data on MMF overdose have been reported in clinical trials and during post-registration use. In most cases, no adverse events have been reported. The adverse events that developed in overdose were consistent with the known safety profile of the drug.

Predicted symptoms: An overdose of MMF is expected to likely result in immunosuppression (resulting in increased susceptibility to infections) and bone marrow suppression.

Treatment: If neutropenia develops, Selsept should be stopped or the dose decreased.

MFC cannot be removed from the body by hemodialysis. However, at high plasma concentrations of MFCG (>100 µg/ml), small amounts are still eliminated.

Bile acid-binding drugs, such as colestyramine, can help eliminate MFKH from the body by increasing its excretion.