Date of approval.
Date of revision.
Mortylmacrolate Capsules Instructions
Please read the instructions carefully and use under the guidance of a physician
WARNING
WARNING
Immunosuppression increases susceptibility to infection and may promote the development of lymphoma and other neoplasms. It should only be used by specialists experienced in immunosuppressive therapy and in patients undergoing organ transplantation, and patients should be treated with appropriate medical equipment and laboratory personnel and with supportable medical conditions. The physician responsible for long-term patient follow-up should have comprehensive information about the patient in order to provide the necessary follow-up.
Because of the mutagenic and teratogenic effects of this product, female patients of childbearing potential should have a negative pregnancy test prior to initiating treatment with this product and should use contraception from the time of initiation until 6 weeks after discontinuation of this product. The use of this product during pregnancy may increase the risk of miscarriage and congenital malformations.
Drug Name]
Generic name: Mycophenolate Myristate Capsules
English name: Mycophenolate Mofetil Capsules
Hanyu Pinyin: Matimaikaofenzhi Jiaonang
Ingredients
The main ingredient of this product is: mortyl mescaline
Chemical name: (E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methyl-4-hexenoic acid 2-(morpholin-4-yl)ethyl ester
Chemical structure formula.
Molecular formula: C23H31NO7
Molecular weight: 433.49
Properties
This product is hard capsule, the contents are white or off-white powder or granule.
Indications
This product is indicated for use with corticosteroids and cyclosporine or tacrolimus in the treatment of.
Prevention of organ rejection in patients receiving an allogeneic kidney transplant.
Prevention of organ rejection in patients undergoing allogeneic liver transplantation.
This product is indicated for the induction phase treatment and maintenance phase treatment in adult patients with lupus nephritis type III-V.
Specification
0.25g
Dosage]
It has been shown that mortification of mortification is teratogenic, therefore opening or crushing of mortification capsules is prohibited. For the powder in the capsule, avoid inhalation or direct contact with skin or mucous membranes. If contact occurs, wash thoroughly with soap and water and flush eyes with water.
For concomitant use of corticosteroids and cyclosporine or tacrolimus with this product, refer to the appropriate full prescribing information.
Renal Transplant.
Adults: For renal transplant recipients, the recommended oral dose is 1 g per dose, twice daily (daily dose of 2 g). Although 1.5 g per dose twice daily (daily dose of 3 g) has been used in clinical trials and is safe and effective, there is no effect advantage in renal transplantation. Patients receiving 2 g of this product per day had a better overall safety profile than those receiving 3 g.
Liver transplantation.
The recommended oral dose for adult liver transplant recipients is 0.5 to 1 g per dose twice daily (daily dose of 1 to 2 g).
Oral treatment with this product should be initiated as soon as possible after kidney or liver transplantation. Food has no effect on mescaline (MPA) AUC, but decreases MPA Cmax by 40%. Therefore, it is recommended that this product be taken on an empty stomach. However, in stable renal transplant recipients, this product can be taken with food if desired.
Patients with lupus nephritis.
Induction phase treatment
The recommended dose for adults is 1.5 to 2 g daily, administered orally in two divided doses.
This product should usually be used in combination with corticosteroids.
Maintenance treatment
The recommended adult dose is 0.5 to 1.5 g per day, administered orally in two divided doses.
Dose adjustment.
Patients with hepatic impairment
Dose adjustment is not recommended for renal transplant recipients with severe hepatic parenchymal lesions. However, it is not clear whether dose adjustments are required for other causes of liver disease (see [Pharmacology and Toxicology] and [Pharmacokinetics]).
No data are available for patients with lupus nephritis with severe hepatic parenchymal lesions.
Patients with renal impairment
Doses greater than 1 g twice daily should be avoided in renal transplant recipients with severe chronic renal impairment (glomerular filtration rate less than 25 ml/min/1.73 m2 ) after passage through the early postoperative period or after treatment of acute or refractory rejection. No dose adjustment is required in patients with delayed graft recovery after renal transplantation, but these patients require close observation. (See [Pharmacokinetics]).
Data are not available for liver transplant recipients with severe renal impairment. It may be used in patients with severe chronic renal impairment after concomitant liver transplantation if the potential benefits outweigh the potential harms.
Data for patients with lupus nephritis with GFR <30 mL/min are currently inadequate and therapeutic drug concentration monitoring is recommended if this product is to be used.
Patients presenting with neutropenia
In the presence of neutropenia (absolute neutrophil count <1.3 x 103/μL), this product should be suspended or reduced, and appropriate diagnostic testing and appropriate therapy should be performed (see [Precautions] and [Adverse Reactions]).
Geriatric patients
The recommended dose for suitable renal transplant recipients is 1 g twice daily and for liver transplant recipients is 0.5 to 1 g twice daily (see [Geriatric Use]). There are insufficient data on the use of this product in elderly patients with lupus nephritis, and there is no recommended dose at this time.
Adverse reactions]
The safety profile presented in this section is based on data from clinical trials and post-marketing experience and has been shown to be similar in the transplant patient population and in the lupus nephritis patient population.
Clinical Trials
In the pivotal clinical trial for the prevention of acute organ rejection, an estimated 1,557 patients were treated with this product. Of these, 991 patients were enrolled in the pooled renal transplant studies ICM1866, MYC022, and MYC023, 277 patients were enrolled in the liver transplant study MYC2646, and 289 patients were enrolled in the heart transplant study MYC1864. Patients in all study groups were also treated with cyclosporine and corticosteroids.
Diarrhea, leukopenia, sepsis, and vomiting were the most common and/or serious adverse drug reactions associated with administration of this product in the pivotal trial.
There is also evidence of a higher frequency of specific types of infections, e.g., opportunistic infections (see [Precautions]).
In the 3 pivotal trials in the prevention of renal transplant rejection, the safety profile of patients treated with 2 g of this product daily was generally better than that of patients treated with 3 g of this product. The safety profile of patients treated with this product for refractory renal transplant rejection was similar to that observed in the pivotal trial for the prevention of renal rejection, in which the dose used was 3 g daily. , nausea, abdominal pain, sepsis, vomiting, and dyspepsia.
Summary table of adverse drug reactions in clinical trials
Adverse drug reactions in clinical trials are listed according to the MedDRA system organ classification and their incidence. The corresponding frequency classification of each adverse drug reaction is based on the following convention: very common (≥1/10); common (≥1/100 to <1/10); occasional (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); and very rare (<1/10,000). The frequency of certain ADRs in renal, liver, and heart transplant recipients is presented separately because of the wide variation observed in the frequency of ADRs in different transplant indications.
