Date of approval.
Date of revision.
Nateglinide Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician.
Drug Name]
Generic name: Nateglinide Tablets
English name: Nateglinide Tablets
Hanyu Pinyin: Nagelienai Pian
Ingredients
The main ingredient of this product is nateglinide, whose chemical name is: (-)-N-[(trans-4-isopropylcyclohexyl)carbonyl]-D-phenylalanine.
Its chemical structure formula is
Molecular formula: C19H27NO3
Molecular weight: 317.43
Properties
This product is a yellow film-coated tablet, which appears white or off-white after removing the coating.
Indications
This product can be used alone for patients with type 2 diabetes who cannot effectively control high blood sugar by diet and exercise. It can also be used for type 2 diabetic patients whose hyperglycemia cannot be effectively controlled with metformin, using a combination with metformin, but not as a substitute for metformin.
Naglinide is not suitable for patients with type 2 diabetes who are not well treated with sulfonylurea hypoglycemic agents.
Specification
120mg
Dosage]
The usual dose is 120 mg before meals, either alone or in combination with metformin, and the dose should be adjusted according to the results of regular HbA1c tests (the maximum recommended dose is 180 mg three times daily). Because the main therapeutic effect of nateglinide is to lower blood glucose at meals (which is an important component of HbA1c), the therapeutic effect of nateglinide can also be monitored by blood glucose 1 to 2 hours after meals. Naglinide is usually taken before the main meal, i.e. breakfast, lunch and dinner. For patients with HbA1c levels close to the therapeutic target at the beginning of treatment (i.e., HbA1c<7.5%), nateglinide may be used alone or in combination with metformin, with 60 mg of nateglinide before meals, and the dose adjusted according to the effect of treatment.
Dosage for patients with liver impairment
No adjustment of drug dose is required in patients with mild to moderate hepatic impairment. No studies have been conducted in patients with severe hepatic impairment; therefore, nateglinide should not be used in patients with severe hepatic impairment.
Dosage in Patients with Renal Impairment
No dose adjustment is required in patients with mild to moderate renal impairment. Despite a 49% reduction in Cmax in dialysis patients, the bioavailability and half-life of nateglinide in diabetic patients with moderate to severe renal insufficiency (creatinine clearance 15-50 ml/min) and in patients requiring dialysis are comparable to those in healthy subjects. However, for safety reasons, the dose should be adjusted in case of low Cmax.
Adverse reactions]
As reported in foreign literature.
Adverse drug reactions (Table 1) are listed according to MedDRA system organ classification. In each system organ category, adverse drug reactions were ranked by frequency of occurrence, with the most frequently occurring adverse reactions listed first. Within each frequency grouping, adverse reactions to drugs are presented in descending order of severity. In addition, the following convention (CIOMS III) was also used to present the adverse reactions for each drug in the corresponding occurrence frequency categories: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000); very Rare (<1/10,000).
As with other antidiabetic drugs, symptoms of hypoglycemia can be observed after taking nateglinide. These symptoms include sweating, shaking, dizziness, increased appetite, palpitations, nausea, fatigue, and weakness. These symptoms are generally mild and manageable, and carbohydrates may be consumed if needed. Clinical studies have reported symptoms of hypoglycemia and a confirmed decrease in blood glucose (blood glucose <3.3 mmol/L) in 2.4% of patients.
Table 1: Adverse drug reactions
Metabolic and nutritional system Common hypoglycemia (including palpitations, nausea, weakness, fatigue, increased appetite, dizziness, tremor, excessive sweating) Abnormal tests Rare elevation of liver enzymes (which are mild and transient and rarely lead to discontinuation) Immune system Rare drug allergy (including rash, pruritus, urticaria) Other adverse reactions
Other adverse events identified in clinical trials, including gastrointestinal reactions (abdominal pain, dyspepsia, diarrhea), headache, and some clinical symptoms that may be associated with diabetes (e.g., respiratory tract infections) occurred at similar rates in the nateglinide treatment group as in the placebo treatment group.
Contraindications]
Naglinide is contraindicated in patients who
Hypersensitivity to the active ingredient or any excipient of the drug
Type 1 diabetes mellitus
Diabetic ketoacidosis
Pregnancy and lactation (see: [Pregnant and lactating women’s medication])
Use with caution in patients with severe infection, before or after surgery, or in patients with severe trauma.
