Mycophenolate Mofetil Dispersible Tablets
For the prevention of organ rejection in patients undergoing allogeneic kidney or liver transplantation, mycophenolate mofetil should be administered simultaneously with cyclosporine A or tacrolimus and corticosteroids.
Key words:
Mycophenolate Mofetil Dispersible Tablets
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Graphic Details
Date of approval: 2007Year 12Month 11
Revision Date: 2010Year 05Month 31
Instructions for Mycophenolate Mofetil Dispersible Tablets
Please read the instructions carefully and use them under the guidance of a physician.
Warning:Due to its immunosuppressive effect, this product can increase the chance of infection and may also cause lymphoma. Physicians with experience in immunotherapy and management of solid organ transplants should use this product only. Patients who use this product should be managed in a medical institution with certain qualifications. Physicians responsible for maintenance care should continually improve patient follow-up information.
Women of childbearing age who use drugs must use contraception. Doctors should inform women that their use during pregnancy may increase the risk of miscarriage and congenital malformations.
【Drug Name]]
Generic name: Mycophenolate Mofetil Dispersible Tablets
英文名:Mycophenolate Mofetil Dispersible Tablets
汉语拼音:Matimaikaofenzhi Fensanpian
[composition]]
Chemical Name:(E)-6-(1, 3-dihydrogen-4-hydroxyl-6-methoxy-7-Methyl-3-oxo-5-isobenzofuranyl)-4-Methyl-4-hexenoic acid-2-Morpholino ethyl ester
Chemical structural formula:
Molecular formula:C23H31NO7
molecular weight:443.50
【Traits]]This product is white or almost white.
indications]
For the prevention of organ rejection in patients undergoing allogeneic kidney or liver transplantation, mycophenolate mofetil should be treated with cyclosporine AOr tacrolimus and corticosteroids at the same time.
"Specifications" 0.25g(PressC23H31NO7)
Usage and dosage]
Kidney transplantation: Adult kidney transplant patients, recommend oral dose of 1g,bid(daily dose is 2g). Although 1.5g per bid (3g daily) has been used in clinical trials and is safe and effective, there is no advantage in efficacy in kidney transplantation. Patients receiving 2g of mycophenolate mofetil per day had a better overall safety profile than those receiving 3g.
Liver transplantation: The recommend oral dose for adult liver transplant patients is 0.5-1g,bid(1-2g daily dose).
Oral mycophenolate mofetil therapy should be started as soon as possible after kidney, heart, or liver transplantation. Food for MPA AUCNo effect, but make MPA CmaxDown 40%. Therefore, it is recommend to take mycophenolate mofetil on an empty stomach. But for stable kidney transplant patients, mycophenolate mofetil can be taken with food if needed.
Patients with abnormal liver function: Renal transplant patients with severe liver parenchymal disease do not need dose adjustment. However, it is unclear whether dose adjustment is necessary for other causes of liver disease (see Pharmacology-Toxicology and Pharmacokinetics). There are no data available on heart transplant patients with severe liver parenchymal lesions.
Elderly: The appropriate recommend dose for kidney transplant patients is 1g,bid,Liver transplant patients are 0.5-1g,bid (see Geriatric use).
Dose adjustment: for severe chronic renal damage (renal bead filtration rate is less than 25 ml/min/1.73m2) renal transplant patients should avoid using more than 1g,bid each time after passing through the early postoperative period.The dose. And these patients need to be closely watched. Patients with delayed recovery of graft function after renal transplantation do not need dose adjustment (see Pharmacology-Toxicology, Pharmacokinetics, and Precautions).
Data on patients with severe chronic renal insufficiency undergoing simultaneous heart or liver transplantation are lacking. If the potential benefits outweigh the potential harms, mycophenolate mofetil may be used after concomitant heart or liver transplantation in patients with severe chronic renal insufficiency.