Summary of adverse drug reactions in patients treated with this product in key clinical trials
Adverse Drug Reactions
(MedDRA)
Systemic Organ Classification
Renal transplantation
n = 991 Liver transplantation
n = 277 Heart transplantation
n = 289 Incidence (%) Frequency Incidence (%) Frequency Incidence (%) Frequency Infections and Infectious Diseases Various bacterial infections 39.9 very common 27.4 very common 19.0 very common Various fungal infections 9.2 common 10.1 very common 13.1 very common Various viral infections 16.3 very common 14.1 very common 31.1 very common Benign, malignant and Tumors of unknown nature (including cystic and polypoid) Benign skin tumors 4.4 common 3.2 common 8.3 common tumors 1.6 common 2.2 common 4.2 common skin cancers 3.2 common 0.7 occasional 8.0 common blood and lymphatic system disorders anemia 20.0 very common 43.0 very common 45.0 very common petechiae 3.6 common 8.7 common 20.1 very common Leukocytosis 7.6 common 22.4 very common 42.6 very common Leukopenia 28.6 very common 45.8 very common 34.3 very common Pancytopenia 1.0 common 3.2 common 0.7 occasional Pseudolymphoma 0.6 occasional 0.4 occasional 1.0 common Thrombocytopenia 8.6 common 38.3 very common 24.2 very common Metabolic and Nutritional disorders acidosis 3.4 common 6.5 common 14.9 very common hypercholesterolemia 11.0 very common 4.7 common 46.0 very common hyperglycemia 9.0 common 43.7 very common 48.4 very common hyperkalemia 7.3 common 22.0 very common 16.3 very common hyperlipidemia 7.6 common 8.7 common 13.8 very common hypocalcemia 3.2 common 30.0 very common 8.0 common hypokalemia 7.8 common 37.2 very common 32.5 very common hypomagnesemia 1.8 common 39.0 very common 20.1 very common hypophosphatemia 10.8 very common 14.4 very common 8.7 common weight loss 1.0 common 4.7 common 6.2 common psychotic-like blurred state of consciousness 1.4 common 17.3 very common 14.2 very common depression 3.7 common 17.3 very common 20.1 very common insomnia 8.4 common 52.3 very common 43.3 very common all types of neurological disorders dizziness 7.8 common 16.2 very common 34.3 very common headache 14.8 very common 53.8 very common 58.5 very common hypertonia 3.3 common 7.6 Common 17.3 very common sensory confusion 6.3 common 15.2 very common 15.6 very common drowsiness 2.6 common 7.9 common 12.8 very common tremor 9.2 common 33.9 very common 26.3 very common heart organ disorders tachycardia 4.3 common 22.0 very common 22.8 very common vascular and lymphatic vessel disorders hypertension 27.5 very common 62.1 very common 78.9 very common hypotension 4.9 very common 18.4 very common 34.3 very common venous thrombosis* 4.4 common 2.5 common 2.4 common respiratory, thoracic and mediastinal disorders cough 11.4 very common 15.9 very common 40.5 very common dyspnea 12.2 very common 31.0 very common 44.3 very common thoracic Effusion 2.2 common 34.3 very common 18.0 very common gastrointestinal system diseases abdominal pain 22.4 very common 62.5 very common 41.9 very common colitis 1.6 common 2.9 common 2.8 common constipation 18.0 very common 37.9 very common 43.6 very common decreased appetite 4.7 common 25.3 very common 14.2 very common diarrhea 30.4 Very common 51.3 Very common 52.6 Very common dyspepsia 13.0 Very common 22.4 Very common 22.1 Very common esophagitis 4.9 Common 4.3 Common 9.0 Common gastrointestinal gas 6.4 Common 18.8 Very common 18.0 Very common gastritis 4.4 Common 4.0 Common 9.3 Common gastrointestinal bleeding 2.7 Common 8.3 Common 7.6 Common gastrointestinal Ulcer 3.1 common 4.7 common 3.8 common intestinal obstruction 2.4 common 3.6 common 2.4 common nausea 18.4 very common 54.5 very common 56.1 very common oral mucositis 1.4 common 1.4 common 3.5 common vomiting 10.6 very common 32.9 very common 39.1 very common hepatobiliary system disorders elevated blood alkaline phosphatase 5.2 common 5.4 Common 9.3 Common Elevated blood lactate dehydrogenase 5.8 Common 0.7 Occasional 23.5 Very common Elevated liver enzymes 5.6 Common 24.9 Very common 17.3 Very common Hepatitis 2.2 Common 13.0 Very common 0.3 Occasional Skin and subcutaneous tissue disorders Alopecia 2.2 Common 2.2 Common 2.1 Common Rash 6.4 Common 17.7 Very common 26.0 Very common Various Musculoskeletal and connective tissue disorders arthralgia 6.4 common 6.1 common 10.0 very common muscle weakness 3.0 common 4.0 common 13.8 very common renal and urinary disorders elevated blood creatinine 8.2 common 19.9 very common 42.2 very common elevated blood urea 0.8 occasional 10.1 very common 36.7 very common hematuria 10.0 very common 5.1 common 5.2 common systemic disease and various reactions at the site of administration weakness 10.8 very common 35.4 very common 49.1 very common chills 2.0 common 10.8 very common 13.5 very common edema 21.0 very common 48.4 very common 67.5 very common hernia 4.5 common 11.6 very common 12.1 very common discomfort 2.4 common 5.1 common 9.0 common pain 9.8 common 46.6 very common 42.2 very common fever 18.6 very common 52.3 very common 56.4 very common *Adverse events reported after intravenous administration.
Description of selected adverse drug reactions
Infections
Increased risk of bacterial, viral, and fungal infections (some of which may lead to lethal outcomes) in all patients receiving immunosuppressive therapy, including infections resulting from opportunistic infectious drugs and latent virus reactivation (see [Precautions]). The risk increases with increasing immunosuppressive load (see [Precautions]). The most serious infections are sepsis and peritonitis. The most common opportunistic infections in patients receiving this product in combination with other immunosuppressive agents are cutaneous mucocutaneous candidiasis, cytomegalovirulinaemia/syndrome, and herpes simplex virus infection. The proportion of patients with cytomegalovirusemia/syndrome was 13.5%.
Malignancies
Patients receiving this product in combination with other immunosuppressive agents have an increased risk of lymphoma and other malignancies, particularly of cutaneous malignancies (see [Precautions]).
In the 3-year safety data in kidney and heart transplant recipients, no unintended changes in the incidence of malignancies were observed compared to the 1-year data. In liver transplant recipients all were followed for more than 1 year and less than 3 years.
In supportive clinical trials for treatment-refractory renal transplant rejection, the incidence of lymphoma was 3.9% at a mean follow-up of 42 months.
Blood and lymphatic system disorders
Hematocrit, including leukopenia, anemia, thrombocytopenia, and pancytopenia, are known risks associated with mescaline and may cause or contribute to the development of infection and bleeding (see [Precautions]).
Gastrointestinal System Disorders
The most serious gastrointestinal system disorders are ulceration and bleeding, which are known risks associated with this product. In pivotal clinical trials, oral, esophageal, gastric, duodenal, and intestinal ulcers commonly complicated by bleeding, as well as vomiting blood, black stool syndrome, hemorrhagic gastritis, and colitis, were frequently reported. However, the most common gastrointestinal disorders are diarrhea, nausea and vomiting. Endoscopic examination of patients with diarrhea associated with this product revealed isolated cases of intestinal villous atrophy (see [Precautions]).
Systemic disease and various reactions at the site of administration
A very common adverse reaction reported in the pivotal trial was edema, including peripheral, facial, and scrotal edema. Musculoskeletal pain, including myalgia and neck and back pain, have also been reported as very common adverse reactions.
Special Populations
Children (between the ages of 3 months and 18 years)
In a clinical study of 100 pediatric patients between the ages of 3 months and 18 years, the type and frequency of adverse drug reactions following administration of 600 mg/m2 of morte-macrolide orally twice daily were overall similar to those observed in adult patients given 1 g of this product orally twice daily. However, the following treatment-related adverse events, which occurred at a frequency of ≥10% in children, were more common in the pediatric population, particularly in children younger than 6 weeks of age, compared to the frequency of treatment-related adverse events in adults: diarrhea, leukopenia, sepsis, infection, and anemia.
