Cellsept® [Mofetil mycophenolate]

Pharmacological properties

Mofetil mycophenolate is mycophenolic acid 2-morpholinoethyl ester, a powerful selective non-competitive and reversible inosine monophosphate dehydrogenase inhibitor that inhibits the synthesis of de novo guanosine nucleotides without inclusion in the DNA. Mycophenolic acid 2-morpholinoethyl ester has a more pronounced cytostatic effect on lymphocytes than on other cells, since the proliferation of t- and b-lymphocytes is largely dependent on the synthesis of de novo purines, while other types of cells can switch to metabolic bypass pathways .

Pharmacokinetics

Suction. After oral administration, rapid and complete absorption and complete presystemic metabolism of mycophenolate mofetil occur with the formation of an active metabolite of mycophenolic acid.

Based on the suppression of acute kidney transplant rejection, the immunosuppressive activity of the Cellsept drug is correlated with the concentration of mycophenolic acid. The oral bioavailability of mycophenolate mofetil according to the AUC value is on average 94% of that when given intravenously. Eating does not affect the degree of absorption of mycophenolate mofetil when it is prescribed 1.5 g 2 times a day to patients after kidney transplantation. However c_max Mycophenolic acid 2-morpholinoethyl ether when using the drug with food is reduced by 40%. After oral administration, the concentration of mycophenolate mofetil in blood plasma is not determined.

Distribution. As a rule, approximately 6–12 hours after taking the drug, a secondary increase in the concentration of 2-morpholinoethyl ester of mycophenolic acid in the blood plasma is noted, which indicates hepatic-intestinal recirculation of the drug. With the simultaneous use of colestyramine, AUC decreases by approximately 40%, which indicates an interruption of hepatic-intestinal recirculation. In clinically significant concentrations, mycophenolic acid binds to plasma plasma albumin by 97%.

Metabolism. Mycophenolic acid 2-morpholinoethyl ester is metabolized mainly by the action of glucuronyl transferase to form the pharmacologically inactive phenolic glucuronide of mycophenolic acid 2-morpholinoethyl ester.

A small amount of the drug (1% of the dose) is excreted in the urine in the form of 2-morpholinoethyl ester of mycophenolic acid. After oral administration of radioactively labeled mycophenolate mofetil, 93% of the dose taken is excreted in the urine, 6% with feces. A significant portion (about 87%) of the administered dose is excreted in the urine in the form of glucoronide 2-morpholine ester of mycophenolic acid. Concentrations of 2-morpholinoethyl ester of mycophenolic acid and glucuronide of 2-morpholine ester of mycophenolic acid, which are determined clinically, are not excreted by hemodialysis. However, at high concentrations of glucuronide 2-morpholine ester of mycophenolic acid (100 μg / ml), some of it can be removed. Sequestrants of bile acids such as colestyramine reduce AUC by interrupting hepatic-intestinal recirculation.

In the early post-transplant period (up to 40 days after kidney, heart, or liver transplantation), mean AUCs were approximately 30%, and C_max - 40% lower than in the late post-transplant period (3–6 months after transplantation).

Pharmacokinetics in special cases

In studies with a single dose of the drug in patients with severe renal failure (glomerular filtration rate of 25 ml / min / 1.73 m²) AUC was 28–75% higher than in healthy volunteers and patients with less pronounced kidney damage. After taking a single dose, AUC is 3–6 times greater in patients with severe renal failure, which confirms the known data on the liver elimination of glucuronide 2-morpholine ester of mycophenolic acid.Multiple mycophenolate mofetil withdrawal studies in severe renal failure have not been studied. There is no data on patients with severe chronic renal failure after heart and liver transplantation.

