Pharmacological properties Myfortic:
mikofenolovaya acid (IFC) inhibits the proliferation of T and B lymphocytes than other cells because, unlike other types of cells that are able to re-utilize purines, lymphocyte proliferation is critically dependent on the synthesis of purines de novo. Therefore, the mechanism of action of Myfortic complements the mechanism of action of inhibitors of calcineurin, violating production of cytokines and affecting T cells at rest.
Suction. After oral mycophenolate sodium is absorbed rapidly. Time to reach maximum concentration of IFC is reached after approximately 1,5-2 hours in vitro studies have shown that enteric-soluble film coating Myfortic prevents the release of the IFC in the acidic environment similar to that of the stomach.
In patients with stable kidney transplant, receiving a basic immunosuppressive therapy in the form of cyclosporine microemulsion, the degree of absorption of the IFC from the gastrointestinal tract was 93%, and bioavailability – 72%. In the studied dose range from 180 to 2160 mg Myfortic pharmacokinetics had a linear dose-dependent nature. The value of AUC when receiving Myfortic fasting did not differ from that while taking the drug with food high in fat (55 g fat, 1000 calories). However, the maximum concentration of the IFC has declined by 33%.
Distribution. The volume of distribution at steady state IFC is 50 liters. As the IFC and the glucuronide mikofenolovoy acid (GMFK) have high protein binding – 97 and 82% respectively. In the face of declining plasma concentrations of free protein (uremia, hepatic failure, hypoalbuminemia, the simultaneous use of drugs with high protein binding) may increase the plasma concentrations of free IFC and, consequently, increasing the risk of side effects.
Metabolism. Half-life of the IFC is 11.7 hours, clearance – 8.6 l / h. IFC is primarily metabolized with glyukuroniltransferazy with the formation of phenolic glucuronide IFC – GMFK. GMFK is the main metabolite of IFC and does not possess biological activity. In patients with stable kidney transplant, receiving a basic immunosuppressive therapy in the form of cyclosporine microemulsion, about 28% of oral dose of Myfortic GMFK goes into the first passage through the liver by presystemic metabolism. Half Life GMFK is 15.7 hours, clearance – 0.45 L / h.
Excretion. IFC is derived mainly from the urine in the form GMFK and a very small amount (≤ 1,0%) – unchanged. GMFK also secreted with bile into the intestine, where the splits (by dekonyugatsii) flora of the intestine. Generated as a result of this splitting IFC can then reabsorbed. After 6-8 h after administration of Myfortic with a second peak concentration of the IFC, which corresponds to the re-absorption dekonyugirovannoy IFC.
Pharmacokinetics in patients with renal transplant receiving cyclosporine basic immunosuppressive therapy in the form of microemulsions. The table presented average values of pharmacokinetic parameters of the IFC after taking Myfortic. The value of pharmacokinetic parameters of singly dose Myfortic can provide Myfortic pharmacokinetics after repeated and prolonged dosing. In the early post-transplant period, the average AUC and Cmax were approximately half of IFC values determined at 6 months after transplantation.
Pharmacokinetics IFC does not depend on renal function. On the contrary, the influence of GMFK increases with a decrease in renal function, the effect GMFK about 8 times higher in anuria. Hemodialysis does not affect the clearance of the IFC and GMFK. Concentration of free IFC can significantly increase in renal failure. This may be associated with decreased binding of the IFC to plasma proteins at a high concentration of urea in the blood.
Hepatic failure. In patients with liver cirrhosis found no effect of lesions of the liver parenchyma on the processes glyukuronirovaniya IFC. Influence on this process may depend on the specific disease of the liver. Although liver disease associated with the biliary system, such as biliary cirrhosis, may have a different effect.
Children. Experience of using Myfortic for the treatment of children is limited. The above table shows the average values of pharmacokinetic parameters of the IFC in children with stable renal transplant are at a basic immunosuppressive therapy, cyclosporine in microemulsion form. The value of Cmax and AUC of IFC in children compared with those in adult patients with kidney transplants were more variable. Mean AUC values IFC at the same dose was higher than that of adults when taking the usual dose of 720 mg. The average value of clearance IFC was 7.7 l / h. We can expect that the application of Myfortic in a dose of 200-300 mg / m 2, AUC IFC will be within 30-50 mcg • h / ml.