Elderly patients (≥65 years of age)
Compared to younger adults, older patients, particularly those receiving this product as part of a combined immunosuppressive regimen, are at increased risk for certain infections (including cytomegalovirus tissue invasive disease), possible gastrointestinal bleeding, and pulmonary edema (see [Precautions]).
Postmarketing Experience
Adverse drug reactions are listed according to the systemic organ classification in MedDRA, and the corresponding frequency classification estimates for each adverse drug reaction are based on the following conventions: very common (≥1/10); common (≥1/100 to <1/10); occasional (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000) ; very rare (<1/10,000).
Adverse drug reactions identified in postmarketing experience
Adverse drug reactions
(MedDRA)
System Organ Classification Incidence (%) Frequency Classification Infections and Infectious Diseases Protozoal Infections N/A Occasionally 2 Benign, Malignant and Tumors of Unknown Nature (including cystic and polypoid) Lymphoma N/A Occasionally 2 Lymphoproliferative Disorders N/A Occasionally 2 Hematologic and Lymphatic System Disorders Erythrocytic Aplastic Anemia Simple N/A Occasionally 2 Bone Marrow Failure N/A Occasionally 2 Gastrointestinal System Disorders Pancreatitis 1.801 Common immune system disorders hypersensitivity reactions 3.101 Common hypogammaglobulinemia 0.401 Occasional respiratory, thoracic and mediastinal disorders bronchiectasis N/A Occasional 2 interstitial lung disease 0.201 Occasional pulmonary fibrosis 0.401 Occasional vascular and lymphovascular-like disorders lymphocysts N/A Occasional 21 Highest incidence observed during pivotal clinical trials
2 The frequency classification for ADRs observed in the postmarketing setting only was defined as the upper limit of the 95% confidence interval calculated based on the total number of patients exposed to the product in the pivotal trial.
Infections.
Serious life-threatening infections such as meningitis and infective endocarditis have been reported occasionally, and there is evidence of a higher incidence of certain types of infections such as tuberculosis and atypical mycobacterial infections.
Progressive multifocal leukoencephalopathy (PML) and BK viral nephropathy have been reported in patients treated with this product (see [Precautions]).
Congenital disorders and during pregnancy, puerperium and perinatal period.
See ([Use in Pregnant and Lactating Women]) for further information.
Lupus Nephritis Studies
The ALMS (Aspreva Lupus Management Study/NCT00377637) study, a prospective randomized controlled global multicenter study of mortification of lupus nephritis, was conducted abroad. Details of the study are provided in the Clinical Trials section.
The safety information presented in this section is for all adverse events that occurred after the subjects were treated with the drug in the clinical trial, and there is not necessarily a causal association between the adverse event and the treatment.
Induction Period Studies
A total of 184 patients were treated with oral MMF (morte-macrolide) and 180 patients were treated with intravenous infusion of CTX (cyclophosphamide) during the induction treatment period.
Safety results
No significant differences were observed in the proportion of adverse events between the two groups (96.2% in the MMF group and 95.0% in the CTX group). The most common types of adverse events were both infections (68.5% in the MMF group and 61.7% in the CTX group) and gastrointestinal system disorders (61.4% in the MMF group and 66.7% in the CTX group). the incidence of diarrhea was 28.3% and 12.8% in the MMF and CTX groups, respectively, with no statistical difference between the two groups. 27.7% and 22.8% of patients in the MMF and CTX groups, respectively At least one serious adverse event occurred in 27.7% and 22.8% of patients in the MMF and CTX groups, respectively. The most frequently reported type of serious adverse event in both treatment groups was infection, with an incidence of 12.0% and 10.0% in the MMF and CTX groups, respectively; the incidence of gastrointestinal disorders was 4.3% and 1.7% in the MMF and CTX groups, respectively, and the incidence of renal and urinary disorders was 4.3% and 1.7%, respectively. There were 24 (13.0%) and 13 (7.2%) withdrawals due to adverse events in the MMF and CTX groups, respectively. there were 9 (4.9%) and 5 (2.8%) deaths in the MMF and CTX groups, respectively, with no statistically significant differences. In the MMF group, 7 (3.8%) deaths were due to infection, 1 (0.5%) death was due to interstitial lung disease, and the cause of death was unknown in 1 (0.5%) case. In the CTX group, 2 (1.1%) deaths due to infection and 2 (1.1%) deaths due to systemic lupus erythematosus occurred. 7/9 (77.8% of the patients who died) deaths in the MMF group occurred in Asia. Severe baseline disease (GFR of 30 ml/min/1.73 m2 in 32 patients) as well as severe underlying SLE disease and rapidly worsening respiratory symptoms were possible reasons for this difference. Analysis showed no statistically significant differences in the incidence of death, serious adverse events, and infections between the MMF and CTX groups.
Maintenance period study
During the maintenance period, a total of 226 patients who eventually achieved remission after induction therapy were randomly assigned to receive treatment, 115 patients receiving the oral formulation of MMF and 111 patients receiving the oral capsule formulation of AZA (azathioprine).
Safety results
The incidence of adverse events during treatment was similar in both groups: 98.3% (113 patients) in patients treated with MMF and 97.3% (108 patients) in patients treated with AZA. The most common adverse event in both groups was infection, with an incidence of 79.1% in the MMF group and 78.4% in the AZA group. the incidence of serious infection was 9.6% in the MMF group and 11.7% in the AZA group. a higher proportion of patients in the AZA group (39.6%) than in the MMF group (25.2%) experienced withdrawal due to adverse events. The number of patients with at least one serious adverse event was less than that in the AZA group, but there was no statistical difference (23.5% and 33.3% in the MMF and AZA groups, respectively).
Contraindications
This product is contraindicated in persons with known hypersensitivity to morte-malcophenolate, mescaline or any of the components of this product.
This product is contraindicated in pregnant women.
This product is contraindicated in women of childbearing age who are not using an effective method of contraception.
This product is contraindicated in women of lactating age.
【Caution】.
Note: When this product is used for the treatment of lupus nephritis, it should be administered by a specialist with experience in the treatment of lupus nephritis.
It should not be taken after the expiration date indicated on the package.
Please store the medicine out of the reach of children.
Lymphoma and other tumors.
Patients receiving immunosuppressive therapy, including combination therapy, receiving this product as partial immunosuppressive therapy are at increased risk of developing lymphoma and other malignancies, particularly of the skin (see [ADVERSE REACTIONS]). The risk is related to the intensity and duration of immunosuppression, but not to the specific immunosuppressive agent.
Because of the increased risk of skin cancer in patients, exposure to sunlight and ultraviolet light should be reduced by wearing protective clothing or sunscreens containing high protective factors.
Infections.
Excessive suppression of the immune system can increase susceptibility to infections, including conditional opportunistic infections, lethal infections, and sepsis. Such infections include reactivation of latent viruses, such as hepatitis B or C virus, or infections caused by polyomaviruses. Cases of hepatitis caused by reactivation of hepatitis B or C virus in hepatitis virus carriers treated with immunosuppressive drugs have been reported.
Cases of progressive multifocal leukoencephalopathy (PML) associated with JC virus have been reported in patients treated with this product, and some cases have been fatal. PML usually presents with mild hemiparesis, apathy, confusion, cognitive impairment, and ataxia. Reported cases generally have risk factors for PML, including immunosuppressive therapy and immune deficiency. In immunosuppressed patients, physicians should consider taking a differential diagnosis of PML in patients reporting neurological symptoms and should also seek a specialist expert opinion from a neurologist.