Delayed Renal Transplant Function

In patients with delayed renal transplant function after transplantation, the average AUC_0-12 for 2-morpholinoethyl ester of mycophenolic acid is comparable to that in patients in whom the graft began to function after transplantation without delay, and the average AUC value_0-12 for glucuronide, 2-morpholine ester of mycophenolic acid in blood plasma was 2-3 times greater. Perhaps a transient increase in the free fraction and the concentration of mycophenolic acid in blood plasma in patients with delayed renal transplant function. Correction of the dose of Cellsept in such cases is not required.

Patients with liver failure

In volunteers with alcoholic cirrhosis of the liver, it was revealed that the defeat of the liver parenchyma does not relatively affect the process of glucuronidation of mycophenolic acid. The effect of hepatic pathology on the process depends on the specific disease. In the case of liver disease with a predominance of biliary tract damage (for example, primary miliary cirrhosis), the effect may be different.

Children aged 2–18 years

Pharmacokinetic parameters were studied in 49 children after kidney transplantation, who received mycophenolate mofetil at a dose of 600 mg / m² orally 2 times a day. When applying this dose, the AUC was similar to that in adult patients after kidney transplantation who received Cellsept at a dose of 1 g 2 times a day in the early and late post-transplant period. The value of AUC in different age groups was comparable in the early and late post-transplant period.

Elderly patients

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

Oral contraceptives

Mofetil mycophenolate does not affect the pharmacokinetics of oral contraceptives. When taken concomitantly with combined oral contraceptives that contain 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), Cellsept (1 g 2 times a day) does not have a clinically significant effect on the level of progesterone, LH and FG. Thus, Cellsept does not affect the suppression of ovulation by oral contraceptives.

Indications

Prevention of acute organ rejection in patients after allogeneic transplantation of a kidney, heart, liver as part of combination therapy with cyclosporine and corticosteroids.

Application

Prevention of kidney rejection

Adults The drug should be started within 72 hours after the transplantation. Patients with renal transplants are recommended to take 1 g 2 times a day (daily dose - 2 g).

Children aged 2–18 years. The recommended dose is 600 mg / m² orally 2 times a day (up to a maximum daily dose of 2 g). Cellsept capsules should be prescribed to those patients whose body surface area is at least 1.25 m². Patients with a body surface area of ​​1.25–1.5 m² Cellsept, capsules, can be prescribed in a dose of 750 mg 2 times a day (daily dose - 1.5 g). Patients with a body surface area of ​​1.5 m² Cellsept, capsules, can be prescribed in a dose of 1 g 2 times a day (daily dose - 2 g). Since some adverse reactions occur more often in children and adolescents than in adults, there may be a need for a temporary dose reduction or discontinuation of treatment with the drug. In this case, important clinical factors should be taken into account, including the severity of the reaction.

Children aged 2 years. There is limited evidence regarding the safety and effectiveness of the drug for children aged 2 years. Therefore, the use of the drug in children aged 2 years is not recommended.

Heart rejection prevention

AdultsThe drug should be started within 5 days after transplantation. Patients with kidney transplants are recommended to take 1.5 g 2 times a day (daily dose - 3 g).

Children. There are no data on the safety and efficacy of Cellsept in children after heart transplantation.

Prevention of liver rejection

Adults After liver transplantation, the first dose of Cellsept should be taken as soon as possible. The recommended dosage regimen is 1.5 g 2 times a day (daily dose - 3 g).

Children. There are no data on the safety and efficacy of Cellsept in children after liver transplantation.

Special dosage recommendations

Elderly patients

For elderly patients (≥65 years), after a kidney transplant, the recommended dose is 1 g 2 times a day, and after a heart and liver transplant, 1.5 g 2 times a day.

Patients with kidney failure

Patients with severe chronic renal failure (glomerular filtration rate 25 ml / min / 1.73 m²) doses not exceeding 1 g 2 times a day should be avoided in the immediate post-transplant period or in the post-treatment state due to acute or refractory rejection. Such patients must be carefully monitored.

Dose adjustment in patients with delayed renal transplant function is not required. There is no data on patients with severe renal failure who underwent a heart or liver transplant.