Paul. Clinically significant differences between pharmacokinetic parameters depending on the patient’s gender was not revealed.
Elderly patients. Based on previous data, the effect of the IFC shall not clinically significantly vary depending on the patient’s age.
Indications Myfortic:
Prevention of acute graft rejection in patients with allogeneic transplants kidneys, receiving combination immunosuppressive therapy with cyclosporine (in the form of a microemulsion) and corticosteroids.
APPLICATION Myfortic:
Myfortic therapy should only be carried out by qualified doctors transplant.
Myfortic should be given to patients within the first 24 hours after transplantation. The recommended dose is 720 mg (4 tablets of 180 mg or 2 tablets of 360 mg) 2 times a day (daily dose – 1440 mg). In patients receiving mycophenolate mofetil at a dose of 2 g / d, this treatment can be replaced with Myfortic dose of 720 mg 2 times a day (daily dose – 1440 mg).
Myfortic take regardless of the meal.
Elderly patients. In the correction of dosing for this age group of patients is not necessary.
Use of the drug in patients with impaired renal function. Careful monitoring of patients with severe renal impairment (glomerular filtration rate ≤ 25 mL / min).
Use of the drug in patients with impaired liver function. In patients with significant lesions of the liver parenchyma correction dosing is not required.
Treatment during the reaction of graft rejection. The reaction of graft rejection does not lead to changes in the pharmacokinetics of the IFC, a dose reduction or discontinuation of Myfortic is not required.
CONTRAINDICATIONS Myfortic:
Hypersensitivity to mycophenolate sodium, IFC, mycophenolate mofetil, or any components of the drug, children’s age, the period of lactation.
SIDE EFFECTS Myfortic:
the most common (≥ 10%) of adverse drug reactions associated with the use of Myfortic in combination with cyclosporin (as microemulsion) and corticosteroids include leukopenia, and diarrhea.
Malignant neoplasms. Patients receiving combination immunosuppressive therapy, including Myfortic, have an increased risk of developing lymphomas and other malignancies, particularly skin. Cases of malignant tumors were observed in clinical trials of Myfortic, have the following characteristics: lymphoproliferative disease or lymphoma developed in 2 patients de novo (0,9%) patients and 2 patients with stable functioning renal transplant on a continuous maintenance therapy (1,3% ) taking Myfortic for 1 year non-melanoma skin carcinoma occurred in 0,9% de novo patients and 1.8% of patients with stable functioning renal transplant on a continuous maintenance therapy, taking Myfortic for 1 year, other types of malignancies occurred in 0,5% de novo patients and 0.6% of patients with stable functioning renal transplant on a continuous maintenance therapy.
Opportunistic infektsii.Vse patients with kidney transplants have an increased risk of opportunistic infections, the risk increases with a high degree of immunosuppression. The most common opportunistic infections in de novo renal transplant patients treated with Myfortic combined with other immunosuppressants in controlled clinical trials lasting 1 year, belonged to the cytomegalovirus (CMV), candidiasis and herpes simplex. CMV infection (serologically confirmed, nayavnostyu viremia or clinical data) reported in clinical studies of Myfortic, was observed in 21,6% de novo patients and 1.9% of patients with stable functioning renal transplant on a continuous maintenance therapy.
In assessing the incidence of other adverse events probably or possibly associated to the use of Myfortic, used these criteria: very common (≥ 1 / 10), often (≥ 1 / 100, ≤ 1 / 10); uncommon (≥ 1 / 1000, ≤ 1 / 100), rare (≥ 1 / 10 000, ≤ 1 / 1000); very rare (≤ 1 / 10000).
Infections and infestations: very common – viral, bacterial and fungal infections, often – upper respiratory tract infections, pneumonia, rarely – wound infection, sepsis, osteomyelitis.
Violations of the circulatory and lymphatic system: very often – leukopenia, often – anemia, thrombocytopenia, rarely – lymphocele, lymphopenia, neutropenia, lymphadenopathy.
Violation of the nervous system: often – headache, infrequent – tremor, and insomnia.
Violation of the respiratory system: often – cough infrequently – pulmonary congestion, shortness of breath.