BK virus-associated nephropathy has been reported in patients treated with this product after renal transplantation, and this infection can have serious consequences, sometimes leading to renal transplant failure. Monitoring of patients can help identify their risk of developing BK virus-associated nephropathy. Patients with confirmed signs of BK virus-associated nephropathy should consider lowering their immunosuppressive dosage.
Blood and Immune System.
Severe neutropenia [neutrophil count (ANC) <0.5 x 103/mL] was observed in 2.0% and 3.6% of renal and liver transplant recipients treated with 3 g of this product daily, respectively. Patients should complete a complete blood count test weekly during the first month of treatment with this product, twice monthly during the second and third months of treatment, and then monthly through one year. The presence of neutropenia should be specifically monitored (see [Precautions]: Laboratory Tests). The development of neutropenia may be related to this product, but may also be related to coadministered drugs, viral infections, or a combination of causes. If neutropenia (ANC <1.3 × 103/mL) develops, interrupt administration of this product or reduce the dose and observe closely (see [Dosage]). The most common time observed for the prevention of neutropenia in patients with rejection of renal or liver transplantation is 31 to 180 days after transplantation.
Pure red blood cell aplasia (PRCA) has been reported in patients treated with this product in combination with other immunosuppressive agents. The mechanism by which this product causes PRCA is not known; the role of other immunosuppressive agents as co-applications in causing PRCA in immunosuppressive therapy is also not known. In some cases, PRCA has been found to be reversible as the dose of this product is reduced or discontinued. However, in transplant recipients, reduced immunosuppression may put the graft at increased risk of rejection.
Patients receiving this product should be advised to report immediately any signs of infection, unexpected ecchymosis, bleeding, other bone marrow suppression, or gastrointestinal symptoms.
Blood Donation.
Patients should not donate blood during treatment and for at least 6 weeks after discontinuation of this product.
Vaccinations.
Patients should be advised that vaccinations administered as part of treatment with this product may be less effective. And live attenuated vaccines should be avoided (see [Drug Interactions]). Influenza vaccination is beneficial. For influenza vaccination, prescribers should refer to national guidelines.
Gastrointestinal System.
This product has been associated with an increased incidence of gastrointestinal adverse reactions, including rare gastrointestinal ulceration, bleeding, and perforation, so it should be used with caution in patients with active gastrointestinal disease.
Theoretically, because it is an inhibitor of hypoxanthine mononucleotide dehydrogenase (IMPDH), it should be avoided in patients with rare genetic defects in hypoxanthine-guanine phosphate ribosyltransferase (HGPRT), such as Le-Ny syndrome and Kelley-Seegmiller syndrome.
Interactions.
Caution is required when switching from a combination immunosuppressive regimen containing this product because some drugs can affect the hepatic-intestinal circulation of MPA, e.g., switching from cyclosporine to tacrolimus, sirolimus, or belacip may avoid interference with the hepatic-intestinal circulation of MPA
or vice versa, may result in changes in MPA exposure (see [Drug Interactions]).
Therapeutic drug monitoring of MPA may be required when switching combination therapy (e.g., switching from cyclosporine to tacrolimus or vice versa) or to ensure adequate immunosuppression in patients at high immune risk (e.g., risk of rejection, antibiotic therapy, addition or removal of interacting drugs).
Caution should be exercised when combining this product with other types of drugs that interfere with the hepatic-intestinal circulation of MPA (e.g., abciximide, sevelamer, antibiotics), as these drugs may decrease the plasma concentration and efficacy of this product (see [Drug Interactions]). Sevelamer and other non-calcium phosphate binding agents should be applied 2 hours after administration of this product to minimize their effect on MPA absorption.
The combination of this product and azathioprine is not recommended because both may cause myelosuppression and no clinical studies have been conducted on this co-administration.
Special Population Dosage.
Geriatric Patients.
Elderly patients have a higher risk of certain infections (including cytomegalovirus tissue invasive disease), possible gastrointestinal bleeding, and adverse events such as pulmonary edema than younger patients (see [ADVERSE REACTIONS]).
Pregnant and Lactating Women.
This product is contraindicated in pregnant and lactating women (see [Pregnancy and Lactation]).
Sperm Donation.
Male patients should not donate sperm during treatment and for 90 days after discontinuation of this product.
Substance Abuse and Dependence.
There are no available data indicating the potential for drug abuse and dependence with this product.
Effects on Driving and Machine Operation.
This product may have a moderate effect on the ability to drive and operate machinery.
Patients should be advised to use this product with caution when driving or operating machinery if they experience adverse drug reactions such as drowsiness, confusion, dizziness, tremors, or hypotension during treatment with this product (see [ADVERSE REACTIONS]).
Females and males of childbearing potential.
Fertility
This product is contraindicated in women of childbearing age who are not using highly effective methods of contraception (see [Contraindications]). Malformations (including anophthalmia, anencephaly, and hydrocephalus) were observed in the first generation offspring of female rats receiving mortification by oral administration of mortification, but no maternal toxicity was observed. No effect on fertility was observed in male rats receiving mortylmacrolate administration.
Pregnancy test
Female patients of childbearing potential must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mlU/mL prior to initiation of treatment with this product. a second test should be performed 8 to 10 days after the initial test. Patients should have a repeat pregnancy test test during routine follow-up. The physician should discuss all pregnancy test results with the patient. Patients should be fully aware that they need to consult their physician immediately after becoming pregnant.
Contraception
Women
This product is contraindicated in women of childbearing age who are not using highly effective methods of contraception (see [Contraindications]).
Female patients of childbearing potential must be fully aware of the increased risk of pregnancy loss and congenital malformations prior to initiating treatment with this product and must consult with their physician for advice on contraception and pregnancy. Female patients of childbearing potential are advised to use two reliable contraceptive methods, including at least one highly effective method, or to choose abstinence as a contraceptive measure, before starting treatment with this product, during treatment and for 6 weeks after termination of treatment. This also includes patients with a history of infertility, and patients who have undergone hysterectomy do not require contraception.
Men
There are limited clinical data on paternal exposure to this product. These data do not suggest an increased risk of malformation or miscarriage following paternal exposure to mescaline.
Non-clinical data suggest that the dose of mescaline transferred to a potentially pregnant partner via semen is 1/30th of the non-teratogenic concentration in animals and 1/200th of the lowest teratogenic concentration in animals. therefore, the risk of damage via semen is considered negligible. However, genotoxic effects were observed in animal studies where exposure was approximately 2.5 times the therapeutic exposure in humans. Therefore, the risk of genotoxic effects on sperm cells cannot be completely excluded.
Due to insufficient data to exclude the risk of harm to the conceived fetus during or after paternal treatment, the following precautions are recommended.
It is recommended that sexually active male patients use condoms for contraception during treatment and for at least 90 days after treatment termination. Condoms are indicated both for male patients with reproductive capacity and for male patients after vasectomy, as there may also be a risk of conception associated with post-vasectomy male patients. In addition, female partners of male patients are advised to use highly effective methods of contraception during their treatment and for at least 90 days after the last dose of this product is administered.
Patient Information.
Present patients with complete dosing instructions and also inform them of the possible increased risk of lymphoproliferative disorders and certain other malignancies.
Inform the patient that repeated laboratory tests will be required of the patient during treatment with this product.
Inform women of childbearing potential that when this product is used during pregnancy, there may be an increased risk of miscarriage during the first 3 months and also an increased risk of birth defects and that they must use effective contraception.
Discuss pregnancy plans with female patients of childbearing age.
Women of childbearing potential must use highly effective contraception (both measures) for 4 weeks prior to initiating treatment with this product and must continue to use contraception for 6 weeks after treatment with this product is discontinued (see [Use in Pregnant and Lactating Women]).