Patients with liver failure

Patients after kidney transplantation with severe damage to the liver parenchyma do not need dose adjustment. There are no data on patients with severe damage to the liver parenchyma who underwent heart transplantation.

Treatment for episodes of rejection

Mycophenolic acid is an active metabolite of mycophenolate mofetil. Renal transplant rejection does not lead to a change in the pharmacokinetics of mycophenolic acid. In such cases, discontinuation of Cellsept treatment or reduction of its dose is not required. There is no data on the pharmacokinetics of mycophenolic acid during liver transplant rejection. There is no data on dose adjustment for rejection of a heart transplant.

Patients with neutropenia

With neutropenia (the absolute number of neutrophils is 1300 in 1 μl of blood), it is necessary to stop treatment with the drug or reduce its dose and carefully monitor the patients condition.

Contraindications

Hypersensitivity to mofetil mycophenolate, mycophenolic acid and other components of the drug; lactation period.

Side effects

Clinical trial data

The main adverse reactions associated with the use of the drug in combination with cyclosporine and corticosteroids are diarrhea, leukopenia, sepsis and vomiting; There is also evidence of an increase in the incidence of opportunistic infections (see SPECIAL INSTRUCTIONS).

Malignant neoplasms

Patients receiving combination immunosuppressive therapy, including Cellsept, have an increased risk of lymphomas and other malignant neoplasms, in particular the skin (see SPECIAL INSTRUCTIONS). Lymphoproliferative diseases or lymphomas develop in 0.6% of patients treated with Cellsept (at a dose of 2 or 3 g / day) in combination with other immunosuppressants in controlled clinical trials in patients after kidney transplantation (at a dose of 2 g), as well as after heart and liver transplants, which were followed for at least 1 year. Skin carcinoma (with the exception of melanoma) was detected in 3.6% of patients, malignant neoplasms of other types - in 1.1% of patients. The three-year safety data for patients after a kidney or heart transplant does not contain information about any unexpected changes in the incidence of malignant neoplasms compared with the figures for the year. After a liver transplant, patients were observed for at least 1 year, but less than 3 years.

Opportunistic infections

The risk of opportunistic infections was increased in all patients and increased with an increase in the total dose of immunosuppressants.When prescribing mycophenolate mofetil (2 or 3 g / day) in combination with other immunosuppressants in patients who were observed for one year after a kidney transplant (at a dose of 2 g), heart and liver, candidiasis of the skin and mucous membranes were the most common infections, cytomegalovirus viremia / cytomegalovirus syndrome (13.5%), herpes simplex virus infection.

Children aged 2–18 years

The type and frequency of adverse reactions in a clinical study in which 92 children aged 2–18 years who received mycophenolate mofetil at a dose of 600 mg / m took part² orally 2 times a day, in general, were similar to those in adults who received Cellsept at a dose of 1 g 2 times a day. However, compared with adults, the following adverse reactions associated with treatment were more often observed in children, in particular in children aged 6 years: diarrhea, sepsis, leukopenia, anemia, and infections.

Elderly patients (≥65 years old)

Elderly patients generally have an increased risk of adverse reactions due to immunosuppression. In elderly patients, when treated with the drug as a combination therapy, the risk of certain infections (including tissue invasive forms of manifest cytomegalovirus infection), as well as gastrointestinal bleeding and pulmonary edema, is higher than in younger patients (see SPECIAL INSTRUCTIONS).

Other adverse reactions

Side effects were observed in ≥10 and in 3–10% of patients who received treatment with Cellsept in combination with cyclosporine and corticosteroids after a kidney, heart, and liver transplant.

The following categories are used to determine the frequency of adverse reactions: very often (≥1 / 10), often (≥1 / 100 and 1/10), sometimes (≥1 / 1000 and 1/100), rarely (≥1 / 10,000 and 1/1000), very rarely (10 000), the frequency is unknown (cannot be determined from known data).

