Sirolimus oral solution

Sirolimus inhibits the activation and proliferation of T lymphocytes stimulated by antigens and cytokines (interleukins IL-2, IL-4 and IL-15) through a mechanism of action that is completely different from other immunosuppressants. Sirolimus also inhibits the production of antibodies. In cells, sirolimus binds to the immunophilin, FK binding protein-12 (FKBP-12), to form an immunosuppressive complex. This sirolimus FKBP-12 complex has no effect on the activity of calcineurin. This complex binds to the mammalian sirolimus target molecule (mTOR, a key regulatory kinase) and inhibits its activity. This inhibition blocks the proliferation of cytokine-driven T cells, that is, inhibits the progression from the G1 phase to the S phase of the cell cycle. Experimental model studies have shown that sirolimus can prolong the survival of allogeneic transplants (kidney, heart, skin, pancreatic islets, small intestine, pancreato-duodenal and bone marrow) in mice, rats, pigs and/or primates. Sirolimus reverses acute rejection of heart and kidney allografts in rats and prolongs graft survival in presensitized rats. In some studies, the immunosuppressive effects of sirolimus persist up to 6 months after cessation of treatment. This immune tolerance effect is alloantigen specific. In rodent models of autoimmune disease, sirolimus inhibits immune-mediated responses associated with the following diseases: systemic lupus erythematosus, collagen-induced arthritis, autoimmune type I diabetes, autoimmune myocarditis, experimental allergic encephalomyelitis, graft-versus-host disease, and autoimmune uveoretinitis. Carcinogenesis, Mutagenesis, and Impairment of Fertility: Sirolimus was not genotoxic in the in vitro microbial reverse mutation assay, the Chinese hamster ovary cell chromosome aberration assay, the mouse lymphoproliferative tumor cell forward mutation assay, or the in vivo mouse micronucleus assay. Carcinogenicity studies were conducted in female mice and male and female rats, but not in male mice. In an 86-week study in female mice, doses were set at 0, 12.5, 25, and 50/6 mg/kg/day (at week 31, the dose was reduced from 50 mg/kg/day to 6 mg/kg/day due to infection secondary to immunosuppression). There was a statistically significant increase in malignant lymphomas in all dose groups (approximately 6-135 times the clinical dose corrected for body surface area) compared with the control group. In a 104-week study in rats, doses were set at 0, 0.05, 0.1, and 0.2 mg/kg/day, and there was a statistically significant increase in the incidence of testicular adenomas in the 0.2 mg/kg/day group (approximately 0.4-1 times the clinical dose corrected for body surface area). In female rats, sirolimus doses up to 0.5 mg/kg (approximately 1-3 times the clinical dose corrected for body surface area) had no effect on fertility. In male rats, the fertility rate of the 2 mg/kg dose group (4-11 times the clinical dose corrected for body surface area) was no different from that of the control group. In rats at 0.65 mg/kg (approximately 1-3 times the clinical dose corrected for body surface area) and above, and in monkeys at 0.1 mg/kg (approximately 0.4-1 times the clinical dose corrected for body surface area) and above, testicular weight decreased and/or histological damage (such as tubular atrophy and tubular giant cells) occurred. Male rats took 6 mg/kg of sirolimus (approximately 12-32 times the clinical dose corrected for body surface area) for 13 consecutive weeks, and their sperm count decreased, but recovered 3 months after stopping the drug. Embryotoxicity: In rats at 0.1 mg/kg and above dose groups (approximately 0.2-0.5 times the clinical dose corrected for body surface area), sirolimus was toxic to the embryo and fetus, manifested as stillbirth and fetal weight loss (accompanied by delayed skeletal ossification). However, no teratogenicity occurred. The embryo/fetal mortality rate of mice treated with cyclosporine was higher than that of mice treated with this drug alone. The female toxic dose of 0.05 mg/kg of this drug (about 0.3-0.8 times the clinical dose corrected for body surface area) had no effect on the development of rabbits. The acute oral LD50 of mice and rats exceeded 800 mg/kg.

Sirolimus

This product is light yellow to yellow clear viscous liquid.

Suitable for patients receiving kidney transplants to prevent organ rejection.

