Dopagliflozin Tablets

Pharmacological action: Dogliflozin is a glucokinase (GK) activator that can improve the catalytic efficiency of GK in glucose metabolism, increase the uptake of glucose by hepatocytes, and promote glucose-stimulated insulin release. Toxicological studies: The results of the Ames test, human peripheral blood lymphocyte chromosome aberration test, and rat in vivo bone micronucleus test for genetic toxicity of dogliflozin were all negative. Reproductive toxicity: Male rats were orally administered dogliflozin at 50, 120, and 240 mg/kg/day for 8 consecutive weeks from 4 weeks before mating to the mating period (mating with untreated female rats to 2 weeks after mating). Mild to severe shrinkage and degeneration of the seminiferous tubules, mild to moderate cell debris in the epididymis, and decreased sperm in the epididymis were observed in the testes at ≥120 mg/kg/day; reduced sperm count, sperm motility, fertility index, and mating success rate were observed at 240 mg/kg/day: the 240 mg/kg/day group mated In the successfully pregnant rats, a trend of decreased number of implantations and increased pre-implantation loss rate was observed. The no significant adverse effect level (NOAEL) for male fertility is 50 mg/kg/day (about 1.6 times the recommended adult dose of 75 mg twice daily in terms of AUG). Female rats were orally given dopagliflozin 25, 60 and 120 mg/kg/day from 2 weeks before mating, during mating (mating with untreated male rats) to the 7th day of pregnancy. 120 mg/kg/day showed an increased post-implantation loss rate and decreased fetal loss. The NOAEL for female fertility and early embryonic development is 60 mg/kg/day (about 3.9 times the recommended daily dose for adults, based on body surface area). Rats were orally given 30, 60 and 120 mg/kg/day of dogliflozin from day 6 to 17 of pregnancy. ≥ 60 mg/kg/day can lead to decreased fetal weight and length and increased bone variation, mainly manifested as increased incidence of incomplete ossification of the sternum and increased incidence of multiple ribs; 120 mg/kg/day can lead to It causes fetal skeletal and visceral malformations, mainly manifested as an increased rate of missing 5-6 sternal segments and an increased incidence of microphthalmia. The NOAEL for embryo-fetal development in rats is 30 mg/kg/day (based on AUC, about 1.2 times the recommended adult dose of 75 mg twice daily). Rabbits were given dogliflozin 20, 40 and 80 mg/kg/day orally from the 6th to the 18th day of pregnancy. ≥40 mg/kg/day can lead to increased maternal abortion rate or vaginal bleeding rate, reduced weight gain, and uterine and placental weight; may lead to an increase in the rate of post-implantation embryo loss and a decrease in the number of live fetuses; may lead to an increase in the incidence of fetal skeletal variation and/or morphology. Skeletal variation is mainly manifested as incomplete vertebral ossification, and skeletal deformity is mainly manifested as fusion of vertebrae, rib loss, rib bifurcation and thoracic vertebral separation. The NOAEL for rabbit embryo-fetal development is 20 mg/kg/day (based on AUC, approximately 0.6 times the recommended adult dose of 75 mg per day). In the perinatal developmental toxicity test in rats, rats Oral administration of dogliflozin at 10, 25, and 50 mg/kg/day from the 6th day of pregnancy to the 20th day of lactation did not affect the reproductive function and lactation behavior of F0 generation mothers, the weight and weight gain of F1 generation mice, the functional development before weaning (flat and aerial righting, hearing and dark hole reflex), the functional development after weaning (spontaneous activity and learning and memory), sexual maturity, and fertility. No effect was observed on the viability, weight, and weight gain of the F2 generation. The NOAEL for prenatal/postnatal development and reproductive capacity is 50 mg/kg/day (about 3.2 times the recommended daily dose for adults based on body surface area). Dolagliptin can be secreted through rat milk. Carcinogenic rasH2-Tg. mice were given dolagliptin at 10, 25 and 50 mg/kg/day orally for 26 consecutive weeks, and no evidence of carcinogenicity related to dolagliptin was found. Based on AUC. The exposure of 50 mg/kg/day is about 2 times the recommended adult dose of 75 mg twice daily. .1 times. Wistar Han rats were orally administered dogliptin for 104 consecutive weeks, with female doses of 10, 25, and 50 mg/kg/day and male doses of 25, 50, and 100 mg/kg/day. No evidence of carcinogenicity related to dogliptin was found. Pharmacologically related hypoglycemia and secondary sciatic nerve degeneration were observed at all doses. Based on AUC, the burst doses of male and female high doses were approximately 3.7 times and 2.1 times the exposure of adults at the recommended dose of 75 mg twice daily, respectively.

