Rosiglitazone
Generic name rosiglitazone hydrochloride tablets? Rosiglitazone? hydrochloride
Composition rosiglitazone hydrochloride. Chemical name: 5-{4-[2- (methyl -2- pyridylamino) ethoxy] benzyl}-2,4- thiazolidinedione hydrochloride dihydrate.
Description: This product is a film-coated tablet, which is white or white-like.
Pharmacology and Toxicology This product belongs to thiazolidinedione antidiabetic drug, which can effectively control blood sugar by improving the sensitivity of insulin. This product is a highly selective and potent agonist of peroxisome proliferator-activated receptor γ (PPAR-γ). Human PPAR receptor exists in the main target tissues of insulin, such as liver, fat and muscle. This product activates PPAR-γ nuclear receptor and can regulate the transcription of insulin response genes involved in the production, transport and utilization of glucose. In addition, PPAR-γ reaction genes are also involved in the regulation of fatty acid metabolism. In the clinical study of this product, the results of fasting blood glucose (FPG) and HbA 1c show that this product can improve blood glucose control and reduce postprandial blood glucose and insulin levels. This product has a long-term effect on improving blood sugar control, which can last for 52 weeks. The main pathophysiological feature of type 2 diabetes is insulin resistance. The antidiabetic effect of this product has been shown in animal models of type 2 diabetes (hyperglycemia and/or abnormal glucose tolerance due to insulin resistance of target tissues). It can effectively reduce the blood sugar of Ob/0b obese mice, db/db diabetic mice and fa/faZucker obese rats, relieve their hyperinsulinemia, and delay the development of diabetes in db/db mice and Zucker obese rats. Animal studies show that the antidiabetic effect of this product is achieved by improving the sensitivity of liver, muscle and adipose tissue to insulin and increasing the gene expression of insulin-regulated glucose transporter GLUT-4 in adipose tissue. In model animals with type 2 diabetes and/or abnormal glucose tolerance, the use of this product alone will not lead to hypoglycemia. Animal toxicity: When the doses of this product to mice, rats and dogs were 3mg/kg/ day, 4mg/kg/ day and 2mg/kg/ day respectively (equivalent to 5, 22 and 2 times of the maximum recommended daily dose AUC), the heart weight increased, and ventricular hypertrophy was observed by morphological examination, which may be related to the increase of heart load caused by the increase of blood volume. Genotoxicity: the results of bacterial gene mutation test in vitro, chromosome aberration test of human lymphocytes in vitro, micronucleus test of mice in vivo and unscheduled DNA synthesis test of rats in vitro and in vivo were all negative. In vitro test of mouse lymphoma, the mutation rate increased slightly (about 2 times) under the condition of metabolic activation. Reproductive toxicity: the dose of this product is 40mg/kg/ day (equivalent to 1 16 times of AUC at the maximum recommended daily dose), which has no effect on the mating and fertility of male rats. This product can change the estrous cycle of female rats (2mg/kg/ day, equivalent to 20 times of AUC at the maximum recommended daily dose), reduce the fertility of female rats (40mg/kg/ day, equivalent to 200 times of AUC at the maximum recommended daily dose), and be accompanied by the decrease of progesterone and estrogen in blood. At the dose of 0.2mg/kg/ day (equivalent to 3 times of AUC at the maximum recommended daily dose), the above changes were not observed. The dosage of this product is 0.6mg/kg/ day and 4.6mg/kg/ day (equivalent to 3 times of AUC and 15 times of the maximum recommended daily dosage), which can reduce the serum estradiol level in follicular phase of monkeys, further reduce the luteinizing hormone level and progesterone level in luteal phase, and cause amenorrhea, which may be related to the direct inhibition of ovarian steroid hormone production by this product. Taking this product to rats in early pregnancy has no effect on implantation or embryo; However, in the second and third trimester of pregnancy, this product can cause embryo death and growth retardation in rats and rabbits. When the dose of rats and rabbits reached 3mg/kg/ day and 100mg/kg/ day (20 times and 75 times AUC of the maximum recommended daily dose), there was no teratogenic effect. When rats receive a dose of 3 mg/kg/day, the placenta will have pathological changes. Continuous administration during