Mycophenolate Mofetil for Injection

1. Pharmacological action Mycophenolate mofetil (MMF) is a 2-ethyl ester derivative of mycophenolic acid (MPA). MPA is a highly efficient, selective, non-competitive, and reversible inhibitor of inosine mononucleotide dehydrogenase (IMPDH), which can inhibit the classical synthesis pathway of guanine nucleotides. MPA has a highly selective effect on lymphocytes. The MPA concentration required to inhibit lymphocyte proliferation has no inhibitory effect on most lymphocytes. MPA can also inhibit the formation of antibodies by directly inhibiting the proliferation of B cells. Therapeutic doses of MMF do not inhibit the production of interleukin-I by polysaccharide-activated human peripheral blood lymphocytes, nor do they inhibit the synthesis of interleukin-II and its receptor expression by mitogen-activated peripheral lymphocytes, which is also different from cyclosporine and FK-506. In addition, MPA-mediated depletion of guanosine triphosphate in lymphocytes in vitro can inhibit the conversion of mannose and fucose into glycoproteins. Through this mechanism, MPA can reduce the aggregation of lymphocytes and monocytes in chronic inflammatory sites. MMF mainly acts by interfering with purine metabolism. There are two main pathways for the synthesis of purine nucleotides in the body's cells, namely the classical pathway and the salvage pathway. Purine monophosphate dehydrogenase (IMPDH) is one of the key rate-limiting enzymes in the classical pathway. It has two isoforms (type I and type II). When lymphocytes are stimulated to differentiate, the expression of type II IMPDH gene is significantly upregulated, while the expression of type I IMPDH gene remains unchanged. MPA is a potential, selective, reversible, non-competitive inhibitor of IMPDH. Type II IMPDH is extremely sensitive to it (its inhibitory effect is 4-5 times that of type I). MPA depletes intracellular guanosine (GTP and dG-PT) by inhibiting IMPDH, thereby interfering with DNA synthesis and fixing cells in the GI-S phase and unable to proliferate. Studies have shown that human T and B lymphocytes are different from other cells. They are highly dependent on the classical pathway to synthesize guanine nucleotides. Therefore, MMF exhibits a stronger anti-proliferative effect on lymphocytes than other cells. MMF significantly reduces the content of GTP and dGTP in lymphocytes by inhibiting the activity of IMPDH. The biological effect is manifested as an imbalance in the ratio of adenylate/guanylate, which affects DNA synthesis; it blocks cell proliferation during the DNA synthesis period and reduces the number of cells. 2. Toxicological effects 1) Acute toxicity study: Oral acute toxicity study of adult mice showed that no mouse death occurred at a dose of 4000 mg/kg. The non-lethal dose for adult monkeys is 1000 mg/kg. Based on the body surface area, these doses are 11 times and about 7 times the recommended doses for kidney transplant patients and heart transplant patients, respectively. Adult rats died after a single oral administration of 500 mg/kg of this drug. Based on the body surface area, this dose is about 3 times that of heart transplant patients. 2) Local toxicity study: Stimulation tests showed that multiple intravenous drips of 100 mg/kg and 6 mg/ml concentrations in rabbits had no vascular irritation to rabbits and did not cause obvious lesions in the perivascular tissues. Sensitization tests showed that intravenous administration of 6 mg/ml injection of mycophenolate mofetil had no allergic effect on guinea pigs. Hemolysis test shows that 6mg/ml injection of mycophenolate mofetil has no obvious in vitro hemolysis and agglutination effect on rabbit red blood cells. 3) Long-term drug safety study: Clinical studies on MMF for injection have confirmed that MMF has good tolerance and safety. In Europe, a 3-year double-blind, placebo-controlled study showed that this drug can not only reduce the occurrence of acute rejection but also reduce the failure of transplantation in the later stage. In transplant patients with cyclosporine-induced nephrotoxicity, it is safe to stop using cyclosporine and switch to MMF, and renal function can be restored and improved. MMF is effective in treating stubborn rejection reactions and has few side effects. Compared with azathioprine, the biggest feature of MMF is that it has no hepatotoxicity, nephrotoxicity and bone marrow suppression, and has no side effects such as hypertension, diabetes, pancreatitis and osteoporosis. When MMF is used in combination with immunosuppressants such as cyclosporine A, it can reduce the frequency of corticosteroids and anti-lymphocyte antibodies while suppressing rejection reactions, and reduce the non-immune reaction toxicity caused by these drugs. 4) Special toxicity studies: A. Carcinogenicity: In a 104-week carcinogenicity study conducted on mice, mycophenolate mofetil was administered at a daily dose of 180 mg/kg and showed no carcinogenicity. Based on body surface area, the highest dose was 0.5 and 0.3 times the recommended dose for renal transplant patients (2 g/d) and heart transplant patients (3 g/d), respectively. In a 104-week carcinogenicity study conducted on rats, mycophenolate mofetil was administered at a daily dose of 15 mg/kg and showed no carcinogenicity. Based on body surface area, the highest dose was 0.08 and 0.05 times the recommended dose for renal transplant patients (2 g/d) and heart transplant patients (3 g/d), respectively. Although the dose administered to animals is lower than the human dose, it is the maximum dose for animals and is sufficient to evaluate the possible risks for human use. B. Mutagenicity study: Five tests were conducted to investigate the mutagenicity of mycophenolate mofetil. Mycophenolate mofetil showed genotoxicity in the mouse lymphoma/thymidine kinase test and the in vivo mouse micronucleus test. No genotoxicity was shown in the bacterial reversion mutation test, the yeast mitotic gene conversion test, and the Chinese hamster mammalian cell chromosome aberration test. C. Reproductive toxicity study: Mycophenolate mofetil did not show reproductive toxicity in male rats at an oral dose of 20 mg/kg/d. Based on body surface area, this dose is 0.1.0.07 times the recommended dose for renal and heart transplant patients. Female animal reproductive toxicity studies showed that oral administration of 4.5 mg/kg/d caused teratogenesis in offspring animals (mainly in the head and eyes). Based on body surface area, this dose is 0.02.0.01 times the recommended dose for renal and heart transplant patients. There was no significant effect on the fertility and reproductive parameters of mother and offspring mice. Teratogenic studies have shown that fetal resorption and malformations occurred in rats at 6 mg/kg/d and in rabbits at 90 mg/kg/d. Based on calculations based on body surface area, these doses are 0.03-0.92 and 0.02-0.61 times the recommended doses for renal transplant patients and heart transplant patients, respectively.