Precautions]
This product can cause hypoglycemia, the frequency of which is related to the severity of diabetes, the level of blood glucose control, and other related conditions of the patient. Elderly patients, malnourished patients, patients with adrenal or pituitary insufficiency or severe kidney injury are more sensitive to hypoglycemic drugs and are prone to hypoglycemia. The risk of hypoglycemia increases with strenuous exercise, alcohol consumption, diarrhea and vomiting, reduced food intake, or the combination of other anti-diabetic drugs. Hypoglycemia may be difficult to detect in patients with autonomic neuropathy or in combination with ß-blockers. Naglinide must be taken orally before meals to reduce the risk of hypoglycemia. Patients should not take nateglinide when they are not going to eat. Naglinide is not recommended for use in patients with severe hepatic impairment.
Uncontrolled blood glucose may occur when patients stably treated with this product are exposed to stressful conditions, such as fever, trauma, infection, or surgery. In this case, the use of this product should be stopped and insulin replacement should be temporarily used.
This product has the effect of rapidly promoting insulin secretion. This point of action is the same as that of sulfonylurea preparations. However, the clinical effects and safety of the addition and multiplication of this product with sulfonylurea preparations have not been confirmed, so it should not be used with sulfonylurea preparations.
Effects on the ability to drive and operate machinery
Patients should be reminded to take precautions to avoid hypoglycemia when driving or operating machinery.
[For pregnant and lactating women].
Women of childbearing age.
Women of childbearing age should use very effective contraception during treatment with this product.
Pregnancy.
Naglinide is not teratogenic in rats. Studies in rabbits have shown toxicity to embryonic development at high doses (see [Pharmacologic Toxicology]). There is insufficient experience with this drug in pregnant women; therefore, the safety of this product in human pregnancy cannot be estimated. This product should not be used during pregnancy.
The effects of nateglinide on human labor are not known.
Lactation.
Naglinide is excreted from the milk of rats after oral administration. Studies in rats have shown that high doses reduce the body weight of rat pups after birth (see [Pharmacology and Toxicology]). Although it is not known whether nateglinide is excreted in human milk, the possibility of hypoglycemia in breastfed infants exists. Therefore, nateglinide should not be used in nursing women.
Reproduction.
Naglinide does not impair reproduction in male or female rats (see [Pharmacology and Toxicology]).
Pediatric Use]
The safety and efficacy of nateglinide have not been evaluated for use in pediatric patients. Therefore, nateglinide is not recommended for use in children.
Geriatric Use]
No differences in safety and efficacy have been observed between elderly patients and the general population. In addition, age does not affect the pharmacokinetic profile of nateglinide. Therefore, no dose adjustment is required for elderly patients.
Drug Interactions]
According to foreign literature.
Effects of nateglinide on other drugs.
Data from in vivo and in vitro studies indicate that nateglinide is metabolized primarily by the cytochrome P450 enzyme CYP2C9 (70%) and partially by CYP3A4 (30%). Nateglinide inhibits the metabolism of methanesulfonylurea, a substrate of CYP2C9, in vitro. In vitro experiments showed that the drug did not inhibit the metabolic response to CYP3A4. These findings suggest that the potential for clinically meaningful pharmacokinetic interactions with other drugs is low.
Naglinide has no effect on the pharmacokinetic profile of warfarin (substrate of CYP3A4 and CYP2C9), diclofenac (substrate of CYP2C9), troglitazone (CYP3A4 inducer), and digoxin. Therefore, no dose adjustment is required for the combination of nateglinide, digoxin, warfarin or diclofenac. Similarly, there are no clinically significant pharmacokinetic interactions between nateglinide and other oral antidiabetic agents, such as metformin or glibenclamide.
Effects of other drugs on nateglinide.
A modest increase in the AUC of nateglinide (28%) was observed in healthy subjects when coadministered with benztropine (a potent selective CYP2C9 inhibitor), while the mean Cmax and elimination half-life were unchanged. When nateglinide is co-administered with potent CYP2C9 inhibitors (e.g. fluconazole, gemfibezil, sulfopiridone), or when the patient is known to be a slow metabolizer of CYP2C9 substrates, the risk of prolonged drug duration of action and hypoglycemia cannot be excluded.
The binding of nateglinide to serum proteins is high (98%), mainly to albumin. In vitro replacement experiments with drugs with high protein binding found that they had no effect on the protein binding of nateglinide. These drugs were tachykinuria, takayasu, captopril, nicardipine, pravastatin, glibenclamide, warfarin, phenytoin sodium, acetylsalicylic acid, methylsulfonylurea, and metformin. Similarly, nateglinide has no effect on the serum protein binding of psilocybin, gliphenylurea, nicardipine, warfarin, phenytoin sodium, acetylsalicylic acid, and methylsulfonylurea.
