[Approval Date] March 28, 2007
【Revision Date】Mar. 30, 2008
October 13, 2010
February 16, 2013
January 02, 2014
December 22, 2015
2016 xx xx
Instructions for Repaglinide Tablets
Please read the instructions carefully and use under the guidance of your physician.
[Drug Name].
Generic name: Repaglinide Tablets
Trade name: Novaluron®
English Name: Repaglinide Tablets
Chinese Pinyin: Ruigelienai Pian
Ingredients
The main ingredient of this product is Repaglinide.
Chemical name: S(+)-2-ethoxy-4[2-[[3-methyl-1-[2-(1-piperidinyl)phenyl]-butyl]amino]-2-oxoethyl]benzoic acid.
Chemical structure formula.
Molecular formula: C27 H36 N2 O4
Molecular weight: 452.6
Excipients: anhydrous calcium hydrogen phosphate, microcrystalline cellulose, corn starch, potassium polacillin, povidone, 85% glycerin, magnesium stearate, glucosamine, poloxamer 188, iron oxide.
【Properties】.
It is white tablet (0.5mg) or yellow tablet (1.0mg) or peach tablet (2.0mg) with Novo Nordisk logo (Apis cow) engraved on the surface.
【Indications】.
For adults with type 2 diabetes whose hyperglycemia cannot be effectively controlled by diet control, weight reduction and exercise.
When metformin alone cannot effectively control their hyperglycemia, Repaglinide tablets can be used in combination with metformin. Treatment should start with adjuvant therapy of diet control and exercise to lower blood glucose at mealtime.
【Specifications】.
(1) 0.5mg; (2) 1.0mg; (3) 2.0mg.
Dosage]
Repaglinide tablets should be taken before meals and the dose varies from person to person to achieve optimal blood glucose control. While patients self-monitor their blood glucose and/or urine glucose, the minimum effective dose of the medication for patients should be determined by regular monitoring of blood glucose values by a healthcare provider. Glycosylated hemoglobin levels are also meaningful for monitoring the patient’s treatment effectiveness. Regular monitoring is necessary to detect inadequate hypoglycemic effects at the recommended maximum dose level (e.g., primary failure) and reduced hypoglycemic effects after a period of initial effective therapy (e.g., secondary failure).
Short-term use of Repaglinide can be effective in controlling blood glucose in the event of transient control failure in patients with type 2 diabetes who are well controlled by dietary control.
The drug is usually taken within 15 minutes before a meal, but can also be taken within 0-30 minutes before a meal (e.g., before 2, 3, or 4 meals a day). Patients who miss a meal (or an additional meal) should reduce (or increase) the dose by one dose for that meal accordingly.
In case of concomitant use of other active drugs, please refer to [Precautions] and [Drug Interactions] for dose assessment.
Recommended starting dose
Take Repaglinide tablets as prescribed by your doctor. The dose varies from person to person and is based on individual blood glucose. The recommended starting dose is 0.5 mg, which may be adjusted weekly or biweekly if needed. The recommended starting dose for patients who are receiving other oral hypoglycemic agents to switch to treatment with Repaglinide Tablets is 1 mg.
Maintenance Dose
The maximum recommended single dose is 4 mg taken with meals. However, the maximum daily dose should not exceed 16 mg.
Patients switching from other oral hypoglycemic agents (OHAs) to this product
Patients can be directly transferred from other oral hypoglycemic agents to this product. However, there is no clear dose relationship between this product and other oral hypoglycemic agents. The recommended starting dose for switching to this product is 1 mg before meals.
Combination of drugs
When metformin alone is not sufficient to control blood glucose, this product can be combined with metformin. In this case, the dose of metformin should be the same as when taken alone, and this product should be taken together. The starting dose of Repaglinide is 0.5 mg before meals. the dose of each drug needs to be adjusted according to blood glucose.
Special patient groups
Please refer to [Precautions].