If neutropenia occurs (absolute neutrophil count <1.3× 103/ΜL), mycophenolate mofetil should be suspended or reduced for appropriate diagnostic testing and appropriate treatment (see Precautions, Warnings, and Adverse Reactions).
adverse reaction]
According to foreign clinical experimental data:
The occurrence of side effects of immunosuppressants is often not clear, because on the one hand, the existence of basic diseases, on the other hand, the combination of other drugs. The main adverse effects of taking mycophenolate mofetil or a combination of mycophenolate mofetil, cyclosporine, and corticosteroids include diarrhea, leukopenia, sepsis, and vomiting, and frequent certain types of infections. (See Warnings)
The safety of the use of mycophenolate mofetil tablets in the treatment of refractory renal transplant rejection was compared with the three groups of controls, daily 3The same safety profile was observed in the prevention of rejection trials. Compared with patients receiving intravenous cyclosporine, diarrhea and leukopenia, accompanied by anemia, nausea, abdominal pain, sepsis, nausea and vomiting, and dyspepsia were the main reported side effects.
Patients receiving immunosuppressive regimens, including those with concomitant medications, and those receiving mycophenolate mofetil as part of the immunosuppression, are at increased risk of developing lymphomas and malignancies, especially of the skin (see Warnings). Postoperative 3During the year, lymphoproliferative disease or lymphoma occurred in patients receiving mycophenolate mofetil tablets in an immunization regimen, in a controlled trial to prevent renal transplant rejection, 3 per dayThe incidence was 1.6 percent in patients with gram, 0.6 percent in patients with 2 grams per day, 0 percent in the placebo group, and 0.6 percent in the azathioprine group. In controlled trials of treatment-refractory kidney transplants, the incidence of lymphoma was 3.9 percent with a mean follow-up of 42 months.
All patients are at increased risk of opportunistic infections, which increases with immunosuppressive burden (see Warnings). The overall incidence of opportunistic infections was similar in renal transplant patients treated with mycophenolate mofetil and with azathioprine.
Older adults, especially those receiving mycophenolate mofetil as part of a combined immunosuppressive regimen, are at increased risk for some infections (including cytomegalovirus tissue invasive disease), possible gastrointestinal hemorrhage, and pulmonary edema compared with younger adults.
Clinical study of mycophenolate mofetil tablets in the treatment of renal allograft rejectionIIIperiod-controlled experiments, reported greater than 10% and 3-<10% of adverse reactions are listed in the following table:
body system
|
Adverse events reported in renal transplant patients (n = 991)*
|
|
systemic reaction
|
≥10%
|
Weakness, fever, headache, infection, pain (including abdomen, back, and chest), edema, sepsis
|
3-<10%
|
Cysts (including cystic lymphangiomas and water cysts), abdominal enlargement, facial edema, flu syndrome, bleeding, hernia, malaise, pelvic pain
|
|
blood and lymph
|
≥10%
|
Anemia (including anemia with too little hemoglobin), leukocytosis, leukopenia, thrombocytopenia
|
3-<10%
|
Egg, Polycythemia
|
|
genitourinary system
|
≥10%
|
hematuria, tubular necrosis, urinary tract infection
|
3-<10%
|
Proteinuria, dysuria, hydronephrosis, impotence, pyelonephritis, urinary frequency
|
|
Cardiovascular system
|
≥10%
|
Hypertension
|
3-<10%
|
Angina pectoris, atrial fibrillation, hypotension, orthostatic hypotension, tachycardia, thrombosis, vasodilation
|
|
metabolism and nutrition
|
≥10%
|
Hypercholesterolemia, Hyperglycemia, Hyperkalemia, Hypokalemia, Hypophosphatemia
|
3-<10%
|
Acidosis, elevated alkaline phosphatase, elevated enzyme levels (g-Glutamyl transpeptidase, Lactate dehydrogenase, SGOTand SGPT), increased creatinine, hypercalcemia, hyperlipidemia, hypervolemia, hypocalcemia, hypoglycemia, hypoproteinemia, hyperuricemia, weight gain
|
|
Digestion
|
≥10%
|
Constipation, diarrhea, indigestion, nausea, vomiting, mouth ulcers
|
3-<10%
|
Abnormal liver function, anorexia, flatulence, gastroenteritis, gastrointestinal bleeding, gastrointestinal ulcers, gingivitis, gingival hyperplasia, hepatitis, intestinal obstruction, esophagitis, stomatitis
|
|
respiratory system
|
≥10%
|
Increased cough, difficulty breathing, pharyngitis, pneumonia, bronchitis
|
3-<10%
|
Asthma, pleural effusion, pulmonary edema, rhinitis, sinusitis
|
|
Skin and appendages
|
≥10%
|
acne, herpes simplex
|
3-<10%
|
Hair loss, Benign exoderms of the skin, Mycotic dermatitis, Herpes zoster, Hirsutism, Pruritus, Skin cancer, Skin hypertrophy, Sweating, Skin ulcers, Rash
|
|
Nerve
|
≥10%
|
Dzziness, insomnia, tremor
|
3-<10%
|
restlessness, depression, hypertonia, paresthesia, lethargy
|
|
Muscles and bones
|
≥10%
|
|
3-<10%
|
Joint pain, leg cramps, myalgia, muscle weakness
|
|
Feeling
|
≥10%
|
-
|
3-<10%
|
Amblyopia, cataracts, conjunctivitis,
|
|
Endocrine
|
≥10%
|
-
|
3-<10%
|
Diabetes Mellitus, Parathyroid Dysfunction
|
According to the foreign experience of the product after the market
Digestive system: isolated cases of colitis (sometimes caused by cytomegalovirus), pancreatitis, and small intestinal villous atrophy.