Physicians should consider the interaction of a number of drugs with nateglinide that have an effect on glucose metabolism.
The hypoglycemic effect of oral antidiabetic agents can be enhanced by certain drugs, including NSAIDs, salicylates, monoamine oxidase inhibitors, non-selective b-adrenergic blockers, anabolic hormones (e.g., methandrostenolone), guanethidine, Musa vine extract, glucomannan, and lipoic acid.
Patients receiving nateglinide therapy should be closely monitored for changes in blood glucose when adding or stopping the above drugs.
The hypoglycemic effect of oral antidiabetic agents can be diminished by certain drugs, including thiazides, cortisone, thyroid agents, sympathomimetics, growth hormones, growth inhibitor analogs (e.g., lanreotide, octreotide), rifampin, phenytoin, and St. John’s wort.
Patients receiving nateglinide therapy should be closely monitored for changes in blood glucose when adding or stopping the above drugs.
[Drug overdose].
As reported in foreign literature.
Clinical studies have shown that patients can still tolerate a gradual increase in the dose of nateglinide to 720 mg daily for 7 days. There is no experience with clinical trials of nateglinide overdose. However, overdose may enhance the hypoglycemic effect and result in hypoglycemic symptoms. Hypoglycemic symptoms that are not associated with loss of consciousness or neurological symptoms can be treated with oral glucose, drug dose adjustment, or/and food. Hypoglycemic reactions with coma, seizures, or other neurological symptoms are treated with intravenous glucose. Because of the high protein binding rate of nateglinide, dialysis is not an effective way to remove it from the blood.
Pharmacology and Toxicology
Naglinide is an amino acid derivative, an oral antidiabetic drug used for the treatment of type 2 diabetics. The action of nateglinide depends on the function of pancreatic islet b-cells. By binding to and closing the ATP-sensitive K+ channel receptors on the b-cell membrane, nateglinide depolarizes the cell, opens the calcium channels, and stimulates the secretion of insulin and lowers blood glucose. The insulinotropic effect of nateglinide is dependent on glucose levels, and at lower glucose levels, insulinotropic secretion is diminished. Naglinide is highly tissue selective and has low affinity for cardiac and skeletal muscle.
Toxicological studies
Genotoxicity
Ames test, mouse lymphoma test, Chinese hamster lung cell chromosome aberration test, and mouse in vivo micronucleus test did not show any mutagenic effect of this product.
Reproductive toxicity: No effect on fertility in rats at doses up to 600 mg/kg/d. No teratogenic effect was observed in rats at doses up to 1000mg/kg/d. There were adverse effects on embryonic development in rabbits given at a dose of 500mg/kg/d. In rabbits given at 300 and 500 mg/kg/d (approximately 24 and 28 times the maximum recommended human therapeutic dose of 180 mg three times daily before meals), the incidence of gallbladder hypoplasia or microcystosis was increased; no such effect was observed at 150 mg/kg/d (approximately the maximum recommended human therapeutic dose of 180 mg three times daily and 17 times the maximum recommended human therapeutic dose of 180 mg three times daily before meals). (17 times the maximum recommended human therapeutic dose of 180 mg three times daily, administered before meals). The administration of 1000 mg/kg/d to rats had no effect on delivery. In rats administered at 1000 mg/kg/d, postnatal body weight was reduced (approximately 40 times the maximum recommended human therapeutic dose of 180 mg three times daily before meals) (see [Use in Pregnant and Lactating Women]).
Carcinogenicity: No evidence of carcinogenicity was observed with nateglinide in mice administered at a dose of approximately 400 mg/kg/d or in rats administered at a dose of approximately 900 mg/kg/d for 104 weeks.
Pharmacokinetics]
According to foreign literature, it is reported that
Absorption
After taking nateglinide tablets with a meal, nateglinide is rapidly absorbed, and the mean peak drug concentration usually occurs within 1 hour of dosing. When taken orally as a solution, nateglinide is almost completely and rapidly absorbed (≥90%). The absolute bioavailability of oral dosing is approximately 72%. After administration of nateglinide 60-240 mg daily before three meals for a total of 1 week, nateglinide showed a linear pharmacokinetic profile with both AUC and Cmax in patients with type 2 diabetes. And Tmax was not dependent on drug dose.