Adverse reactions
The most common adverse reactions to taking Repaglinide are changes in blood glucose levels, such as hypoglycemia. As with all diabetes treatments, the occurrence of these reactions depends on individual factors such as diet, dose, exercise, and stress response.
Clinical use of Repaglinide and other hypoglycemic agents has shown that the following adverse reactions may occur with Repaglinide, the incidence of which are defined as follows: common adverse reactions (≥1/100 to <1/10); rare adverse reactions (≥1/1,000 to ≤1/100); rare adverse reactions (≥1/10,000, ≤1/1,000); very rare adverse reactions (≤ 1/10,000), unknown adverse reactions (no relevant data available)
Immune system dysregulation
Very rare adverse reactions: allergic reactions
General hypersensitivity reactions (e.g., anaphylactic reactions) or immune reactions (e.g., vasculitis)
Metabolic and nutritional disorders
Common adverse reactions: hypoglycemia. These reactions are usually mild and are easily corrected by the administration of carbohydrates. As with other hypoglycemic drugs, hypoglycemia may occur with Repaglinide. Symptoms include anxiety, dizziness, sweating, tremors, hunger, and difficulty concentrating.
Unknown adverse reactions (no relevant data available): hypoglycemic coma and hypoglycemic loss of consciousness. If more severe, glucose may be administered with the assistance of another person. Combination with other drugs may increase the risk of hypoglycemia (see [Drug Interactions]).
Eye abnormalities
Very rare: visual abnormalities
Changes in blood glucose levels are known to cause temporary blurred vision and visual abnormalities, especially when treatment with glucose-lowering medications is initiated. These changes are usually transient.
Cardiac conditions
Rare: Cardiovascular disease
Type 2 diabetes is associated with an increased risk of cardiovascular disease. An epidemiological trial suggested that treatment with Repaglinide may increase the risk of developing acute coronary syndrome in patients, but a causal relationship could not be established.
Gastrointestinal discomfort
Common: abdominal pain and diarrhea
Very rare: vomiting and constipation
Unknown: nausea
Gastrointestinal reactions such as abdominal pain, diarrhea, nausea, vomiting, and constipation have been reported in clinical trials. There is no difference in the frequency and severity of these symptoms when compared to other oral insulin-producing drugs.
Hepatobiliary disorders
Very rare: hepatic dysfunction
Severe hepatic dysfunction has been reported very rarely; however, an association with Repaglinide has not been established.
Very rare: elevated liver function enzymes
Most cases are mild and transient, and very few patients discontinue treatment due to elevated liver enzyme markers.
Skin and subcutaneous tissue abnormalities
Unknown: Allergic reactions
Allergic reactions, such as erythema, pruritus, rash, urticaria, may occur.
[Contraindicated].
Patients with known hypersensitivity to Repaglinide or any of the excipients in Repaglinide tablets
Patients with type 1 diabetes mellitus, C-peptide negative diabetes mellitus
Patients with diabetic ketoacidosis with or without coma
Severe liver function abnormalities
Concomitant use of gemfibezil (see [Drug Interactions])
[Precautions].
General patient population
Repaglinide is used for the treatment of patients with symptoms of diabetes mellitus whose blood glucose cannot be effectively controlled by diet, weight reduction and exercise.
Like most other oral insulin-producing hypoglycemic drugs, Repaglinide can cause hypoglycemia.
The combination of drugs increases the risk of hypoglycemia. Failure of glycemic control may occur when a patient experiences a stressful reaction, such as fever, trauma, infection, or surgery, while taking any oral hypoglycemic agent regularly. At this point, it is necessary to stop taking Repaglinide in favor of short-term insulin therapy.
Oral hypoglycemic agents may have a diminished hypoglycemic effect as the duration of medication increases in most patients. This may be due to progression of diabetes or due to a reduced response to the drug. Unlike primary failure, which occurs when the drug fails on the first dose, this phenomenon is secondary failure. Dose adjustment and adherence to dietary control and exercise should be considered before secondary failure is determined.