Violation of the gastrointestinal tract: very often – diarrhea, often – bloating, abdominal pain, constipation, dyspepsia, flatulence, gastritis, and rare bowel movements, nausea, vomiting, infrequently – abdominal tenderness to palpation, pancreatitis, belching, halitosis, obstruction intestine, inflammation of the esophagus, stomach and duodenum, subileus, color change of language, gastrointestinal bleeding, dry mouth, sores on the lips, impaired outflow from the parotid gland, gastroesophageal reflux, hypertrophic gingivitis, peritonitis.
Systemic violations and local reactions: often – fatigue, pyrexia, infrequently – flu-like symptoms, swelling of the lower extremities, pain, fever, thirst, weakness.
Violation of the metabolic and nutritional: Infrequent – anorexia nervosa, hyperlipidemia, diabetes mellitus, hypercholesterolemia, hypophosphatemia.
Violations of the skin: Infrequent – alopecia.
Hepatobiliary disorders: frequent – abnormal liver function tests.
Violations of the cardiovascular system: Infrequent – tachycardia, pulmonary edema, ventricular extrasystoles.
Violations by the organ of vision: Infrequent – conjunctivitis, blurred vision.
Violations of the musculoskeletal system and connective tissue disorders: infrequent – arthritis, back pain, muscle cramps.
Benign and malignant tumors: Infrequent – skin papilloma, basal cell carcinoma, Kaposi’s sarcoma, lymphoproliferative disorders, squamous cell carcinoma.
Mental disorders: infrequent – sleep disturbance, hallucinations.
Violation of the kidney and urinary system: often – increase of creatinine in serum, infrequently – hematuria, renal tubular necrosis, narrowing of the urinary canal.
Violation of the reproductive system: Infrequent – erectile dysfunction.
The following side effects associated with drugs containing IFC (including mycophenolate mofetil) as a “class effect”.
From the digestive tract: colitis, gastritis, esophagitis (including CMV – cytomegalovirus etiology), pancreatitis, perforation of the bowel wall, gastrointestinal bleeding, peptic ulcer and duodenal ulcer, intestinal obstruction.
Violations related to immunosuppression: serious, sometimes life-threatening infections, including meningitis, bacterial endocarditis, tuberculosis, atypical mycobacterial infection.
From the hematopoietic system: neutropenia, pancytopenia.
SPECIAL INSTRUCTIONS Myfortic:
Myfortic – инозинмонофосфатдегидрогеназы inhibitor, so theoretically, this drug should not be used in patients with extremely rare hereditary deficiency hypoxanthine-guanine fosforibozil-transferase, such as Lesch syndrome – Nihena and Kelly – Sigmillera. Patients receiving combination immunosuppressive therapy, including Myfortic, increased risk of developing lymphomas and other malignancies, particularly skin. Most likely, this risk is associated with the intensity and duration of immunosuppressive therapy than the use of certain specific substances. To reduce the risk of skin cancer, it is necessary to limit the influence of sunlight and UV radiation by protecting the skin clothing and use sunscreen with a high degree of protection. Patients receiving Myfortic, should inform the doctor about any cases of infection, unexpected occurrence of bruising, bleeding, or any other forms of oppression of the bone marrow. Patients taking the IFC, should conduct regular blood counts weekly during the first month, 2 times a month during the second and third months of treatment, then monthly during the first year. With the development of neutropenia (absolute neutrophil count ≤ 1,5 h109 / l), which may be due to the influence of the IFC directly, and concomitant medications, viral infections or a combination of these factors, it is advisable to interrupt or discontinue therapy with Myfortic. Patients should be warned that during the treatment of IFC vaccination may be less effective and that it should avoid the use of live attenuated vaccines. Vaccination against influenza may be helpful. This question should be consistent with national recommendations for influenza vaccination. As preparations containing IFC cause frequent side effects from the digestive tract, including cases of peptic ulcer gastrointestinal tract, gastrointestinal bleeding and intestinal perforation, should be carefully administered to patients with existing IFC serious diseases of digestive system.
During pregnancy and lactation. Adequate and well controlled studies of the drug during pregnancy have not been conducted. In the case of the drug during organogenesis in pregnant rats and rabbits, it was noted the negative impact on fetal development (including malformations).