Patients planning to become pregnant should not be treated with this product unless unsuccessful treatment with other immunosuppressive agents.
Laboratory Tests.
A complete blood count should be completed weekly during the first month of treatment, twice monthly during the second and third months of treatment, and then monthly through one year.
[For pregnant and lactating women].
See [Precautions] for fertility, pregnancy tests and contraception.
Teratogenic effects: Pregnancy classification D (FDA classification)
Animal studies have shown reproductive toxicity of this product. In animal reproductive toxicology studies, there was an increased incidence of fetal resorption and malformations when no maternal toxicity was present. Based on body surface area conversion, female rats and female rabbits received doses of morte-macrolide (MMF) equivalent to 0.02 to 0.9 times the human dose received by renal transplant recipients. Malformations that occurred in rat offspring included anophthalmia, anencephaly, and hydrocephalus. Malformations occurring in rabbit offspring include cardiac heterotaxy, renal heterotaxy, diaphragmatic hernia, and umbilical hernia.
Pregnant women
Due to the mutagenic and teratogenic potential of this product, its use is contraindicated during pregnancy (see [Contraindications]). It is a human teratogen and increases the risk of spontaneous abortion (primarily in early pregnancy) and can cause congenital malformations if maternal exposure occurs during pregnancy (see [Postmarketing Experience]). The reported rate of spontaneous abortion is 45-49% in pregnant patients treated with morte-macrolide and 12-33% in solid organ transplant recipients treated with other immunosuppressive agents, according to the medical literature.
The rate of congenital malformations in live-born fetuses, including multiple malformations in individual neonates, was 23-27% in pregnant patients treated with mortification with mortification, as reported in the published literature. In the total population, the live birth fetal malformation rate was 2%; in solid organ transplant recipients treated with immunosuppressive agents other than mortification mescaline, the live birth fetal malformation rate was approximately 4 to 5%.
Congenital malformations, including multiple malformations, have been reported post-marketing in children of patients treated with a combination of morte-mescaline and other immunosuppressive agents during gestation.
The most frequently reported malformation-related adverse events, as described below, are
– Facial anomalies, (e.g. cleft lip, cleft palate, small jaw deformity and widened eye spacing)
– Ear anomalies, (e.g., abnormal or absent outer/middle ear development) and eye anomalies (e.g., ocular tissue defects, microphthalmia)
– Finger anomalies, (e.g. polydactyly, syndactyly, short fingers, short toes)
– Cardiac anomalies, (e.g., atrial septal defect, ventricular septal defect)
– Esophageal malformations, (e.g. esophageal atresia)
– Neurological malformations, (e.g. spina bifida)
The above results are consistent with the results of teratogenicity studies in rats and rabbits, where embryonic resorption and malformations occurred, but no maternal toxicity occurred.
Delivery: The safety of this product for use during delivery has not been established.
Lactation.
Studies in rats have found that this drug can be secreted from breast milk. However, it is not known if the drug is secreted into breast milk in humans. This product is contraindicated in nursing women because it may cause serious adverse reactions in nursing infants (see [Contraindications]).
[Pediatric use].
Based on pharmacokinetic and safety data in children after renal transplantation, the recommended dose is 600 mg/m2 twice daily (up to a maximum of 1 g twice daily) per dose orally of mortifamate (see [Dosage], [Adverse Reactions], [Clinical Trials], and [Pharmacology and Toxicology]).
Safety and efficacy in pediatric patients receiving liver allografts have not been established.
Safety and efficacy in pediatric patients with lupus nephritis are currently inadequate. It is not recommended for use in children.
[Geriatric Use].
Clinical trials of this product did not include enough elderly people aged 65 years or older to determine whether the effects in the elderly differ from those in younger people. Other reported clinical experiences have also not established differences in effectiveness between older and younger adults. Overall, dose selection in the elderly should be cautious because of decreased renal, cardiac, and hepatic function and the combined application of other medications in the elderly compared to younger adults. Adverse reactions may be more common in the elderly than in younger people.
See [Dosage], [Adverse Reactions] and [Precautions].
Drug Interactions]
DNA polymerase inhibitors (acyclovir, ganciclovir)
Acyclovir: When this product and acyclovir are taken together, the plasma concentrations of both phenolized glucuronide mescaline (MPAG) and acyclovir are increased compared to when the drug is administered alone. Because MPAG plasma concentrations are elevated in response to renal impairment and acyclovir concentrations are also elevated, the potential for competition between the two drugs for secretion from the renal tubules exists, making it likely that plasma concentrations of both drugs will be further elevated.
Ganciclovir: Based on the results of the recommended dose studies of single doses of oral morte-macrolide and intravenous ganciclovir, and the known effects of renal impairment on the pharmacokinetics of this product (see [Pharmacokinetics] and [Precautions]) and ganciclovir, it is expected that co-administration of these agents (a mechanism of competition for renal tubular secretion) will result in increased concentrations of MPAG and ganciclovir. No substantial changes in MPA pharmacokinetics are expected and no adjustment of the dose of this product is required. In patients with renal impairment, this product should be carefully monitored when co-administered with ganciclovir or its prodrugs, such as valganciclovir.
Antacids and Proton Pump Inhibitors (PPIs)
A reduction in MPA exposure can be observed with concomitant administration of this product and antacids (e.g., magnesium hydroxide and aluminum hydroxide) or proton pump inhibitors (including lansoprazole and pantoprazole). However, there was no significant difference in the rate of graft rejection or graft loss when comparing patients taking concomitant proton pump inhibitors with those not taking concomitant proton pump inhibitors. Based on these data, this result can be extrapolated to all antacids, as the reduction in MPA exposure was smaller with concomitant administration of this product and magnesium hydroxide or aluminum hydroxide than with concomitant administration of this product and PPI.
Chelating agents
Abciximide: In normal healthy subjects, the AUC of MPA decreased by approximately 40% with a single dose of 1.5 g of this product administered for 4 days in advance at 4 g each time, three times daily. Caution is required when combining this product with drugs that affect the hepatic and intestinal circulation (see [Precautions]).
Sevelamer: In adult and pediatric patients, the combined use of Sevelamer and this product reduced the Cmax and AUC0-12 of MPA by 30% and 25%, respectively (see [Precautions]). These data suggest that sevelamer and other calcium free phosphate binding agents should be applied 2 hours after administration of this product to minimize their effect on MPA absorption.
Immunosuppressants
Cyclosporine A: The pharmacokinetics of cyclosporine A (CsA) are not affected by this product. However, in renal transplant recipients, the combined use of this product and cyclosporine A, which interferes with the hepatic-intestinal circulation of MPA, reduces MPA by 30-50% compared to patients on similar doses of this product in combination with sirolimus or belacip. Conversely, patients switching from cyclosporine A to an immunosuppressant that does not interfere with the hepatic-intestinal circulation of MPA would be expected to have a change in MPA exposure.
Tacrolimus: The combined use of tacrolimus and this product had no effect on the AUC or Cmax of MPA in patients undergoing liver transplantation. Similar results were observed in a recent study conducted in renal transplant recipients.
In renal transplant recipients, this product was found not to alter the concentration of tacrolimus.
However, in liver transplant recipients, the AUC of tacrolimus increased by approximately 20% after multiple doses of this product (1.5 g per dose, twice daily) were given to tacrolimus recipients.