Mycophenolate mofetil

This product is white to off-white loose mass or powder.

This product is used as a preventive medication for organ rejection in patients receiving allogeneic kidney, heart or liver transplants.

Usage and drug preparation: This product must be prepared with 5% glucose solution for intravenous use. Two vials are equivalent to a 1-gram dose. The recommended concentration is 6 mg/ml. A two-step dilution method is recommended. Step 1: 1 Inject 20 ml of 5% glucose solution into each vial and shake well. Pay attention to aseptic operation. 2 Gently shake the vial to dissolve the drug (if the room temperature is low, it can be slightly heated). 3 The dissolved solution should be a light yellow liquid without impurities and precipitates. Otherwise, it should be discarded. Step 2: Use 125 ml of 5% glucose solution to further dissolve the solution. The final drug concentration is about 6 mg/ml. 2 Observe whether the solution is transparent and free of impurities, otherwise it should be discarded. The solution of this product should be used immediately or within 4 hours after preparation. The first dose of this product should be used within 24 hours after kidney transplantation and continue for 14 days. The recommended dose is 1 gram twice a day.

Safety research data of oral administration of this drug: Due to the existence of primary diseases and the simultaneous use of other drugs, it is often difficult to determine the adverse reactions of immunosuppressants. The main adverse reactions include: diarrhea, leukopenia, sepsis, vomiting and certain types of infection. Adverse reactions in Phase III clinical trials with an incidence rate of ≥10% include: systemic: sepsis, infection, abdominal pain, fever, chest pain, headache, back pain, fatigue, hernia, ascites, chills, peritonitis, abdominal distension; blood and lymphatic system: anemia, leukopenia, thrombocytopenia, hypochromic anemia, leukocytosis, ecchymosis; genitourinary system: urinary tract infection, urinary tract dysfunction, renal tubular necrosis, hematuria, oliguria; cardiovascular system: hypertension, hypotension, cardiovascular disease, tachycardia, arrhythmia, bradycardia, pericardial effusion, heart failure; metabolic and nutritional system: hyperkalemia, hyperglycemia, hypoglycemia, hypokalemia, hypercholesterolemia, peripheral edema, edema, increased creatinine, increased blood urea nitrogen, lactobionic acid Increased dehydrogenase, increased SGOT, increased blood volume, hypomagnesemia, acidosis, increased SGPT, hypocalcemia, weight gain, hyperuricemia, bilirubinemia; Digestive system: diarrhea, vomiting, constipation, nausea, dyspepsia, oral candidiasis, abnormal liver function test, flatulence, anorexia, cholecystitis, hepatitis, jaundice; Respiratory system: emphysema, infection, dyspnea, tracheitis, pharyngitis, cough, sinusitis, pleurisy, asthma, pneumonia, pulmonary edema; Skin and appendages: herpes simplex, acne, skin diseases, itching, hyperhidrosis; Nervous system: dizziness, insomnia, tremor, anxiety, paresthesia, hypertonia, depression, excitement, drowsiness, mental tension; Musculoskeletal system: leg cramps, muscle weakness, myalgia. The safety of 2 grams of this drug per day is higher than that of 3 grams of this drug per day. Infections were slightly more common in the treatment group, mostly related to cytomegalovirus. Among digestive system diseases, the incidence of diarrhea was significantly higher in this drug group than in the azathioprine group and the placebo group, and vomiting was also slightly increased. Urinary tract infections were common in all groups, and slightly higher in this drug group. Leukopenia was also common, especially in the 3-gram daily group. Compared with the 2-gram daily group and the control group, cytomegalovirus tissue invasive disease was more common in the 3-gram group. The incidence of invasive Candida and invasive aspergillosis was also slightly increased. Three transplant rejection studies found that the incidence of fatal infections in this drug and the control group was similar when other immunosuppressants were used in combination. 