Immunosuppressive disordersSevere life-threatening infections, such as meningitis and infective endocarditis, have occasionally been reported, and there is evidence of a higher frequency of certain types of infections, such as tuberculosis and atypical microbial infections.
Progressive multifocal leukoencephalopathy reported in patients treated with this product (PML) The patient died in the case, and the reported cases generally have PML.Risk factors include immunosuppressive therapy and immunodeficiency.
congenital diseasesCongenital malformations, including ear malformations, have been reported in newborns of pregnant women taking mycophenolate in combination with other immunosuppressants during pregnancy.
respiratory systemInterstitial pulmonary abnormalities, including fatal pulmonary fibrosis, have rarely been reported, but this should be considered in the diagnosis of pulmonary symptoms such as dyspnea and respiratory failure in patients taking this product after transplantation.
Other adverse effects after the product was listed were similar to those in the control kidney, heart, and liver inhibition studies.
taboo]
An allergic reaction to this drug has been observed. Therefore, mycophenolate mofetil is contraindicated in patients with hypersensitivity to mycophenolate mofetil and mycophenolic acid.
[Note]]
Warning:
Patients receiving immunosuppressive therapy, including combination therapy, receiving mycophenolate mofetil tablets as part of immunosuppressive therapy, are at increased risk of developing lymphoma and other malignancies, especially of the skin. (See Adverse Reactions). The risk is related to the intensity and duration of immunosuppression, but not to the specific immunosuppression.
Because of the increased risk of skin cancer in all patients, exposure to sunlight and UV rays should be limited by wearing protective clothing or high-factor sunscreens.
Excessive suppression of the immune system can increase susceptibility to infections, including opportunistic infections, lethal infections, and sepsis.
General Notes:
Patients receiving immunosuppressive therapy often use combination therapy. When taking mycophenolate mofetil tablets as combined immunosuppressive drugs, there is an increase in lymphoma and other malignant tumors (especially skin cancer)Danger of occurrence. This risk is related to the intensity and duration of immunosuppression, not to a particular drug.
Excessive suppression of the immune system may also increase susceptibility to infection. In clinical trials, mycophenolate mofetil tablets have been used in combination with anti-lymphocyte ball antibodies, cyclosporine and corticosteroids to prevent rejection and treat refractory rejection.
Progressive multifocal leukoencephalopathy reported in patients treated with this product (PML) The patient died in the case, and the reported cases generally have PML.Risk factors include immunosuppressive therapy and immunodeficiency. In immunosuppressed patients, physicians should consider the differential diagnosis of PML in patients who report neurologic symptoms, and should also consider the opinion of a neurologist as a clinical indication.
Inform women of childbearing age of the possible risks associated with the use of the product during pregnancy (miscarriage/fetal malformation). Women of childbearing age are required to receive contraceptive counselling and must use effective contraceptive measures. It is recommended that patients who plan to become pregnant should not use this product unless other immunosuppressive drugs cannot be effectively treated.
Laboratory monitoring:
Patients taking mycophenolate mofetil had a complete blood count once a week for the first month, twice a month for the second and third months, and monthly for the remainder of the year. If neutropenia occurs (Absolute neutrophil count <1.3 × 103/microliter)The use of mycophenolate mofetil tablets should be discontinued or reduced, and these patients should be closely observed.
