| 简介：
部份中文那格列奈处方资料（仅供参考）
英文名称：Nateglinide
商标名称：STARLIX
通用名称：那格列奈片
药品简介
批准日期：200年4月12日 公司：Novartis Pharmaceuticals Corporation
STARLIX（那格列奈 nateglinide）片剂，供口服使用
初始美国批准：2000
作用机制
那格列奈通过刺激胰岛中胰岛β细胞的胰岛素分泌来降低血糖水平，那格列奈与胰腺β细胞上的ATP敏感性钾（K + ATP）通道相互作用。 胰岛素释放的程度依赖于葡萄糖，在低葡萄糖水平下降低。那格列奈具有高度组织选择性，对心脏和骨骼肌的亲和力低。
适应症和用法
STARLIX（那格列奈）是表示作为辅助饮食和锻炼，以改善与2型糖尿病的成年人的血糖控制列奈类。
使用限制：不适用于治疗1型糖尿病或糖尿病酮症酸中毒
用法和管理
推荐剂量是每日三次120毫克
在开始治疗时接近血糖目标的患者中，可以施用60mg每日三次。
饭前1至30分钟
如果跳过膳食，跳过预定剂量以降低低血糖风险。
剂型和强度
片剂：60毫克和120毫克
禁忌症
那格列奈或其非活性成分过敏史
警告和注意事项
低血糖：... STARLIX可能导致低血糖辖饭前，以减少低血糖的风险跳过STARLIX的一个计划剂量，如果一餐被跳过，以减少低血糖的风险（5.1）
大血管结果：目前还没有临床研究建立STARLIX降低大血管病变风险的确凿证据。
不良反应
与STARLIX（3％或更高的发病率）有关的常见不良反应为上呼吸道感染，背痛，感冒等症状，头晕，关节病，腹泻（6.1）
要报告疑似不良反应，请联系诺华1-888-669-6682或FDA电话：1-800-FDA-1088或www.fda.gov/medwatch。
药物相互作用
药物可能增加了潜在的低血糖：施用共当STARLIX剂量减少和增加的血糖监测频率，可能需要
药物可能增加的可能性高血糖：施用共当STARLIX剂量的增加和增加的的葡萄糖监测频率，可能需要
这可能钝体征和低血糖的症状的药物：的血糖监测频率增加时给予合作，可能需要
在特定人群中使用
护理母亲：停止STARLIX或护理
如何提供/储存和处理
如何提供
60毫克
带有“STARLIX”的粉红色圆形斜面薄膜包衣平板，一侧凹陷，另一侧凹陷“60”。
100瓶....................................................... NDC 0078-0351-05
120毫克
带有“STARLIX”的黄色，椭圆形薄膜包衣片剂在一侧凹陷并且在另一侧“120”。
100瓶....................................................... NDC 0078-0352-05
存储和处理
在25°C（77°F）下储存;允许在15°C - 30°C（59°F - 86°F）的温度下漂移。
完整说明书附件：https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5cbda9bc-3c0d-4d75-a37a-994844680c8c
1. DESCRIPTION
Nateglinide is an oral antidiabetic agent used in the management of Type 2 diabetes mellitus [also known as non-insulin dependent diabetes mellitus (NIDDM) or adult-onset diabetes]. Nateglinide, (-)-N-[(trans-4-isopropylcyclohexane)carbonyl]-D-phenylalanine, is structurally unrelated to the oral sulfonylurea insulin secretagogues. The structural formula is as shown:
Nateglinide is a white powder with a molecular weight of 317.43. It is freely soluble in methanol, ethanol, and chloroform, soluble in ether, sparingly soluble in acetonitrile and octanol, and practically insoluble in water. Nateglinide biconvex tablets contain 60 mg, or 120 mg, of nateglinide for oral administration.
Inactive Ingredients: colloidal silicon dioxide, croscarmellose sodium, hydroxypropyl methylcellulose, iron oxides (red or yellow), lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, talc, and titanium dioxide.
2. INDICATIONS AND USAGE
Nateglinide is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
3. DOSAGE AND ADMINISTRATION
Nateglinide should be taken 1 to 30 minutes prior to meals.