Myfortic therapy is recommended to start only after it is received a negative pregnancy test. In the case of pregnancy the patient should immediately consult a doctor.
Before therapy Myfortic, during treatment and for 6 weeks after its completion should use effective methods of contraception.
It is not known whether the IFC released in breast milk. Due to the fact that there is a potential risk of serious adverse events in a child under the influence of mycophenolate sodium is necessary to resolve the issue or terminating the application of Myfortic, either, given the importance of treatment with this drug for a mother to breast-feed during the entire treatment and during 6 weeks after its completion.
Children. Not applicable. Safety and efficacy of the drug in children has not been established. Pharmacokinetic data in children with kidney transplants is limited.
Special safety measures. Myfortic tablets can not crush, must preserve the integrity of enteric-soluble shell. It is not permissible inhalation or direct contact with the powder the skin or mucous membrane is damaged the integrity of the tablets Myfortic.
Ability to influence the reaction rate on driving and operating other machinery. No data regarding the impact on the ability to drive and work with other mechanisms. Mechanism of action of Myfortic, pharmacodynamic profile and registered side effects indicate a low probability of such influence.
INTERACTION Myfortic:
Acyclovir. In patients with impaired renal function may increase the concentration in the blood as GMFK and acyclovir. Perhaps both drugs compete at the level of removal from the body, as secreted renal tubules. Such patients require careful monitoring.
Antacids containing magnesium hydroxide and aluminum. If concomitant administration with antacids mycophenolate sodium intake is reduced. The simultaneous use of Myfortic and antacids containing magnesium hydroxide and aluminum hydroxide, leads to a decrease of 37% systemic effects of IFC and a decrease of 25% of the maximum concentration of the IFC. Therefore, caution should be exercised with concomitant use of Myfortic with antacids containing magnesium hydroxide and aluminum.
Azathioprine. Because of special studies of the interaction Myfortic and azathioprine have not performed, these drugs should not be used simultaneously.
Kolestiramin and drugs that affect enterohepatic circulation. In connection with its ability to block the absorption of drugs in the intestine, can reduce kolestiramin sitemnoe impact of IFC. In connection with a possible decrease in the effectiveness of Myfortic should use caution in the combined use kolestiramina and drugs that violate the enterohepatic circulation.
Ganciclovir. The use of ganciclovir has no effect on the pharmacokinetics of IFC and GMFK. Clearance of ganciclovir is not changed when a therapeutic concentration of the IFC. However, in patients with renal insufficiency in combined therapy with Myfortic, and ganciclovir may be necessary to correct dosing regimen of ganciclovir, and patients need careful monitoring.
Oral contraceptives. Oral contraceptives are metabolized by oxidation reactions, while Myfortic – glucuronidation. Effect of oral contraceptives on the pharmacokinetics of Myfortic is unlikely and, therefore, hardly possible any clinically significant interactions. However, given that the effect of prolonged therapy with Myfortic pharmacokinetics of oral contraceptives has not yet been studied, we can not exclude the reduced effectiveness of contraceptives.
Live vaccines. You should not use live vaccines in patients with impaired immune response. When using other vaccine antibody response – antibody production can be reduced.
Tacrolimus. In the crossover study of calcineurin in patients with stable renal graft constant level pharmacokinetics Myfortic measured both during treatment with cyclosporine and tacrolimus. The mean value of AUC IFC was higher by 19%, Cmax – approximately 20% lower. On the contrary, AUC and Cmax GMFK was lower by about 30% during treatment with tacrolimus, compared with therapy with cyclosporine.
Cyclosporine A. In a study of patients with stable renal graft against the backdrop of stable concentrations of Myfortic pharmacokinetics of cyclosporine A does not change.
OVERDOSE Myfortic:
cases of overdose were reported. Although dialysis may be used to remove the inactive metabolite GMFK, but he was unable to remove a clinically significant amount of the active component of the IFC. This is mainly due to a very high degree of binding of the IFC to plasma proteins – 97%. Sequestrant of bile acids, such as kolestiramin, affecting the enterohepatic circulation IFC, may reduce the systemic effects of IFC.