Antibiotics
Rifampin: After dose correction, a 70% decrease in MPA exposure (AUC0-12h) was observed in patients with single heart-lung transplantation when combined with rifampin administration. Therefore, it is recommended that MPA exposure levels be monitored when this drug is combined and the dose of this product be adjusted accordingly to maintain clinical efficacy.
Antibiotics that clear β-glucuronidase-producing bacteria in the small intestine (e.g., aminoglycosides, cephalosporins, fluoroquinolones, and penicillins) may interfere with MPAG/MPA enterohepatic circulation, further resulting in reduced systemic exposure to MPA (see [Precautions], [Interactions]).
For information on the availability of the following antibiotics.
Ciprofloxacin or amoxicillin clavulanic acid: The initial dose concentration (trough) of MPA has been reported to decrease by 54% on the day of administration following oral administration of ciprofloxacin or amoxicillin clavulanic acid in renal transplant recipients. This effect tended to diminish with continued antibiotic administration and disappeared after discontinuation of the drug. Changes in initial dose levels may not accurately reflect systemic exposure to MPA, so the clinical relevance of these observations is unclear.
Norfloxacin and metronidazole: After a single administration of this product, the combination of norfloxacin and metronidazole resulted in a 30% reduction in the AUC0-48 of MPA. Combining this product with either antibiotic alone did not have an effect on systemic exposure to MPA.
Methotrexate/sulfamethoxazole: The combination of methotrexate/sulfamethoxazole had no effect on systemic exposure to MPA (AUC, Cmax).
Oral contraceptives
The pharmacokinetics of oral contraceptives are not affected by coadministration of this drug. 18 studies in women with psoriasis over 3 menstrual cycles have shown that this drug (1 g twice daily) in combination with ethinylestradiol (0.02-0.04 mg) and levonorgestrel (0.05-0.20 mg), deprenylene (0.15 mg) or pregnenolone (0.05-0.10 mg) containing No significant effect on serum progesterone, LH and FSH levels was observed with co-administration of type I oral contraceptives, suggesting that this product may have no effect on ovarian suppression of oral contraceptives.
Other interactions
Coadministration of drugs that inhibit MPA glucosylation may increase MPA exposure (e.g., a 35% increase in MPA AUC0-∞ when esaconazole is coadministered). Therefore, caution should be exercised when such drugs are combined with this product.
Combination with temisartan reduces the concentration of MPA by approximately 30%. Temisartan can alter the elimination of MPA by increasing PPAR γ expression (peroxisome proliferator-activated receptor γ), which then leads to an increase in UGT1A9 expression and activity, thereby enhancing glucosylation. When comparing the incidence of graft rejection, incidence of graft failure, or adverse reactions in patients given this product in combination with and without temisartan, no clinical results of pharmacokinetic drug-drug interactions (DDIs) were observed.
The combination of this product with probenecid resulted in a 3-fold increase in plasma MPAG AUC in monkey trials. Therefore, other drugs known to be secreted from the renal tubules may compete with MPAG and therefore increase plasma concentrations of MPAG and other drugs secreted through the renal tubules.
Live vaccines: Live vaccines should not be used in patients with impaired immune response. The antibody response to other vaccines may also be reduced.
[Drug overdose].
Overdose of morte-malciprate has been reported in clinical trials and post-marketing experience. Many of these cases were without adverse events. In those overdose cases where adverse events were reported, the adverse events were within the known safety profile of the drug.
It is estimated that morte-mescaline overdose may result in excessive suppression of the immune system and increased susceptibility to infection and myelosuppression (see [PRECAUTIONS]). Discontinue this product or reduce the dose if decreased neutrophils occur (see [Precautions]).
MPA is not cleared by hemodialysis; however, small amounts of MPAG may be cleared if MPAG plasma concentrations are high (greater than 100 μg/ml.) In addition, MPA may be eliminated by bile acid binding agents, such as abciximide, by increasing drug secretion (see [Pharmacokinetics]).
Pharmacology and Toxicology
Pharmacological effects
Mortylmacrolate (MMF) is a 2-ethyl ester derivative of mescaline (MPA), a potent, selective, non-competitive, reversible inhibitor of hypoxanthine mononucleotide dehydrogenase (IMPDH), which inhibits the classical synthesis pathway of guanine nucleotides, inhibits T and B lymphocyte proliferation induced by mitogens and cognate specific stimuli, and inhibits B lymphocyte production of antibodies, inhibits glycosylation of lymphocyte and monocyte glycoproteins, and therefore inhibits leukocyte entry into sites of inflammation and graft rejection. It does not inhibit the early responses of peripheral blood mononuclear cell activation, such as interleukin-1 and interleukin-2 production, but it does inhibit the DNA synthesis and proliferation responses that result from these early responses.
Toxicological studies
Genotoxicity.
Positive results for morte-macrolide mouse lymphoma/thymidine kinase assay and in vivo micronucleus assay in mice, negative results for microbial mutation analysis, yeast gene conversion analysis and chromosomal aberration assay in Chinese hamster ovary cells.
Reproductive toxicity.
No significant effect of mortification at 20 mg/kg/d on fertility was observed in male rats, which was 0.1 times the clinically recommended dose for kidney transplantation and 0.07 times the dose for heart transplantation, as extrapolated from body surface area. In reproduction and fertility tests in female rats, no toxic effects were observed in females at a dose of 4.5 mg/kg/d. Malformations (mainly head and eye) were seen in the F1 generation, 0.02 times the clinically recommended dose for renal transplantation and 0.01 times the dose for cardiac transplantation. No significant effects on F1 generation or offspring fertility were seen.
Carcinogenicity.
No carcinogenicity was seen in mice given mortifamol ester orally for 104 weeks at doses up to 180 mg/kg/day, which is 0.5 times the clinically recommended dose for renal transplantation (2 g/d) and 0.3 times the dose for cardiac transplantation (3 g/d). In rats given orally for 104 weeks at a dose of 15 mg/kg/day, no carcinogenicity was observed, which is 0.08 times the clinically recommended dose for renal transplantation and 0.05 times the dose for cardiac transplantation.
[Pharmacokinetics].
After oral or intravenous administration, morte-mescaline is rapidly and completely metabolized to the active metabolite MPA, which is rapidly and almost completely absorbed orally. MPA is metabolized to the phenolized glucuronide mescaline acid (MPAG) form, which has no pharmacological activity. The prodrug morte-mescaline is detectable in the body during intravenous administration and the concentration of morte-mescaline is below the lower limit of quantification (0.4 μg/ml) when the injection is stopped or a short time after oral administration (approximately 5 minutes).
Absorption: The mean absolute bioavailability of oral morte mescaline in 12 healthy volunteers was equivalent to 94% of that of a sedative injection (AUC according to MPA). In renal transplant recipients given multiple doses up to 3 g per day, the area under the plasma concentration time curve (AUC) of MPA exhibited an increase proportional to the dose (see table of pharmacokinetic parameters below).
At 1.5 g per dose twice daily in renal transplant recipients, food (27 g fat, 650 calories) had no effect on the extent of absorption (based on the AUC of MPA). However, food reduced the Cmax of MPA by 40% (see [dosage]).
Distribution: The mean (± standard deviation) apparent volume of distribution of intravenous and oral MPA in 12 healthy volunteers was 3.6 (± 1.5) and 4.0 (± 1.2) L/kg, respectively. 97% of MPA was bound to plasma albumin at concentrations corresponding to clinical practice. This value is dependent on renal function; changes in albumin binding after initiation of treatment could explain the non-smooth nature of MPA pharmacokinetics. At normal concentrations of MPAG in stable kidney transplant recipients, 82% of MPAG was bound to plasma albumin; however, at elevated concentrations of MPAG (seen in patients with renal impairment and delayed graft function after renal transplantation), MPA binding to albumin decreased because MPAG and MPA competed for binding to albumin. The average ratio of blood to plasma radioactivity concentrations was approximately 0.6, indicating that MPA and MPAG are not widely distributed to the cellular components of the blood.