This product should be used under the guidance of experienced clinicians. 1. This product should be used within 72 hours after surgery together with cyclosporine and corticosteroids, once a day. For patients who have received a transplant, a loading dose three times the maintenance dose should be given for the first time. The recommended maintenance dose for renal transplant patients is 2 mg per day, and the loading dose is 6 mg. The dose should be adjusted regularly according to the whole blood trough concentration. According to the results of domestic clinical trials of sirolimus, it is recommended that the whole blood trough concentration of sirolimus be controlled at 5-10 ng/ml for 0-3 months after surgery; and 3-8 ng/ml for 4-6 months. 2. For patients with a body weight of less than 40 kg and an age of ≥13 years old, the dose needs to be adjusted. The maintenance dose should be 1 mg/m2/day, and the loading dose should be 3 mg/m2. 3. For patients with impaired liver function, the maintenance dose of this product should be reduced by 1/3, while the loading dose remains unchanged. Patients with abnormal renal function do not need to adjust the dose. 4. In order to make the concentration of sirolimus in the body more constant, the relationship between taking the medicine and eating should be fixed during the use of this product, or the medicine should be taken on an empty stomach each time, or it should be taken with food each time. This product can only be taken after diluting with water or orange juice. 5. This product should be taken 4 hours after the administration of cyclosporine oral solution or cyclosporine capsules. Usage: Use a special syringe for oral administration to draw the required amount of sirolimus oral solution from the bottle, inject it into a glass or plastic container containing at least 60ml of water or orange juice, stir it vigorously and take it immediately. Then add another 120ml of water or orange juice to this container, stir it vigorously and take it immediately.

Adverse reactions related to sirolimus include hyperlipidemia, hypertension, rash, acne, anemia, joint pain, diarrhea, hypokalemia, thrombocytopenia, etc. The increase in triglycerides and cholesterol, and the decrease in platelets and hemoglobin are related to the dosage of sirolimus, and the incidence of adverse reactions is significantly reduced in patients with a maintenance dose of less than 2 mg/day.

The following patients are contraindicated to use this product: 1. Patients who are allergic to sirolimus and its derivatives or drugs containing its ingredients. 2. Patients with severe liver damage. 3. Pregnant and lactating women.

Precautions for children: The safety and efficacy of this drug for pediatric patients under 13 years of age have not been established. When using this drug in pediatric patients under 13 years of age, blood trough concentrations should be monitored. Precautions for pregnancy and lactation: Use during lactation: Sirolimus is secreted in trace amounts in the milk of lactating rats. It is not clear whether sirolimus is secreted in human milk. The pharmacokinetics and safety of sirolimus in infants are also unclear. Considering that many drugs are secreted in human milk and the potential adverse reactions of sirolimus to lactating infants, the decision to discontinue breastfeeding or discontinue the drug should be based on the importance of this drug to the mother. Precautions for the elderly: There are not enough cases of patients aged 65 years and above to determine whether the safety and efficacy of the drug in this population are different from those in younger patients. Data on trough concentrations of sirolimus indicate that this drug does not need to be adjusted in dose according to age for elderly patients with kidney disease.

1. Sirolimus is metabolized by CYP3A4 isoenzyme to the maximum extent in the intestinal wall and liver and excreted by P-glycoprotein, so the absorption and elimination of this product will be affected by other drugs affecting the isoenzyme. CYP3A4 inhibitors (nicardipine, verapamil, clotrimazole, fluconazole, erythromycin, etc.) will reduce the metabolism of sirolimus and increase the blood concentration of sirolimus. CYP3A4 inducers (carbamazepine, phenobarbital, phenytoin and rifampicin, etc.) will increase the metabolism of sirolimus and reduce the blood concentration of sirolimus. 2. Taking sirolimus and cyclosporine at the same time can increase the blood concentration of sirolimus. Therefore, this product should be taken 4 hours after the administration of cyclosporine oral solution or cyclosporine capsules.

Protect from light, seal tightly and store in a cool place.

50ml:50mg

December

Fujian Kerui Pharmaceutical Co., Ltd.

• Founded in:

  1999-09-07

• Address:

  No. 1069-15, Niuzhai Village, Haikou Town, Fuqing City, Fuzhou City, Fujian Province

• Tax NO.:

  913501816110101446

• Registered Funds:

  25 million yuan

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