Monotherapy and Combination with Metformin or a Thiazolidinedione
The recommended starting and maintenance dose of nateglinide, alone or in combination with metformin or a thiazolidinedione, is 120 mg three times daily before meals.
The 60-mg dose of nateglinide, either alone or in combination with metformin or a thiazolidinedione, may be used in patients who are near goal HbA1C when treatment is initiated.
Dosage in Geriatric Patients
No special dose adjustments are usually necessary. However, greater sensitivity of some individuals to nateglinide therapy cannot be ruled out.
Dosage in Renal and Hepatic Impairment
No dosage adjustment is necessary in patients with mild-to-severe renal insufficiency or in patients with mild hepatic insufficiency. Dosing of patients with moderate-to-severe hepatic dysfunction has not been studied. Therefore, nateglinide should be used with caution in patients with moderate-to-severe liver disease (see PRECAUTIONS, Hepatic Impairment).
4. CONTRAINDICATIONS
Nateglinide is contraindicated in patients with:
1. Known hypersensitivity to the drug or its inactive ingredients.
2. Type 1 diabetes.
3. Diabetic ketoacidosis. This condition should be treated with insulin.
5. MECHANISM OF ACTION
Nateglinide is an amino-acid derivative that lowers blood glucose levels by stimulating insulin secretion from the pancreas. This action is dependent upon functioning beta-cells in the pancreatic islets. Nateglinide interacts with the ATP-sensitive potassium (K+ATP) channel on pancreatic beta-cells. The subsequent depolarization of the beta cell opens the calcium channel, producing calcium influx and insulin secretion. The extent of insulin release is glucose dependent and diminishes at low glucose levels. Nateglinide is highly tissue selective with low affinity for heart and skeletal muscle.
6. USE IN SPECIFIC POPULATIONS
6.1 Usage in Pregnancy
Pregnancy Category C
There are no adequate and well-controlled studies in pregnant women. Nateglinide should not be used during pregnancy.
6.2 Labor and Delivery
The effect of nateglinide on labor and delivery in humans is not known.
6.3 Nursing Mothers
It is not known whether nateglinide is excreted in human milk. Because many drugs are excreted in human milk, nateglinide should not be administered to a nursing woman.
6.4 Pediatric Use
The safety and effectiveness of nateglinide in pediatric patients have not been established.
6.5 Geriatric Use
No overall differences in efficacy or safety were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
7. WARNINGS AND PRECAUTIONS
PRECAUTIONS
Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with nateglinide or any other antidiabetic drug.
Hypoglycemia: All oral blood glucose lowering drugs that are absorbed systemically are capable of producing hypoglycemia. The frequency of hypoglycemia is related to the severity of the diabetes, the level of glycemic control, and other patient characteristics. Geriatric patients, malnourished patients, and those with adrenal or pituitary insufficiency or severe renal impairment are more susceptible to the glucose lowering effect of these treatments. The risk of hypoglycemia may be increased by strenuous physical exercise, ingestion of alcohol, insufficient caloric intake on an acute or chronic basis, or combinations with other oral antidiabetic agents. Hypoglycemia may be difficult to recognize in patients with autonomic neuropathy and/or those who use beta-blockers. Nateglinide should be administered prior to meals to reduce the risk of hypoglycemia. Patients who skip meals should also skip their scheduled dose of nateglinide to reduce the risk of hypoglycemia.
Hepatic Impairment: Nateglinide should be used with caution in patients with moderate-tosevere liver disease because such patients have not been studied.
Loss of Glycemic Control
Transient loss of glycemic control may occur with fever, infection, trauma, or surgery. Insulin therapy may be needed instead of nateglinide therapy at such times. Secondary failure, or reduced effectiveness of nateglinide over a period of time, may occur.
8. ADVERSE REACTIONS
Hypoglycemia was relatively uncommon in all treatment arms of the clinical trials. Only 0.3% of nateglinide patients discontinued due to hypoglycemia. Gastrointestinal symptoms, especially diarrhea and nausea, were no more common in patients using the combination of nateglinide and metformin than in patients receiving metformin alone. Likewise, peripheral edema was no more common in patients using the combination of nateglinide and rosiglitazone than in patients receiving rosiglitazone alone. The following table 1 lists events that occurred more frequently in nateglinide patients than placebo patients in controlled clinical trials.