Infections and infestations: very often - sepsis, gastrointestinal candidiasis, urinary tract infections, herpes simplex virus infection, herpes zoster virus infection; often - pneumonia, influenza, respiratory tract infections, respiratory tract candidiasis, gastrointestinal infections, candidiasis, gastroenteritis, infection, bronchitis, pharyngitis, sinusitis, fungal skin infections, skin candidiasis, vaginal candidiasis, rhinitis.

Benign and malignant neoplasms (including cysts and polyps): often - skin cancer, benign skin neoplasm.

Violation of the blood system and lymphatic system: very often - leukopenia, thrombocytopenia, anemia (including hypochromic anemia), ecchymosis; often - pancytopenia, leukocytosis, polycythemia, petechiae, an increase in prothrombin and thromboplastin time.

Metabolic and metabolic disorders: very often - bilirubinemia; increased creatinine, hypervolemia, hyponatremia, weight gain, increased blood urea nitrogen, impaired wound healing, hypoproteinemia; often - acidosis (metabolic or respiratory), hyperkalemia, hypoglycemia, hypokalemia, hyperglycemia, hypomagnesemia, hypocalcemia, hypercholesterolemia, hyperlipidemia, hypophosphatemia, hyperuricemia, gout, anorexia, dehydration, hypoxaemia, hypovolemia.

Mental disorders: often - agitation, confusion, depression, anxiety, impaired thinking, insomnia.

Neurological disorders: very often - psychomotor agitation; often - convulsions, skeletal muscle hypertonicity, tremor, drowsiness, myasthenic syndrome, dizziness, headache, paresthesia, taste disturbance, emotional lability, hallucinations, neuropathy, delirium, dry mouth, psychosis.

Cardiac disorders: very often - arrhythmia, bradycardia, heart failure, pericardial effusion; often - tachycardia, angina pectoris, arrhythmias (supraventricular and ventricular extrasystoles, atrial fibrillation and flutter, supraventricular and ventricular tachycardia), cardiac arrest, congestive heart failure.

Vascular disorders: often - arterial hypotension, including orthostatic, hypertension, vasodilation, thrombosis, pulmonary hypertension, loss of consciousness, vasospasm, increased venous pressure, arterial thrombosis.

Violation of the respiratory system, chest and mediastinal organs: very often - increased cough, pharyngitis, pneumonia, bronchitis; AD, rhinitis, sinusitis; atelectasis; often - pleural effusion, dyspnea, cough, pulmonary edema, apnea, nosebleeds, hemoptysis, neoplasm, pneumothorax, increased sputum production, voice changes, hyperventilation, candidiasis of the respiratory tract, hiccups.

Changes in the skin and subcutaneous tissue: very often - itching, increased sweating; often - skin hypertrophy, rash, acne, alopecia, fungal dermatitis, hirsutism, skin ulcers, hemorrhages, vesiculobullous rash.

Gastrointestinal disorders: very often - vomiting, abdominal pain, diarrhea, nausea, dyspepsia, anorexia; often - gastrointestinal bleeding, peritonitis, intestinal obstruction, colitis, gastric ulcer, duodenal ulcer, gastritis, esophagitis, stomatitis, constipation, dyspepsia, flatulence, belching, dysphagia, gingivitis, gingival hyperplasia, gastroenteritis, chalk mouth ulcers.

Disorders of the hepatobiliary system: very often - cholangitis; often - hepatitis, jaundice (including cholestatic), hyperbilirubinemia.

Disturbances from the musculoskeletal system: very often - cramps in the legs, muscle pain, muscle weakness; often - arthralgia, osteoporosis.

Disorders of the urinary system: very often - hematuria, necrosis of the renal tubules, urinary tract infections, oliguria; often - impaired renal function, albuminuria, dysuria, hydronephrosis, impotence, pyelonephritis, frequent urination, hematuria, nocturia, renal failure, incontinence and urinary retention; acute renal failure, scrotal edema.