The effects of other reagents on MPA binding to serum albumin or plasma proteins were evaluated in in vitro studies, and salicylic acid (at 25 mg/dL in serum albumin) and MPAG (at ≥460 μg/mL in plasma proteins) increased the proportion of free MPA. At concentrations above those encountered in the clinic, cyclosporine A, digoxin, naproxen, prednisone, tretinoin, immunosuppressants, theophylline, toluenosulfonylurea, and warfarin did not increase the proportion of free MPA. concentrations of MPA up to 100 μg/mL had no effect on protein binding of warfarin, digoxin, and tretinoin, but reduced binding of theophylline from 53% to 45% and of phenytoin sodium from 90% to 87%.
Metabolism: After oral or intravenous administration, mortyl mescaline is completely metabolized to the active product MPA, which is metabolized to MPA after oral administration before systemic absorption. MPA is mainly formed by glucuronide convertase to phenolized glucuronide mescaline acid (MPAG), which has no pharmacological activity. In vivo, MPAG is converted to MPA via the hepatic-intestinal circulation. the following 2-hydroxyethylmorpholine components were also detected in the urine of healthy volunteers following oral administration of morte-malcophenolate: N-(2-carboxyethyl)-morpholine, N-(2-hydroxyethyl)-morpholine, and N-(2-hydroxyethyl)-morpholine oxidized at the N-terminus.
A second peak in plasma MPA concentration was observed 6 to 12 hours after dosing. Concomitant administration of abciximide (4 g, 3 times daily) reduced the AUC of MPA by approximately 40% (mainly reducing the drug concentration in the terminal part of the AUC curve). This phenomenon suggests that the hepatic-intestinal circulation raises the plasma concentration of MPA.
In patients with renal impairment, plasma concentrations of metabolites of mortylmacrolide were elevated, with a 50% increase in MPA and a 3- to 6-fold increase in MPAG.
Clearance: Only small amounts are excreted in the urine as MPA (less than 1% of the dose, negligible). After oral administration of radiolabeled morte-macrolide, the original radioactive dose is fully recovered, with 93% of the administered dose recovered in the urine and 6% in the feces. The majority (~87%) of the dose is excreted in the urine as MPAG. At clinically applied concentrations, MPA and MPAG are usually not cleared by hemodialysis. However, small amounts of MPAG may be cleared by hemodialysis at elevated plasma concentrations of MPAG (> 100 μg/mL). Bile acid binding agents, such as abciximide, can reduce the area under the curve of MPA by affecting the hepatic-intestinal circulation of the drug (see [Drug Overdose]).
The mean (± standard deviation) half-life and plasma clearance of MPA were 17.9 (± 6.5) hours and 193 (± 48) mL/min for oral administration and 16.6 (± 5.8) hours and 177 (± 31) mL/min for intravenous administration, respectively.
Pharmacokinetics in healthy volunteers, renal transplant and liver transplant recipients: The following pharmacokinetic parameters of MPA are shown as means (± standard deviation) for a single dose of morte-macrolide in healthy volunteers and for multiple doses in renal transplant and liver transplant recipients. Kidney transplant and liver transplant recipients had approximately 20-41% lower MPA AUC and 32-44% lower mean Cmax in the early post-transplant period (within 40 days post-transplant) compared to the late post-transplant period (3 to 6 months post-transplant).
MPA AUC was approximately 24% higher in renal transplant recipients given intravenous morte-macrolide (1 g per dose, 2-hour infusion, twice daily for 5 days) just after transplantation compared to those given the same dose orally. The mean MPA AUC in liver transplant recipients given intravenous mortifamol ester 1 g twice daily followed by oral administration of 1.5 g twice daily was similar to that given after renal transplantation at 1 g twice daily.
Healthy volunteers (single dose), renal transplant and liver transplant recipients (multiple dosing)
Pharmacokinetic parameters after administration of morte-macrolide
Dosing regimen Dose and route Tmax
(h) Cmax
(μg/mL) Total AUC
(μg-h/mL) Healthy volunteers
(single dose) 1g/oral 0.80
(±0.36)
(n=129) 24.5
(±9.5)
(n=129)63.9
(±16.2)
(n=117) Kidney transplant recipients
(Second daily dose) Post-transplant time dose and route Tmax (h) Cmax (μg/mL) AUC (0-12h) between second doses (μg-h/mL) 5 days 1g/IV 1.58
(±0.46)
(n=31)12.0
(±3.82)
(n=31)40.8
(±11.4)
(n=31) 6 days 1g/oral 1.33
(±1.05)
(n=31)10.7
(±4.83)
(n=31)32.9
(±15.0)
(n=31) Early (within 40 days) 1g/oral 1.31
(±0.76)
(n=25)8.16
(±4.50)
(n=25)27.3
(±10.9)
(n=25) Early (within 40 days) 1.5g/oral 1.21
(±0.81)
(n=27) 13.5
(±8.18)
(n=27)38.4
(±15.4)
(n=27) Late (>3 months) 1.5g/oral 0.90
(±0.24)
(n=23) 24.1
(±12.1)
(n=23)65.3
(±35.4)
(n=23) Liver transplant recipients
(Second daily dose) Post-transplant time dose and route Tmax (h) Cmax (μg/mL) AUC between second doses (0-12h) (μg-h/mL) 4-9 days 1g/IV 1.50
(±0.517)
(n=22)17.0
(±12.7)
(n=22)34.0
(±17.4)
(n=22) Early (5-8 days) 1.5g/oral 1.15
(±0.432)
(n=20) 13.1
(±6.76)
(n=20)29.2
(±11.9)
(n=20) Late (>6 months) 1.5g/oral 1.54
(±0.51)
(n=6) 19.3
(±11.7)
(n=6)49.3
(±14.8)
(n=6) AUC (0-12h) values were extrapolated from data sampled at 4 hours, and 2 tablets of 500 mg were bioequivalent to 4 tablets of 250 mg.
According to foreign literature, the pharmacokinetics of mortylmacrolate has been studied in patients with lupus nephritis. The pharmacokinetic profile of MPA in patients with lupus nephritis is similar to that reported in transplant patients (including the high variability in active drug exposure observed), but is more complex in patients with lupus nephritis due to unpredictable changes in renal function.
Pharmacokinetics in special populations: The following mean values (± standard deviation) are used to indicate the pharmacokinetic parameters of MPA in non-transplant recipients with renal impairment or hepatic impairment who received a single oral dose of mortylmacrolide.