Distribution
The estimated steady-state volume of distribution of nateglinide based on intravenous dosing data is approximately 10 liters. In vitro studies have shown that the majority of nateglinide (97-99%) is bound to plasma proteins, primarily plasma albumin and a small amount of alpha 1 acidic glycoprotein. The ability of nateglinide to bind plasma proteins is independent of the drug concentration in the test range of 0.1 to 10 μg/ml.
Metabolism
Naglinide is primarily metabolized by a mixed-function oxidase system prior to clearance. In humans the major metabolite is derived from hydroxylation of the isopropyl side chain, which occurs either at the hypomethyl carbon atom or at a methyl group and is 5-6 and 3 times less active than nateglinide, respectively. Less frequent metabolites are the diols, isopropyl alcohols and acyl glucuronides of nateglinide. Only a small amount of the isopropanol metabolite of nateglinide was active, with an intensity comparable to that of nateglinide. Data from current in vivo and in vitro experiments indicate that nateglinide is metabolized primarily by CYP2C9 (70%) and partially by CYP3A4 (30%).
Clearance
Clearance of nateglinide and its metabolites is rapid and complete. Approximately 75% of [14C]nateglinide is recovered in the urine within 6 hours of dosing. The majority (83%) of [14C]nateglinide is excreted in the urine and another 10% is excreted in the feces. Approximately 6-16% of the drug taken is excreted in the urine in its original form. In healthy volunteers and patients with type 2 diabetes, plasma concentrations of nateglinide decrease rapidly and the mean clearance half-life of nateglinide is 1.5 hours. Consistent with the short clearance half-life, there was no significant accumulation of nateglinide when the dose was doubled to 240 mg three times daily.
Food Effects
The degree of absorption (AUC) of nateglinide was not affected by the administration of nateglinide after a meal. However, the rate of absorption is reduced, as evidenced by a decrease in peak concentration (Cmax) and a delay in plasma time to peak (Tmax). Therefore, it is recommended to take nateglinide before meals. It is usually taken 1 minute before a meal, but can also be taken within 30 minutes before a meal.
Gender
No clinically meaningful differences in the pharmacokinetics of nateglinide were found between men and women.
Special Populations
Geriatric patients
Age does not affect the pharmacokinetic properties of this product (see [DOSAGE AND ADMINISTRATION]).
Renal impairment
In diabetic patients with mild to moderate (creatinine clearance 31-50 ml/min) and non-dialysis severe (creatinine clearance 15-30 ml/min) renal impairment, the bioavailability and half-life of nateglinide did not differ in a clinically significant manner from healthy subjects. The peak drug concentration (Cmax) of nateglinide was reduced by 49% in hemodialysis patients, and the bioavailability and half-life were comparable to those of healthy subjects. However, for dosing safety reasons, dose adjustment should be made if low Cmax occurs. Repeated dosing of 90 mg daily for 1 to 3 months in diabetic patients with end-stage renal disease (ESRD) resulted in significant M1 metabolite accumulation of 1.2 ng/mL despite dose reductions.M1 concentrations were significantly reduced by hemodialysis. Although M1 metabolites exhibited only a slight hypoglycemic effect (approximately 5-fold lower than that of nateglinide), metabolite accumulation had the potential to increase the hypoglycemic effect of the prescribed dose.
Hepatic Impairment
In non-diabetic subjects with mild to moderate hepatic impairment, the bioavailability and half-life of nateglinide were not clinically significantly different from those of healthy subjects.
Storage]
Store in a dry place, protected from light and sealed.
Store out of the reach of children.
Packaging
1. Polyvinyl chloride/polyethylene/polyvinylidene chloride solid pharmaceutical compound hard tablets/pharmaceutical aluminum foil: 10 tablets/plate/box, 10 tablets/plate x 3 plates/box.
2. HDPE bottle for oral solid medicine: 30 tablets/bottle/box, 60 tablets/bottle/box, 90 tablets/bottle/box.
【Validity period】.
24 months.
Execution standard
Approval number】
State Drug Certificate H20123016
【Manufacturer】
Company Name: Jiangsu Deyuan Pharmaceutical Co.
Production Address: No. 29 Changjiang Road, Lianyungang Economic and Technological Development Zone
Postal Code: 222047
Telephone number: 0518-82340786
Fax number: 0518-82340788
Web address: http://www.pharmdy.com