General disorders: very often - hernia, peritonitis, ascites; often - edema, fever, chills, pain (including abdominal pain, back pain, chest pain), malaise, asthenia, cysts (including lymphocele and hydrocele), facial swelling, flu-like syndrome, bleeding, pain in the area pelvis, cellulitis, neck pain, pallor of the skin, abscess.

Research: often - an increase in the level of liver enzymes, an increase in the level of creatinine in the blood, an increase in the levels of LDH, urea, alkaline phosphatase in the blood, and a decrease in body weight.

Violations of the sensory organs: very often - amblyopia; often - cataracts, conjunctivitis, visual impairment, deafness, ear pain, eye hemorrhage, vestibular dizziness.

Endocrine disorders: often - diabetes mellitus, parathyroid disease, Cushings syndrome, hypothyroidism.

Post-marketing experience

Adverse reactions reported during post-marketing use of the drug were similar to those recorded in controlled trials.

Gastrointestinal Disorders: gingival hyperplasia (≥1 / 100 and 1/10), colitis, including cytomegalovirus colitis (≥1 / 100 and 1/10), pancreatitis (≥1 / 100 and 1/10), intestinal atrophy villus.

Immunosuppression disorders: serious life-threatening infections, including meningitis, endocarditis, tuberculosis, atypical mycobacterial infection. In patients receiving immunosuppressive drugs, including Cellsept, there were cases of VK virus-associated nephropathy, as well as cases of JC virus-associated progressive multifocal leukoencephalopathy. This infection can be associated with serious consequences that sometimes lead to the loss of a kidney transplant.

Agranulocytosis (≥1 / 1000 and 1/100) and neutropenia. Cases of aplastic anemia and bone marrow depression, sometimes fatal, have been reported.

Disorders from the blood system and lymphatic system: cases of red cell aplasia have been reported in patients treated with Cellsept in combination with other immunosuppressants.Certain cases of violations of the morphology of neutrophils, including the Pelger-Huet anomaly. These changes were not associated with impaired neutrophil function and may indicate a leftward shift of the neutrophil maturity index in blood tests, which may be mistakenly perceived as a sign of infection in immunosuppressed patients, for example, treated with Cellsept.

Hypersensitivity reactions: there have been reports of hypersensitivity reactions, including angioedema and anaphylactic reaction.

Congenital developmental deficiencies: Congenital developmental deficiencies, including ear developmental defects, have been reported in newborns whose mothers used mycophenolate mofetil with other immunosuppressive drugs during pregnancy.

Disorders from the respiratory system, chest organs and mediastinum: individual cases of interstitial lung disease and pulmonary fibrosis, sometimes fatal, in patients treated with Cellsept in combination with other immunosuppressive drugs.

special instructions

Special security measures

Since mycophenolate mofetil exerted a teratogenic effect in animal experiments, the Cellsept capsules should not be opened or broken. Avoid inhalation of the powder contained in the capsules or its direct contact with the skin or mucous membranes. If this happens, wash the affected area thoroughly with soap and water, and eyes with clean running water. Unused product must be disposed of as required.

As with combined immunosuppression, when mycophenolate mofetil is prescribed as a component of an immunosuppressive regimen, there is an increased risk of developing lymphomas and other malignant neoplasms, especially skin (see ADVERSE EFFECTS). This risk is associated not with the use of any drug as such, but with the intensity and duration of immunosuppression.

Like all patients with an increased risk of developing skin cancer, patients taking Cellsept should limit the effect of sunlight and UV rays by wearing appropriate clothing and using sunscreens with a high protective factor.

Patients taking mycophenolate mofetil should be informed about the need to immediately inform the doctor of any signs of infection, bleeding, bleeding or other signs of bone marrow depression.