pregnancy and lactation can reduce the litter size, reduce the vitality of newborn rats and delay the growth after birth, but the growth delay can be restored after puberty. The no-effect doses of this product on placenta, embryo/fetus and offspring of rats and rabbits are 0.2 mg/kg and 65,438+0.5 mg/kg/day, respectively, which is about 4 times of the maximum recommended daily dose AUC of human beings. There is no completely strictly controlled clinical research data of pregnant women. Only when the potential benefits to the fetus outweigh the potential dangers can pregnant women take this product. Related substances of this product were detected in rat milk, but it is not clear whether this product is secreted by human milk. Because many drugs can be secreted by human milk, this product is not suitable for lactating women. The existing data clearly suggest that abnormal blood glucose level during pregnancy can increase the incidence, morbidity and mortality of neonatal congenital malformation. Therefore, most experts recommend using insulin alone during pregnancy to maintain normal blood sugar levels as much as possible. Carcinogenicity: mice were given this product by mixing it with food for 2 years, and the doses were 0.4, 1.5 and 6mg/kg/ day respectively (the high dose was equivalent to 12 times of AUC at the maximum recommended daily dose). No carcinogenicity was found, but the dosage above 1.5mg/kg/ day can cause adipose tissue hyperplasia. Oral administration of this product to rats at the doses of 0.05mg/kg/ day, 0.3mg/kg/ day and 2mg/kg/ day for 2 years [the high dose is equivalent to 65,438+00 times (male) and 20 times (female) of the maximum recommended daily dose], and at the dose of 0.3mg/kg/ day and above, the benign fat of rats can be significantly increased. The proliferation reaction found in the above two animals is related to the excessive and lasting pharmacological effect of this product on adipose tissue.
The absolute bioavailability of rosiglitazone is 99%. Healthy adults take rosiglitazone tablets 4mg once, 1 hour, and the blood concentration reaches the highest. Cmax is about 3 19ng/ml (2mg of rosiglitazone tablets once, Cmax is 156 ng/ml) T 1/23-.
Indications This product is suitable for treating type 2 diabetes. Taking this product alone, supplemented by diet control and exercise, can control the blood sugar of patients with type 2 diabetes. This product can be used in combination with metformin or sulfonylurea drugs for patients with type 2 diabetes who have poor blood sugar control after taking this product or a single antidiabetic drug for diet control and exercise. For patients who take the maximum recommended dose of metformin or sulfonylurea drugs and have poor blood sugar control, this product cannot replace the original hypoglycemic agents and needs to be used in combination. Diet control is one of the treatment measures for type 2 diabetes. Limiting calories, losing weight and increasing exercise all help to improve the sensitivity of insulin, so it is not only the basic treatment of type 2 diabetes, but also can effectively maintain the curative effect of drugs. Before taking this product, you should first diagnose and treat diseases that affect blood sugar control, such as infection.
Usage and dosage: Take orally. Taking medicine has nothing to do with eating. Diabetes treatment should be individualized. Monotherapy: the initial dose can be 4mg per day, 1 time or twice per day. If the initial dose is not good, it can be gradually increased to 8mg per day. Combined medication with sulfonylureas: the initial dose can be 4mg per day, 1-2 times per day, and the dose of sulfonylureas should be reduced when hypoglycemia occurs. Combined medication with metformin: the initial dose can be 4mg per day, 1-2 times per day. 12 weeks later, if the fasting blood glucose control is not ideal, the dose is increased to 8mg per day. The maximum recommended dose is 8 mg per day, once or twice a day.
The adverse reaction was 1. Mild to moderate edema, the literature reported that the incidence of edema was 4.8% when single drug was used. ? 2. Anemia, the incidence rate is about 1%. This product may reduce hemoglobin and hematocrit, which may be related to the increase of plasma volume caused by rosiglitazone hydrochloride. ? 3. Hypoglycemia reaction, there is a risk of hypoglycemia when combined with other hypoglycemic drugs. ? 4. Abnormal liver function, all of which are mild to moderate transaminase increase, reversible. ? 5. Elevated blood lipids.