Special Patient Groups
Weak or malnourished patients: cautious dose adjustments are recommended (see [DOSAGE AND ADMINISTRATION]).
Patients with hepatic impairment: no information available.
Pediatric patients: no relevant information.
Patients over 75 years of age: no relevant information.
Hepatic insufficiency: At usual doses, patients with hepatic impairment may be exposed to higher concentrations of repaglinide and its metabolites compared to patients with normal hepatic function. Therefore, Repaglinide should not be used in patients with severe hepatic abnormalities (see [Contraindications]) and the product should be used with caution in patients with hepatic impairment. The adjustment interval for dose adjustment should be extended and the patient’s response should be adequately evaluated (see [Pharmacokinetics]).
Renal insufficiency: Although there is only a weak association between repaglinide levels and creatinine clearance, the plasma clearance of this product is slightly reduced in patients with severe renal impairment. Due to increased insulin sensitivity in diabetic patients with renal impairment, caution should be exercised when increasing the dose in these patients (see [Pharmacokinetics]).
Effects on driving and mechanical maneuverability
Patients may experience inattention and reduced awareness caused by hypoglycemia. This may lead to danger in certain situations (e.g., when driving or operating machinery). Patients should be told to take care to avoid hypoglycemia while driving. Particular attention should be paid to patients who experience reduced or lost consciousness when hypoglycemia occurs, or to patients who experience hypoglycemia frequently. Under the above circumstances, the patient’s ability to drive safely should be considered first.
[For Pregnant and Lactating Women].
Studies have not been conducted in women who are pregnant or breastfeeding. Therefore, the safety of Repaglinide in pregnant women cannot be evaluated.
See [Pharmacology and Toxicology] for more information on reproductive toxicity studies in animals.
Pediatric Dosage]
The safety and efficacy of Repaglinide in children under 18 years of age have not been established. No relevant information is available.
Geriatric Use
Repaglinide has not been studied in patients over 75 years of age.
Drug Interactions]
Some drugs are known to affect the clearance of Repaglinide. Therefore, physicians should consider possible drug-drug interactions.
In vitro studies have shown that repaglinide is metabolized primarily by CYP2C8, but also by CYP3A4.
Data from clinical studies in healthy volunteers suggest that CYP2C8 is the enzyme that plays a major role in the metabolism of repaglinide, while CYP3A4 has a limited role. However, if the action of CYP2C8 is inhibited, the effect of CYP3A4 will be relatively enhanced. Thus the metabolism and clearance of Repaglinide may be altered by the inhibition or induction of the action of cytochrome enzyme P450. Therefore, extra caution should be exercised when using concomitant CYP2C8 and CYP3A4 inhibitors with Repaglinide.
Data from in vitro and in vivo studies suggest that Repaglinide is a substrate actively taken up by the liver (organic anion transport protein OATP1B1 is involved). As shown with cyclosporine, drugs that inhibit OATP1B1 are equally likely to increase plasma concentrations of repaglinide (see below).
The following drugs may potentiate and/or prolong the hypoglycemic effect of repaglinide.
Gemfibezil, meperidine, rifampin, ketoconazole, itraconazole, clarithromycin, cyclosporine, deferasirox, clopidogrel, other types of antidiabetic drugs, monoamine oxidase inhibitors (MAOI), non-selective b-blockers, angiotensin-converting enzyme (ACE) inhibitors, salicylates, non-steroidal anti-inflammatory agents, octreotide, alcohol, and pro-anabolic hormones.
A drug interaction study in healthy volunteers showed that the CYP2C8 and OATP1B1 inhibitor gemfibezil (600 mg twice daily) administered with repaglinide (single dose 0.25 mg) increased the blood AUC of repaglinide by 8.1-fold and the Cmax by 2.4-fold in healthy volunteers, and the elimination half-life (t1/2) was increased from 1.3 hours to 3.7 hours. This may lead to enhanced hypoglycemic effect and prolonged duration of action of repaglinide. The combination of gemfibrozil may increase the plasma drug concentration of repaglinide significantly and therefore the concomitant use of repaglinide and gemfibrozil should be prohibited (see [Contraindications]).