Severe chronic renal impairment (Glomerular filtration rate <25ML/min/1.73 m2), after patients take a single dose of mycophenolate mofetil tablets, the area under the curve of plasma MPA and MPAG is higher than that of patients with mild renal damage and healthy people, the dose exceeding 1g twice a day should be avoided, and these patients should be closely observed (see pharmacokinetics and special dose section).
patients with delayed recovery of renal function after transplantation, mean 0-12Hours of MPAThe area under the curve was similar to that of patients with normal recovery, but the area under the MPAG 0-12 hour curve was 2-3 times higher in the former than in the latter. Dose adjustment is not necessary for these patients with delayed recovery of renal function, but should be closely observed (see Pharmacokinetics and Precautions).
Mycophenolate mofetil tablets cannot be used simultaneously with azathioprine, and the simultaneous use of these two drugs has not been tested.
It has been noted that cholestyramine can significantly reduce MPAArea under the curve. Drugs that interfere with enterohepatic recirculation should not be taken with mycophenolate mofetil because they may reduce the efficacy of mycophenolate mofetil.
Medication for pregnant and lactating women]
Pregnancy classification D.
In pregnant rats and rabbits, the drug has adverse effects on embryonic development (including teratogenicity) after use during organ formation. These reactions occur at doses lower than those associated with maternal toxicity and lower than those clinically recommend for renal transplantation. Adequate controlled studies have not been conducted in pregnant women. However, since this product has been shown to have teratogenic effects in animals, use in pregnant women may cause harm to the fetus. Therefore, the use of the product should be avoided in pregnant women, unless the potential benefit to the fetus outweighs the potential risk.
Women of childbearing age before starting treatment 1Within weeks, serum or urine pregnancy test should be negative with a sensitivity of at least 50mIU/mL. Doctors are advised not to start treatment with this product until a negative pregnancy test has been obtained.
Patients before starting the product treatment, during treatment and after discontinuation of treatment 6Effective contraception must be used every week, including patients with a history of infertility, and patients who have undergone hysterectomy do not need contraception. Unless a method of abstinence is used, patients must use both reliable methods of contraception (see Drug Interactions). If pregnancy occurs during treatment, the doctor and patient should discuss whether to continue the pregnancy.
Lactation
Studies on rats have found that the drug can be secreted through milk. However, it is not known whether it is secreted into breast milk in humans. Because many drugs can be secreted into breast milk, and this drug can have potential serious adverse reactions to lactating newborns, it should be decided to stop lactation or stop the drug according to the importance of this drug to lactating mothers.
children medication]
The safety and efficacy of this drug in children has not been established. Pharmacokinetic data in children are limited and more observation is necessary if used.
elderly medication]
Pharmacokinetics: Pharmacokinetic data for mycophenolate mofetil in the elderly have not been formally studied.
Usage and dosage: the elderly (greater than or equal to 65Years old): for kidney transplant patients, the recommend oral administration is 1g each time.The dose of 2 times a day is suitable for the elderly.
Note: Compared with young people, the elderly have an increased risk of side effects.
drug interaction]
Acyclovir: MMFand acyclovir, MPAGThe plasma concentrations of and acyclovir were higher than when the two drugs were taken alone. Plasma concentrations of both MPAG and acyclovir are elevated when renal function is impaired. The two drugs are discharged competitively through the renal tubules, which may further increase the blood concentration of the two drugs.
Acid-making drugs such as magnesium hydroxide and aluminum hydroxide: When taking acid-making agents at the same time, MMFAbsorption is reduced.
Cholestyramine: healthy people take cholestyramine 4g in advance, three times a day, four days later, give a single dose of MMF 1.5gThe area under the curve of MPA is reduced by 40%.
Cyclosporine A:CsAThe pharmacokinetics were not affected by MMF.
Ganciclovir: no MMF observedThere is a pharmacokinetic crossover between Ganciclovir and IV. But for patients with impaired renal function, taking MMF at the same timeand ganciclovir, patients need to be carefully monitored.
Oral contraceptives: No MMF found so farand oral contraceptives 1There was a reciprocal effect between mg norethisterone/35 μg ethinylestradiol. But this is only the conclusion of a single-dose study, and it does not rule out the possibility of changing the pharmacokinetics of oral contraceptives after long-term use of mycophenolate mofetil tablets, which may lead to a decrease in the efficacy of oral contraceptives.