Renal impairment
(number of patients) Dose Tmax
(h) Cmax
(μg/mL) AUC (0-96h) (μg-h/mL) Healthy volunteers
GFR>80mL/min/1.73m2
(n=6)1g0.75
(±0.27)25.3
(±7.99)45.0
(±22.6) Mild renal impairment
GFR50~80mL/min/1.73m2
(n=6)1g0.75
(±0.27)26.0
(±3.82)59.9
(±12.9)Moderate renal impairment
GFR25~49mL/min/1.73m2
(n=6)1g0.75
(±0.27)19.0
(±13.2)52.9
(±25.5) Severe renal impairment
GFR<25mL/min/1.73m2
(n=7)1g1.00
(±0.41)
16.3
(±10.8)78.6
(±46.4) Liver damage
(Number of patients) Dose Tmax (h) Cmax
(μg/mL) AUC (0~48h) (μg-h/mL) Healthy volunteers
(n=6) 1g0.63
(±0.14)24.3
(±5.73)29.0
(±5.78) Alcoholic liver fibrosis
(n=18) 1g0.85
(±0.58)22.4
(±10.1)29.8
(±10.7)
Patients with renal impairment
In a single-dose study (6 per group), volunteer subjects with severe chronic renal impairment (glomerular filtration rate (GFR) less than 25 ml/min/1.73m2) had 28-75% higher AUC of plasma MPA than normal healthy volunteers and volunteers with mild renal impairment (GFR>80 mL/min/1.73m2). Also the AUC of MPAG was 3-6 times higher in volunteer subjects with severe renal impairment than in normal healthy volunteers after a single dose, which is consistent with our knowledge that MPAG is eliminated by the kidneys. no data are available on the safety of long-term increases in MPAG.
The plasma MPA AUC for a single intravenous dose of 1 g in persons with severe chronic renal impairment (GFR less than 25 ml/min/1.73 m2) was 62.4 (±19.3) μg-h/mL (n=4). The metabolism of multiple doses of mortyl mescaline has not been studied in patients with severe chronic renal impairment (see [Precautions] and [Dosage]). Data from studies in patients with lupus nephritis with severe renal impairment are limited, and therapeutic drug concentration monitoring is recommended for patients with lupus nephritis with GFR <30 mL/min.
The mean AUC of MPA in patients with delayed graft function after renal transplantation (0-12 h) was similar to those postoperative patients with normal graft function. Transient increases in plasma MPA free ratio or elevated concentrations may occur in patients with delayed graft function, but no dose adjustment is required in patients with delayed graft function. The mean AUC of MPAG (0-12h) was 2-3 times higher in patients with delayed graft function after renal transplantation compared to those with normal graft function (see [Precautions] and [Dosage]).
In 8 patients with non-functioning primary grafts after renal transplantation, plasma MPAG concentrations accumulated 6 to 8-fold and MPA concentrations accumulated 1 to 2-fold after 28 days of multiple dosing.
The pharmacokinetics of motilmic acid esters are not altered by hemodialysis. Hemodialysis usually does not clear MPA and MPAG, but small amounts of MPAG may pass through hemodialysis at elevated plasma concentrations of MPAG (> 100 μg/mL).
Patients with liver damage
Eighteen cases of alcoholic cirrhosis and six healthy volunteers participated in a single dose (1 g orally) study, which showed similar pharmacokinetic parameters in healthy volunteers and those with alcoholic cirrhosis, suggesting that the hepatic glucuronidation of MPA is relatively unaffected by parenchymal liver disease. However, it is important to note that for unknown reasons the AUC of healthy volunteers in this trial was 50% lower than that of healthy volunteers in other trials, making comparisons between healthy volunteers and those with alcoholic cirrhosis difficult. Other causes of liver disease such as primary biliary cirrhosis may have different effects. 6 patients with severe liver damage due to alcoholic cirrhosis (less than 0.2% of the dose in the aminopyrine breath test) were given a single dose (1 g administered intravenously) and MMF was rapidly converted to MPA. the MPA AUC was 44.1 (±15.5) μg-h/mL.
Children (age ≤ 18 years)
The pharmacokinetic parameters of MPA and MPAG were evaluated in 55 children (aged 1 to 18 years) who received mortification with mortification after allogeneic transplantation at 600 mg/m2 orally twice daily.The pharmacokinetic parameters of MPA are shown in the following table.
Pharmacokinetic parameters of MPA at different ages and at different times after allografting (mean ± standard deviation)
Age (number of cases) Time Peak time
(h) Cmax after dose correctiona (μg/mL) AUC after dose correctiona (0-12h) (μg-h/mL) 1~2 years (6) d
1~6 years old (17)
6~12 years old (16)
12~18 years (21) Early (7 days) 3.03 (4.70)
1.63 (2.85)
0.94 (0.546)
1.16 (0.830) 10.3 (5.80)
13.2 (7.16)
13.1 (6.30)
11.7 (10.7) 22.5 (6.66)
27.4 (9.54)
33.2 (12.1)
26.3 (9.14)b 1~2 years old (4)d
1~6 years old (15)
6~12 years old (14)
12~18 years (17) Late (3 months) 0.725 (0.276)
0.989 (0.511)
1.21 (0.532)
0.978 (0.484) 23.8 (13.4)
22.7 (10.1)
27.8 (14.3)
17.9 (9.57) 47.4 (14.7)
49.7 (18.2)
61.9 (19.6)
53.6 (20.3)c 1~2 years old (4)d
1~6 years old (12)
6~12 years old (11)
12~18 years old (14) Late (9 months) 0.604 (0.208)
0.869 (0.479)
1.12 (0.462)
1.09 (0.518) 25.6 (4.25)
30.4 (9.16)
29.2 (12.6)
18.1 (7.29) 55.8 (11.6)
61.0 (10.7)
66.8 (21.2)
56.7 (14.0) a Dose adjusted to equivalent to 600 mg/m2
b n=20
c n=16
d A subgroup of 1 to 6 years
The mean MPA AUC values for children taking mortylmacrolate suspension at 600 mg/m2 twice daily (maximum 1 g per capsule twice daily) were similar to those for adults taking mortylmacrolate capsules at 1 g per capsule twice daily in the early post-renal transplant period. The variability of the data was significant. MPA AUC values observed in adults in the early post-transplant period were 45% to 53% of those in the late post-transplant period (> 3 months). In children between the ages of 1 and 18 years, MPA AUC values were similar in the early and late post-transplant period.
Pharmacokinetic studies of primaquine in pediatric patients with lupus nephritis have not been conducted.
Gender
Data from several trials were pooled to see if there were differences in the pharmacokinetics of MPA (dose adjusted to the equivalent of 1 g/m2). MPA AUC (1-12h) values were 32.0±14.5 (n=79) and 36.5±18.8 μg-h/mL (n=4) for men and women, respectively; MPA Cmax was 9.96±6.19 and 10.6±5.64 μg/mL for men and women, respectively. the differences were not clinically significant.
Elderly
No changes in the pharmacokinetics of morte-mescaline and its metabolites have been detected in elderly transplant recipients compared with younger transplant recipients.
Storage
Store in a dry place below 30℃.
Package]
Solid medicine in plastic bottles: 100 capsules/bottle, 120 capsules/bottle, 500 capsules/bottle.
Aluminum-plastic packaging, 10 capsules/plate, 2 plates per box, 4 plates
【Expiration date】
18 months
【Execution standard
【Approval number】
State Drug Authentication H20070081
Marketing authorization holder
Company Name: Hanhui Pharmaceuticals Company Limited
Hanhui Pharmaceuticals Company Limited
Registered address: No. 2, Haizheng Road, Xukou Town, Fuyang District, Hangzhou City, Zhejiang Province
Postal Code: 311404
Telephone number: 400-6236717
Fax Number: 021-53897501
Manufacturer
Company name: Zhejiang HISUN Pharmaceutical Co.
ZHEJIANG HISUN PHARMACEUTICALS CO., LTD.
Production Address: No.1, Haisheng Avenue, Jiaojiang District, Taizhou City, Zhejiang Province
Postal Code: 318000
Telephone number: 4001180618
Fax number：0576-88827887
Web address: www.hisunpharm.com