1,483 patients were followed up for more than one year, and the incidence of malignant tumors in the control group of patients with homologous renal transplants was similar to that reported in the literature. The incidence of lymphoproliferative diseases in the drug treatment group was slightly higher (0.6-1.0%) than in the control group and the azathioprine group. In patients with severe renal impairment, the plasma AUCs of MPA and MPAG increased when a single oral dose of this drug was taken. The dosage should not exceed 1 gram, twice a day, and the patient's condition should be closely monitored. There is no need to adjust the dosage for kidney transplant patients with delayed transplant renal function, but the patient's condition should be monitored.

1. Patients who are highly sensitive to mycophenolate mofetil or mycophenolic acid are contraindicated. 2. Patients who are allergic to polysorbate 80 are contraindicated.

Precautions for children: The safety and efficacy in pediatric patients have not been determined, and its pharmacokinetic data are also limited. Precautions for pregnancy and lactation: This drug has adverse effects on fetal organ development in pregnant mice. However, there are no such reports for pregnant women. Therefore, it is only used in pregnant women when necessary; it is recommended to use it only when the test is negative for pregnant women. At the beginning of pregnancy. You should consult a doctor; effective contraceptive measures should be taken during the initial use of this product and for 6 weeks after discontinuation of treatment. Animal experiments have confirmed that mycophenolate mofetil can be excreted through breast milk. It is not clear whether it can be excreted through breast milk in humans. Given that many drugs can be excreted through breast milk and that mycophenolate mofetil has adverse effects on breastfeeding infants, it is necessary to weigh the pros and cons and decide to stop the drug or stop breastfeeding. Precautions for the elderly: The recommended dose for the elderly is 1 gram, twice a day.

Aticlovir: When mycophenolate mofetil is used in combination with aciclovir, the plasma concentrations of both MPAG and aciclovir are increased compared to when used alone. As with aciclovir, the plasma concentration of MPAG increases in cases of impaired renal function. The two drugs can be competitively excreted through the renal tubules, which further increases the plasma concentration. Antacids containing magnesium hydroxide and aluminum hydroxide: When used in combination with antacids, the absorption of mycophenolate mofetil is reduced. Cyclosporine A: Mycophenolate mofetil has no effect on the pharmacokinetics of cyclosporine A. Ganciclovir: No interaction between the two has been found. Oral contraceptives: At present, there is a correlation between the pharmacokinetics of mycophenolate mofetil and 1 mg norethindrone/35 micrograms ethinyl estradiol, but the effect of long-term use on contraceptives is unknown. Trimethoprim/sulfamethoxazole: No effect on the bioavailability of MPA has been reported. Others: The combined use of mycophenolate mofetil and probenecid can increase the area under the curve of plasma MPAG in monkeys by 3 times. Therefore, any drug that can compete with MPAG for renal tubular excretion will increase the plasma concentrations of both drugs when used together.

Keep away from light, store in a sealed container, and do not use after the expiration date. After preparation, store at 1530℃ and use within 4 hours. The medicine should be stored out of reach of children.

0.5g

24 months

Double-Crane Pharmaceutical(Hainan) Co., Ltd.

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  2004-04-07

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  No. 2, Yaogu Sanheng Road, Yaogu Industrial Park, Haikou National High-tech Zone

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  91460100754396590D

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  150 million yuan

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