Sulfamethoxazole: For MPANo effect on bioavailability.
Other interactions: Monkeys given probenecid and MMFcan make plasma MPAGThe area under the curve increased by a factor of 3. Therefore, other drugs that are excreted through the renal tubules may compete with MPAG, thereby increasing the plasma concentration of MPAG or these drugs.
Patients with impaired immune response should not receive live vaccines. Antibody responses to other vaccinations may be eliminated.
drug overdose]
There is no MMF in humans.Reports of drug overdose, clinical trials have been conducted with a maximum dose of 4g per day.
Hemodialysis does not clear MPAWhen the MPAAt very high plasma concentrations (>100 μg/ml), a small fraction of MPAG is eliminated. MPA may be cleared by increased excretion of the drug (eg, by administration of cholestyramine).
pharmacology and toxicology]
Pharmacological effects: Mycophenolate mofetil (MMF for short)It is a 2-ethyl ester derivative of mycophenolic acid (MPA). MPA is a highly efficient, selective, non-competitive and reversible inhibitor of hypoxanthine mononucleotide dehydrogenase (IMPDH), which can inhibit the classical synthesis pathway of guanine nucleotides. MPA has a highly selective effect on lymphocytes. Mycophenolate mofetil is extremely effective in the prevention of rejection after renal transplantation and in the treatment of refractory rejection.
pharmacokinetics]
According to the literature:
Absorption
After oral administration, it is rapidly absorbed and metabolized to the active ingredient MPA. The average oral bioavailability was 94% for intravenous (according to the area under the MPA curve). MMF was not detected in the circulation after oral administration. The absorption of MMF in renal transplant patients is not affected by food, but the maximum concentration of MPA in blood (Cmax) will be reduced by 40% after eating.
Distribution
Due to the effect of enterohepatic circulation, 6-12 after taking the drugA second plasma MPA will appear at the hourThe peak concentration, taken simultaneously with cholestyramine (4g, three times a day), will reduce the area under the MPA curve by about 40%, indicating that the amount of MPA through the enterohepatic circulation is large. At clinically effective concentrations, 97% of MPA was bound to plasma albumin.
Metabolism
MPAMetabolized to MPA, primarily by glucuronyl transferaseof phenolated glucoside sugars (MPAG)MPAG has no pharmacological activity.
Excretion
MMFVery small amount of MPA after metabolism(<1%) is excreted from urine, most (87%) is excreted from urine in the form of MPAG. In the immediate post-transplant period (<40 days), mean area under the curve (AUC) and peak blood concentration (Cmax) were approximately 50% lower than in normal volunteers and in patients with stable graft function.
Pharmacokinetics in Special Cases
Single-dose studies (6 per groupExample) shows that the area under MPA curve is 28-75% higher than that of normal volunteers and patients with mild renal impairment for severe chronic renal impairment (glomerular filtration rate <25 ml/min/1.73 m2). In the same case, the area under the MPAG curve is 3-6 times higher, consistent with MPAG being excreted primarily by the kidneys. Multiple dose pharmacokinetic studies of MMF in patients with severe chronic renal impairment have not been performed. After transplantation, the area under the 0-12 hour curve (AUC) of MPA with delayed recovery of renal function was not significantly different from that of patients without delayed recovery of renal function, but the area under the 0-12 hour curve of MPAG without active ingredient was 2-3 times higher than that of patients with normal recovery of renal function.
In Alcoholic Cirrhosis Volunteers, Liver Parenchymal Disease on MPAThe process of glycosidation is relatively unaffected, and severe biliary damage, such as primary biliary cirrhosis, may affect this process.
[storage] shading, sealing, dry place to save
[packaging] aluminum plastic packaging, 20Pieces/Box, 40 tablets/box.
Period of Validity 36Months
[executive standard] YBH32212005
[Approval No.] Chinese Medicine H20052165
production enterprise]
Company: Zhejiang Jianfeng Pharmaceutical Co., Ltd.
Production address: No.58, Gaofan Section, Baitang Lower Line, Wucheng District, Jinhua City, Zhejiang Province
Postal Code: 321016
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