Active ingredient: Dogliflozin Chemical name: (2S)-2-[4-(2-chloro-phenoxy)2-oxo-2,5-dihydro-1H-pyrrol 1-yl)-N-{1-([(2R)--2,3-dihydroxypropyl]-1H-pyrazol-3-yl)-4-methylpentanamide Molecular weight: 462.93 Excipients: methacrylic acid-methyl methacrylate copolymer, microcrystalline cellulose colloidal silicon dioxide co-processed product, hydroxypropyl cellulose, cross-linked carboxymethyl cellulose sodium, magnesium stearate, film coating premix.

This product is a light green to green, biconvex round film-coated tablet with "H" engraved on one side and "75" engraved on the other side. It appears white or off-white after removing the coating.

This product is suitable for improving blood sugar control in adult patients with type 2 diabetes. Single drug: This product can be used alone in combination with diet control and exercise to improve blood sugar control in adult patients with type 2 diabetes. Used in combination with metformin hydrochloride: When blood sugar control is poor with metformin hydrochloride alone, this product can be used in combination with metformin hydrochloride to improve blood sugar control in adult patients with type 2 diabetes in combination with diet and exercise. Limitation of use: This product is not suitable for the treatment of type 1 diabetes, diabetic ketoacidosis or hyperglycemia and hyperosmosis.

Recommended dose: The recommended dose of this product is 75 mg, twice a day, taken at any time within 1 hour before breakfast and dinner. Pay attention to the medication time during treatment. If you miss a dose, you do not need to make up for it. Special population medication: Patients with renal insufficiency, no dose adjustment is required for patients with renal insufficiency. Patients with liver damage, no dose adjustment is required for patients with mild liver damage (Child-Pugh A grade). The exposure of this product is increased in patients with moderate liver damage (Child-Pugh B grade), and clinical studies have not been conducted in patients with severe liver damage (Child-Pugh C grade). This product is not recommended for patients with moderate and severe liver damage (Child-Pugh B and C grades, such as: moderate and above cirrhosis) (see Pharmacokinetics). CYP3A4 inducers: This product should be used with caution in combination with CYP3A4 inducers (such as phenytoin, rifampicin and carbamazepine). CYP3A4 Inhibitors Caution should be exercised when this product is used in combination with strong or moderate CYP3A4 inhibitors (e.g., ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and grapefruit juice).

Experience from clinical trials Due to differences in the implementation conditions of clinical trials, the incidence of adverse drug reactions in different clinical trials cannot be directly compared, and may not reflect the incidence of adverse reactions in clinical practice. This product has completed 16 clinical trials, and a total of 1,656 subjects have taken this product at least once. The following safety data are derived from a pooled analysis of 1 Phase II and 2 Phase II clinical trials. The data of 75 mg of this product in Huishang's 3 Anganzhiduijie studies are summarized from a 12-week placebo-controlled trial and 2 clinical trials including a 24-week placebo-controlled double-blind treatment period and a 28-week open treatment period, with a total treatment time of 52 cycles, including monotherapy with this product and combined therapy with metformin, reflecting the use of 75 mg of this product twice a day by 1,206 type 2 diabetes subjects, with a total exposure of 880.35 person-years, including 743 people treated with this product during the placebo control period, and 590 people in the placebo group. The average age of the people using this product was 54.0 years old, with an age range of 19.0 to 74.0 years old. 11.5% of the subjects were over 65 years old, 63.0% were male, and 96.6% were Han nationality. The average duration of type 2 diabetes at baseline was 48.7 months, and the average HbA1c was 8.13%. The medical history was consistent with the typical characteristics of type 2 diabetes patients, that is, they were often accompanied by hypertension (39.9%), hyperlipidemia (37.8%), hepatic steatosis (30.8%), etc. In the dogliflozin group, 3 subjects (0.4%) had adverse reactions related to this product, including: increased aspartate aminotransferase, abnormal electrocardiogram T wave, decreased white blood cell count, increased blood uric acid, low HDL cholesterol, hyperuricemia, hyperlipidemia, and upper respiratory tract infection; 2 subjects (0.3%) had adverse reactions related to this product, including: increased blood triglycerides, increased blood creatine phosphokinase MB, hypercholesterolemia, constipation, myocardial ischemia, and anemia; 1 subject (0.4 ... 1%) Adverse reactions related to this product in subjects include: myocardial fast blood electrocardiogram, decreased platelet count, increased blood alkaline phosphatase, hypokalemia, fat metabolism disease, ketosis, duodenal ulcer, vomiting, indigestion, toothache, gastrointestinal motility disorder, gastroesophageal reflux disease, abdominal distension, hepatic fatty degeneration, bronchitis, first-degree atrioventricular block, coronary artery disease, back pain, flank pain, eyelid edema, eyelid edema, facial edema, drowsiness, erectile dysfunction, rash, and insomnia. Hypoglycemia In the clinical studies completed by this product, no severe hypoglycemia events were reported. This product 75mg monotherapy: The incidence of hypoglycemia events at blood glucose level 3.0mmol/L in the placebo group and the this product group was 0 and 0.6% (2 cases), respectively. This product is combined with metformin for treatment, and the blood glucose in the placebo group and the this product group was The incidence of hypoglycemia events with a level of 3.0mmol/L was 0% and 0.8% (3 cases), respectively. Experimental enrichment: Increased blood triglycerides: In the pooled analysis of placebo-controlled trials, the mean change from baseline in blood triglycerides in the placebo group at week 24 was -0.004mmol/L. At weeks 24 and 52 of this product, the mean changes from baseline in blood triglycerides were 0.415mmot/L and 0.365mmol/L, respectively. Increased liver enzymes: In the pooled analysis of placebo-controlled trials, the mean change from baseline in alanine aminotransferase in the placebo group at week 24 was -0.08U/L. At weeks 24 and 52 of this product, the mean changes from baseline in alanine aminotransferase were 3.94U/L and 3.69U/L, respectively. Both means were in the positive range. Normal range. The mean change of aspartate aminotransferase relative to baseline in the placebo group at week 24 was -0.12U/L. The mean changes of aspartate aminotransferase relative to baseline at week 24 and week 52 of this product were 4.22U/L and 3.68U/L, respectively. The means were within the normal range. Uric acid elevation In the pooled analysis of placebo-controlled trials, the mean change of serum uric acid relative to baseline at week 24 in the placebo group was -3.59umol/L (percentage change was -1.1%). The mean changes of serum uric acid relative to baseline at week 24 and week 52 of this product were 25.53μmol/L (percentage change was 8.3%) and 22.18umolL (percentage change was 7.2%), respectively. The means were within the normal range.