Taboo 1. Mild to moderate edema, the literature reported that the incidence of edema was 4.8% when single drug was used.
2. Anemia, the incidence rate is about 1%. This product may reduce hemoglobin and hematocrit, which may be related to the increase of plasma volume caused by rosiglitazone hydrochloride.
3. Hypoglycemia reaction, there is a risk of hypoglycemia when combined with other hypoglycemic drugs.
4. Abnormal liver function, all of which are mild to moderate transaminase increase, reversible.
5. Elevated blood lipids.
Precautions 1. This product is not suitable for 1 diabetic patients and diabetic ketoacidosis patients.
2. This product may lead to menopause, and women who stop ovulation will ovulate again, so pay attention to contraception during taking the medicine.
3. During taking this product, patients should adhere to diet control and exercise.
4. If the patient has some unexplained symptoms such as nausea, vomiting, abdominal pain, fatigue, loss of appetite and dark urine during taking the medicine, he should immediately inform the doctor.
When you have serious side effects (such as heart attack and congestive heart failure) when using rosiglitazone or rosiglitazone combined with insulin, you should contact your doctor.
6. People who are allergic to such drugs, as well as patients with severe liver injury and acute heart failure, are prohibited from taking such drugs.
The safety of medication for pregnant and lactating women has not been determined, and pregnant women and women who may be pregnant should weigh the advantages and disadvantages. Animal (rat) experiments show that this product can migrate into milk, and breastfeeding should be avoided during taking this product.
The safety of children's medication has not been determined.
Medication for elderly patients? When elderly patients take this product, there is no need to adjust the dose due to age.
Drug interaction? 1. Drugs metabolized by cytochrome P450: In vitro drug metabolism test showed that rosiglitazone did not inhibit the main P450 enzyme at clinical dose. In vitro experimental data confirmed that rosiglitazone was mainly metabolized by CYP2C8, and a small amount was metabolized by CYP2C9. ? 2. Nimodipine and oral contraceptives (ethinylestradiol and norethindrone) are mainly metabolized through CYP3A4 pathway, so the combination of nimodipine and this product (4 mg, twice a day) has no clinical significance for the pharmacokinetics of the above two drugs. ? 3. glibenclamide: For diabetic patients whose condition is stable after taking glibenclamide, this product (2mg/ time, twice a day) and glibenclamide (3.75mg/ day to 10mg/ day) are used together for 7 days, and their 24-hour average steady-state blood glucose level will not change. ? 4. Metformin: For healthy subjects, the combination of this product (2mg/ time, twice a day) and metformin (500mg/ time, twice a day) for 4 days will not change the steady-state pharmacokinetic parameters of this product and metformin. ? 5. Acarbose: Acarbose (100mg/ time, 3 times a day) was taken orally by healthy subjects for 7 days, and a single oral administration had no effect on the pharmacokinetic parameters of this product. ? 6. Digoxin: Healthy subjects taking this product (8mg/ time, daily 1 time) 14 days have no effect on the steady-state pharmacokinetic parameters of digoxin (0.375mg/ time, daily 1 time). ? 7. Warfarin: Continuous administration of this product has no effect on the steady-state pharmacokinetic parameters of warfarin enantiomers. ? 8. Ethanol: Patients with type 2 diabetes who take this product will not increase the risk of acute hypoglycemia if they drink a proper amount of ethanol once. ? 9. Ranitidine: Ranitidine (150mg/ time, twice a day) is taken by healthy subjects for 4 days, and the pharmacokinetic parameters of rosiglitazone will not be changed after a single oral or intravenous injection. The results showed that the increase of pH value in gastrointestinal tract did not affect the oral absorption of this product.
Overdose? According to the clinical research of volunteers, the single dose of this product does not exceed 20mg, and it is well tolerated. In the event of drug overdose, appropriate symptomatic support treatment can be given according to the patient's clinical complaint, which can generally be alleviated.
Storage and shading, sealed preservation.