Excessive suppression of the immune system can also increase sensitivity to infections (bacterial, fungal, viral, and protozoal), including opportunistic, sepsis, and other fatal infections. Such opportunistic infections include VK virus-associated nephropathy and progressive multifocal leukoencephalopathy associated with the JC virus. These infections are often associated with high total immunosuppression and can lead to serious or fatal consequences. These diseases should be considered when conducting differential diagnosis in patients with immunosuppression and impaired renal function or with neurological symptoms.

It is necessary to monitor the condition of patients receiving Cellsept for neutropenia, which may be associated both with the therapy of mycophenolate mofetil, with the use of other drugs, with viral infections, or with a combination of these factors. When treating mofetil with mycophenolate, it is necessary to determine the expanded blood formula for 1 month - weekly, for 2 and 3 months of treatment - 2 times a month, and then for 1 year - every month.In case of neutropenia (the absolute number of neutrophils is 1300 in 1 μl), it is necessary to stop treatment with Cellsept or reduce its dose and carefully monitor the patients condition.

Cases of red cell aplasia have been reported in patients treated with Cellsept in combination with other immunosuppressants. The mechanism of occurrence of red cell aplasia with the use of mycophenolate mofetil is unknown. The effect of other immunosuppressants when combined with immunosuppressive therapy is also unknown. In some cases, red cell aplasia was reversible when the dose was reduced or treatment with Cellsept was discontinued. Changes in treatment with Cellsept should be carried out only with appropriate monitoring of patients after transplantation in order to minimize the risk of transplant rejection.

During treatment with mycophenolate mycophenolate mofetil, vaccination may be less effective; live attenuated vaccines must be avoided. You can vaccinate against influenza according to national guidelines.

Since the use of mycophenolate mofetil may be accompanied by adverse reactions from the gastrointestinal tract (ulceration of the gastrointestinal mucosa, gastrointestinal bleeding, perforation of the gastrointestinal tract), it is necessary to prescribe the drug with caution in patients with gastrointestinal diseases in the acute stage.

Since mycophenolate mofetil is an inosine monophosphate dehydrogenase inhibitor, from a theoretical point of view, it should not be prescribed to patients with a rare genetically determined hereditary hypoxanthine guanine phosphoribosyl transferase deficiency (Lesch-Nyen and Kelly-Zigmiller syndromes).

Mofetil mycophenolate is not recommended to be prescribed simultaneously with azathioprine, since both drugs inhibit the bone marrow and their simultaneous use has not been studied.

Caution should be exercised while taking mycophenolate mofetil with drugs that affect the hepatic-intestinal circulation, since they can reduce the effectiveness of mycophenolate mofetil.

The risk / benefit ratio for the use of mycophenolate mofetil in combination with tacrolimus or sirolimus has not been established.

Pregnancy and lactation

Cellsept therapy should not be started until a negative pregnancy test result has been obtained. Before starting therapy with Cellsept, during treatment and for 6 weeks after its completion, it is necessary to use effective methods of contraception. Patients should be informed of the need for immediate consultation with a doctor after pregnancy.

A patient planning to become pregnant should not use the drug as long as other immunosuppressive drugs are effective. Pregnant Cellsept may be prescribed by a doctor in cases where the potential benefit to the mother outweighs the potential risk to the fetus. Data on the use of Cellsept in pregnant women are limited. Cases of congenital developmental deficiencies have been reported, including abnormalities in ear development in children born to patients who received Cellsept in combination with other immunosuppressants. There were cases of miscarriage in the first trimester of pregnancy. In animal studies, mycophenolate mofetil was the cause of reproductive toxicity.

It is not known whether the drug passes into breast milk. Given the likelihood of serious adverse reactions in breast-fed infants, Cellsept is contraindicated during lactation.

Children. There are no data on the safety and effectiveness of Cellsept in children after liver and heart transplantation. There is limited evidence regarding the safety and efficacy of the drug in children 2 years of age after kidney transplantation.

The ability to influence the reaction rate when driving vehicles or other mechanisms. Studies of the effect on the reaction rate when driving vehicles and working with complex mechanisms have not been carried out. However, extreme caution is advised, given the potential for developing adverse reactions (see ADVERSE EFFECTS).