Do not use if you are allergic to any ingredient in this product.

Precautions for children: The safety and effectiveness of this product in children and adolescent patients under 18 years of age have not been determined. Precautions for pregnancy and lactation: Pregnancy: This product has not yet been clinically studied in pregnant women, and the safety of use in pregnant women is unknown. It is not recommended for pregnant women to use this product. Lactating women: It is not clear whether this product is secreted into human milk, and it is not recommended to use this product during lactation. Precautions for the elderly: No dose adjustment is required for elderly patients. In 1 Phase II and 2 Phase I clinical trials, a total of 1,206 subjects received dopagliflozin 75 mg twice daily. Among them, 139 subjects (11.5%) were over 65 years old. No overall safety or effectiveness differences were found between elderly subjects (65 years old) and younger subjects (≤65 years old). Although no differences between elderly and younger subjects were found in clinical studies, the possibility that some elderly individuals may be more sensitive cannot be ruled out.

In vitro drug interactions The metabolism of dopagliflozin in humans is primarily mediated by CYP3A4. In in vitro studies, dopagliflozin did not inhibit CYP1A2, 2A6, 2C9, 2C19, 2D6, 2E1, or 3A4/5, nor did it induce CYP1A2, 2B6, 2C9, or 3A4 to any clinically significant degree. Dolagliptin is a substrate of P-glycoprotein (P-gp.) and has no clinically significant inhibitory effect on P-gp, OAT1, OAT3, OATP1B1 or OATP1B3 transporters. In vivo drug interactions CYP3A4 enzyme inducers The strong CYP3A4 inducer rifampicin significantly reduces the exposure of dolagliptin. Co-administration with a moderate CYP3A4 inducer (efavirenz) can reduce the area under the plasma concentration-time curve (AUC) and peak plasma concentration (Cmax) of this product by 51% and 23%, respectively. Therefore, this product is not compatible with CYP3A4 inducers. (such as phenytoin, rifampicin and carbamazepine) should be used with caution. CYP3A4 enzyme inhibitors The strong CYP3A4 inhibitor itraconazole significantly increases the exposure of dolagliptin. Co-administration with moderate CYP3A4 inhibitors (verapamil, fluconazole and erythromycin) can increase the AUC and Cmar of this product to 2.4 and 1.2 times, respectively. Therefore, this product should be used with caution when used in combination with strong or moderate CYP3A4 inhibitors (such as ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, teligliptin and grapefruit juice). Diabetes treatment drugs When this product is used in combination with metformin, sitagliptin and empagliflozin, its pharmacokinetic parameters are not significantly affected, and the pharmacokinetic parameters of the combined drugs do not produce clinically significant changes. Therefore, when this product is used in combination with the above drugs, dose adjustment is not recommended. When proton pump inhibitors are used in combination with esomeprazole, the pharmacokinetic parameters of this product are not significantly affected. Therefore, it is not recommended to adjust the dose of this product when it is used in combination with this drug.

Keep in a dark place and sealed at a temperature not exceeding 25℃.

75 mg x 14 tablets x 2 plates

24 months

Changzhou SynTheAll Pharmaceutical Co., Ltd.

• Founded in:

  2013-09-29

• Address:

  No. 589, Yulong North Road, Xinbei District, Changzhou

• Tax NO.:

  91320000078269798E

• Registered Funds:

  4,049.9 million yuan

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