There is no drug interaction between Fenofibrate and Repaglinide.
Meprobamate (160 mg twice daily), a weak CYP2C8 inhibitor, co-administered with repaglinide (single dose 0.25 mg) resulted in a slight increase in repaglinide AUC, Cmax, and biological half-life (1.6-fold, 1.4-fold, and 1.2-fold, respectively), with no statistically significant difference in the increase in blood glucose levels. These data, which lack pharmacodynamic results, were obtained based on low-dose treatment with repaglinide. Caution should be exercised when combining Repaglinide with meperidine because no safety data are available for doses above 0.25 mg with meperidine above 320 mg. If the combination is necessary, the patient’s blood glucose level should be closely monitored and close clinical monitoring should be performed.
Rifampicin is a strong inducer of CYP3A4 and an inducer of CYP2C8, acting as both an inducer and an inhibitor in the metabolism of Repaglinide. Using rifampicin (600 mg) first for 7 days and then in combination with repaglinide (single dose of 4 mg) at day 7, the AUC was reduced by 50% (which is the combined result of induction and inhibition). Repaglinide was administered 24 hours after the last dose of rifampicin and the AUC of Repaglinide was reduced by 80% (induction effect alone).
The combination of rifampin and repaglinide may require adjustment of the dose of repaglinide, and patients should be closely monitored for blood glucose levels at the time of initiation of rifampin (rapid inhibition), at increasing doses (mixed inhibition and induction) and discontinuation of rifampin (induction alone), and at the time of discontinuation of rifampin approximately 1 week after its induction effect, and the dose of repaglinide should be adjusted according to blood glucose levels.
The effect of ketoconazole, a representative drug for potent and competitive inhibitors of CYP3A4, on the pharmacokinetics of repaglinide was studied in healthy subjects. 200 mg of ketoconazole administered concomitantly (single dose of repaglinide 4 mg) resulted in a 1.2-fold increase in repaglinide exposure (AUC and Cmax) with less than 8% change in blood glucose.
The combined administration of 100 mg of the CYP3A4 inhibitor itraconazole in healthy volunteers increased the AUC of repaglinide by 1.4-fold. No significant effect on glucose levels was observed in healthy volunteers.
Coadministration of 250 mg of the strong CYP3A4 inhibitor clarithromycin with repaglinide resulted in a 1.4-fold increase in AUC, a 1.7-fold increase in Cmax, a 1.5-fold increase in mean value-added serum insulin AUC, and a 1.6-fold increase in peak concentration of repaglinide. The exact mechanism of this interaction is unclear.
The combination of the CYP3A4 and OAT1B1 inhibitors cyclosporine (multiple doses, 100 mg each) and repaglinide (single dose, 0.25 mg) in healthy volunteers increased repaglinide Cmax by 1.8-fold and AUC by 2.5-fold.
It is uncertain whether repaglinide interacts with cyclosporine at doses higher than 0.25 mg, and therefore, the combination of the two should be avoided. If combination dosing is indeed required, close clinical observation and glucose monitoring should be performed (see [Precautions]).
In a drug interaction study in healthy volunteers, concomitant administration of the intermediate-acting CYP2C8 and CYP3A4 inhibitor deferasirox (30 mg/kg/day for 4 days) and repaglinide (single dose, 0.5 mg) increased repaglinide systemic exposure (AUC) to 2.3 times that of control (90% CI [2.03-2.63]) and Cmax to 1.6-fold (90% CI [1.42-1.84]), along with a small, but significant, decrease in glucose values. It has not been determined whether repaglinide interacts with deferasirox at doses higher than 0.5 mg, and therefore, their combination should be avoided. If combination dosing is indeed required, close clinical observation and glucose monitoring should be performed (see [Precautions]).