Table 1. Common Adverse Events (≥2% in Starlix® patients) in Starlix® Monotherapy Trials (% of patients)
During post-marketing experience, rare cases of hypersensitivity reactions such as rash, itching and urticaria have been reported. Similarly, cases of jaundice, cholestatic hepatitis and elevated liver enzymes have been reported.
Laboratory Abnormalities
Uric Acid: There were increases in mean uric acid levels for patients treated with nateglinide alone, nateglinide in combination with metformin, metformin alone, and glyburide alone. The respective differences from placebo were 0.29 mg/dL, 0.45 mg/dL, 0.28 mg/dL, and 0.19 mg/dL. The clinical significance of these findings is unknown.
9. OVERDOSAGE
In a clinical study in patients with Type 2 diabetes, nateglinide was administered in increasing doses up to 720 mg a day for 7 days and there were no clinically significant adverse events reported. There have been no instances of overdose with nateglinide in clinical trials. However, an overdose may result in an exaggerated glucose-lowering effect with the development of hypoglycemic symptoms. Hypoglycemic symptoms without loss of consciousness or neurological findings should be treated with oral glucose and adjustments in dosage and/or meal patterns. Severe hypoglycemic reactions with coma, seizure, or other neurological symptoms should be treated with intravenous glucose. As nateglinide is highly protein bound, dialysis is not an efficient means of removing it from the blood.
10. DRUG INTERACTIONS
Nateglinide is highly bound to plasma proteins (98%), mainly albumin. In-vitro displacement studies with highly protein-bound drugs such as furosemide, propranolol, captopril, nicardipine, pravastatin, glyburide, warfarin, phenytoin, acetylsalicylic acid, tolbutamide, and metformin showed no influence on the extent of nateglinide protein binding. Similarly, nateglinide had no influence on the serum protein binding of propranolol, glyburide, nicardipine, warfarin, phenytoin, acetylsalicylic acid, and tolbutamide in vitro. However, prudent eva luation of individual cases is warranted in the clinical setting.
Certain drugs, including nonsteroidal anti-inflammatory agents (NSAIDs), salicylates, monoamine oxidase inhibitors, and non-selective beta-adrenergic-blocking agents may potentiate the hypoglycemic action of nateglinide and other oral antidiabetic drugs.
Certain drugs including thiazides, corticosteroids, thyroid products, and sympathomimetics may reduce the hypoglycemic action of nateglinide and other oral antidiabetic drugs.
When these drugs are administered to or withdrawn from patients receiving nateglinide, the patient should be observed closely for changes in glycemic control.
Drug/Food Interactions
The pharmacokinetics of nateglinide were not affected by the composition of a meal (high protein, fat, or carbohydrate). However, peak plasma levels were significantly reduced when nateglinide was administered 10 minutes prior to a liquid meal. Nateglinide did not have any effect on gastric emptying in healthy subjects as assessed by acetaminophen testing.
11. PHARMACOKINETICS
Absorption
Following oral administration immediately prior to a meal, nateglinide is rapidly absorbed with mean peak plasma drug concentrations (Cmax) generally occurring within 1 hour (Tmax) after dosing. When administered to patients with Type 2 diabetes over the dosage range 60 mg to 240 mg three times a day for one week, nateglinide demonstrated linear pharmacokinetics for both AUC (area under the time/plasma concentration curve) and Cmax. Tmax was also found to be independent of dose in this patient population. Absolute bioavailability is estimated to be approximately 73%. When given with or after meals, the extent of nateglinide absorption (AUC) remains unaffected. However, there is a delay in the rate of absorption characterized by a decrease in Cmax and a delay in time to peak plasma concentration (Tmax). Plasma profiles are characterized by multiple plasma concentration peaks when nateglinide is administered under fasting conditions. This effect is diminished when nateglinide is taken prior to a meal.