Interactions

Interaction studies were performed only in adults.

Acyclovir. With the appointment of mycophenolate mofetil in combination with acyclovir, higher plasma concentrations of glucuronide 2-morpholine ester of mycophenolic acid and acyclovir were noted in blood than when each drug was administered separately. Since plasma concentrations of glucuronide 2-morpholine ester of mycophenolic acid, like acyclovir or its drug valganciclovir, increase with renal failure, it is likely that these two drugs compete with respect to tubular secretion, which can cause a further increase in the concentration of both drugs.

Antacids and proton pump inhibitors. When taken with antacids, the absorption of mycophenolate mofetil decreases.

Colestyramine. After the administration of a single dose of 1.5 g of mycophenolate mofetil to healthy volunteers who previously applied 4 g of colestyramine 3 times a day for 4 days, a decrease in AUC of mycophenolate acid by 40% was noted. Caution must be exercised while prescribing mycophenolate mofetil and colestyramine mofetil in connection with the reliability of decreasing the effectiveness of Cellsept.

Medicines affecting the intestinal-hepatic circulation. Caution should be exercised while taking mycophenolate mofetil with drugs that affect the hepatic-intestinal circulation, since they can reduce the effectiveness of mycophenolate mofetil.

Cyclosporin A. Mofetil mycophenolate does not affect the pharmacokinetics of cyclosporin A. With simultaneous use, the effect of mycophenolic acid is reduced by approximately 30%.

Ganciclovir. According to the results of a study with a single oral administration of mycophenolate mofetil at the recommended doses and iv administration of ganciclovir, taking into account the known effect of renal failure on the pharmacokinetics of mycophenolate mofetil and ganciclovir, it can be assumed that the simultaneous use of these drugs (competing in the process of tubular secretion) will increase the concentration glucuronide 2-morpholine ester of mycophenolic acid and ganciclovir. A significant change in the pharmacokinetics of mycophenolic acid 2-morpholinoethyl ester is not expected; therefore, the dose of mycophenolate mofetil should not be adjusted. If mycophenolate mofetil and ganciclovir or its drug valganciclovir are prescribed for patients with renal failure, the dosage regimen recommended for ganciclovir should be observed and the patient should be carefully monitored.

Oral contraceptives. Mofetil mycophenolate does not affect the pharmacokinetics and pharmacodynamics of oral contraceptives.

Rifampicin. In patients not taking cyclosporine, the simultaneous use of Cellsept and rifampicin was accompanied by a decrease in AUC_0-12 mycophenolic acid by 18–70%. It is recommended that AUC control of mycophenolic acid and dose adjustment of the drug Cellsept to maintain clinical effect with their simultaneous use.

Sirolimus. In patients after kidney transplantation, the simultaneous use of Cellsept and cyclosporin A was accompanied by a 30–50% decrease in AUC of mycophenolic acid compared with patients who received a combination of sirolimus and Cellsept in similar doses.

Sevelamer. Decrease C_max and AUC_0-12 Mycophenolic acid was 30 and 25% respectively observed with the simultaneous use of the drug Cellsept with Sevelamer without any clinical consequences (that is, without transplant rejection). However, in order to minimize the effect of sevelamer on the absorption of mycophenolic acid, it is recommended to take Cellsept at least 1 hour before or 3 hours after taking sevelamer.

Trimethoprim / sulfamethoxazole. Do not affect the bioavailability of mycophenolic acid.

Norfloxacin, metronidazole. In healthy volunteers, there was no significant interaction between Cellsept and one of the antibacterial drugs with simultaneous use. However, the simultaneous use of Cellsept in combination with norfloxacin and metronidazole reduces AUC_0-48 Mycophenolic acid 30% after a single use of Cellsept.

The interaction of the drug Cellsept with ciprofloxacin and amoxicillin with clavulanic acid. For several