Distribution
Based on data following intravenous (IV) administration of nateglinide, the steady-state volume of distribution of nateglinide is estimated to be approximately 10 liters in healthy subjects. Nateglinide is extensively bound (98%) to serum proteins, primarily serum albumin, and to a lesser extent α1 acid glycoprotein. The extent of serum protein binding is independent of drug concentration over the test range of 0.1-10 μg/mL.
Metabolism
Nateglinide is metabolized by the mixed-function oxidase system prior to elimination. The major routes of metabolism are hydroxylation followed by glucuronide conjugation. The major metabolites are less potent antidiabetic agents than nateglinide. The isoprene minor metabolite possesses potency similar to that of the parent compound nateglinide.
In-vitro data demonstrate that nateglinide is predominantly metabolized by cytochrome P450 isoenzymes CYP2C9 (70%) and CYP3A4 (30%).
Elimination
Nateglinide and its metabolites are rapidly and completely eliminated following oral administration. Within 6 hours after dosing, approximately 75% of the administered 14C-nateglinide was recovered in the urine. Eighty-three percent of the 14C-nateglinide was excreted in the urine with an additional 10% eliminated in the feces. Approximately 16% of the 14C-nateglinide was excreted in the urine as parent compound. In all studies of healthy volunteers and patients with Type 2 diabetes, nateglinide plasma concentrations declined rapidly with an average elimination half-life of approximately 1.5 hours. Consistent with this short elimination half-life, there was no apparent accumulation of nateglinide upon multiple dosing of up to 240 mg three times daily for 7 days.
Special Populations
Geriatric: Age did not influence the pharmacokinetic properties of nateglinide. Therefore, no dose adjustments are necessary for elderly patients.
Gender: No clinically significant differences in nateglinide pharmacokinetics were observed between men and women. Therefore, no dose adjustment based on gender is necessary.
Race: Results of a population pharmacokinetic analysis including subjects of Caucasian, Black, and other ethnic origins suggest that race has little influence on the pharmacokinetics of nateglinide.
Renal Impairment: Compared to healthy matched subjects, patients with Type 2 diabetes and moderate-to-severe renal insufficiency (CrCl 15-50 mL/min) not on dialysis displayed similar apparent clearance, AUC, and Cmax. Patients with Type 2 diabetes and renal failure on dialysis exhibited reduced overall drug exposure. However, hemodialysis patients also experienced reductions in plasma protein binding compared to the matched healthy volunteers.
Hepatic Impairment: The peak and total exposure of nateglinide in non-diabetic subjects with mild hepatic insufficiency were increased by 30% compared to matched healthy subjects. Nateglinide should be used with caution in patients with chronic liver disease. (See PRECAUTIONS, Hepatic Impairment.)
12. HOW SUPPLIED/STORAGE AND HANDLING
1) How Available:
a) Brand name: STARLIX, by Novartis.
b) Generic drugs: Nateglinide, by various manufacturers.
2) How Supplied:
Nateglinide tablets (by DR REDDY'S LABS) are available as 60 mg white to off-white, round, biconvex tablets embossed with ‘RDY’ on one side and ‘328’ on other side and they are supplied in bottles of 30, 90, 100, 500 and unit dose package of 100 (10 x 10).
Bottles of 30 NDC 55111-328-30
Bottles of 90 NDC 55111-328-90
Bottles of 100 NDC 55111-328-01
Bottles of 500 NDC 55111-328-05
Unit dose package of 100 (10 x 10) NDC 55111-328-78
Nateglinide tablets are available as 120 mg white to off-white, round, biconvex tablets embossed with ‘RDY’ on one side and ‘329’ on other side and they are supplied in bottles of 30, 90, 100, 500 and unit dose package of 100 (10 x 10).
Bottles of 30 NDC 55111-329-30
Bottles of 90 NDC 55111-329-90
Bottles of 100 NDC 55111-329-01
Bottles of 500 NDC 55111-329-05
Unit dose package of 100 (10 x 10) NDC 55111-329-78
3) Storage:
Store at 20°-25°C (68°-77°F); excursions permitted to 15°-30°C (59°-86°F) [See USP Controlled Room Temperature].
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