In combination with the CYP2C8 inhibitor clopidogrel (300 mg, loading dose), a 5.1-fold increase in exposure (AUC 0-∞) to repaglinide was observed; continued combination (75 mg, daily dose) resulted in a 3.9-fold increase in exposure (AUC 0-∞) to repaglinide and a small but significant decrease in glucose was observed. The safety of combining clopidogrel with repaglinide in these patients has not been established, and the combination of clopidogrel with repaglinide should be avoided. If the combination of repaglinide and clopidogrel is required, close glucose monitoring and clinical observation should be performed.
b-blockers can mask symptoms of hypoglycemia.
The pharmacokinetic parameters of repaglinide were not significantly altered by the combination of repaglinide with cimetidine, nifedipine, estrogens, or simvastatin, all CYP3A4-acting substrates.
Drug interaction studies in healthy volunteers found no effect of repaglinide on the pharmacokinetic properties of digoxin, theophylline, and warfarin. Therefore, no dose adjustment of these drugs is required when used in combination with Repaglinide.
The hypoglycemic effect of repaglinide may be attenuated by the following drugs.
Oral contraceptives, rifampicin, phenobarbital, carbamazepine, thiazides, corticosteroids, danazol, thyroid hormones and sympathomimetics.
The combination of oral contraceptives (ethinyl estradiol/levonorgestrel) does not alter the total bioavailability of repaglinide to the relevant clinical range, although it does shorten the time to peak of repaglinide. Repaglinide has no clinically meaningful effect on the bioavailability of levonorgestrel, but an effect on the bioavailability of ethinyl estradiol cannot be excluded.
Patients should be monitored closely for changes in blood glucose while on or off these drugs in patients treated with Repaglinide.
Pediatric Populations
Drug interaction studies have not been conducted in pediatric and adolescent populations.
[Drug Overdose].
In a clinical trial in patients with type 2 diabetes, the dose of repaglinide was increased weekly from 4 mg to 20 mg over a time frame of more than 6 weeks. patients took the drug four times daily with meals. There were essentially no adverse events, except for the predictable effects associated with lowering blood glucose. Since the study was conducted by increasing caloric intake to reduce the occurrence of hypoglycemic symptoms, a relative overdose may manifest itself as an increase in hypoglycemic effects and the development of hypoglycemic symptoms (dizziness, sweating, tremors, headache, etc.). Once these reactions occur, effective measures should be taken to correct the hypoglycemia (oral carbohydrates). For more severe hypoglycemia with seizures, loss of consciousness and coma, glucose should be given intravenously.
Pharmacology and Toxicology
Repaglinide is a short-acting insulinotropic agent. Repaglinide lowers blood glucose levels by promoting the release of insulin from the pancreas. This effect is dependent on the functional b-cells in the islets of the pancreas.
By binding to receptors on b-cells to close ATP-dependent potassium channels in the b-cell membrane, repaglinide depolarizes the b-cells, opens calcium channels, and increases calcium influx. This process induces insulin secretion from b cells.
In type 2 diabetic patients taking oral Repaglinide, a proinsulin secretory response occurs within 30 minutes after a meal. This causes a decrease in blood glucose during the meal. The plasma level of Repaglinide decreases rapidly, and 4 hours after taking the drug, the plasma concentration of the drug is very low in patients with type 2 diabetes.
Studies have shown a dose-dependent decrease in blood glucose concentrations in type 2 diabetic patients taking Repaglinide 0.5-4 mg.
The results of clinical studies suggest that Repaglinide should be taken before a meal. It should usually be taken within 15 minutes before a meal, and the dosing time can also be kept to 0-30 minutes before a meal.
Preclinical Safety Data
Based on traditional safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenicity tests, preclinical data do not indicate a specific risk to humans.
No teratogenic effects of Repaglinide have been identified in animal studies. In studies with high doses administered to rats during late gestation and lactation, abnormal non-teratogenic limb growth was observed in fetuses and pups. In addition, Repaglinide was detected in the milk of test animals. Therefore, it is recommended that it be contraindicated in pregnant and lactating women.
Pharmacokinetics
Absorption
Repaglinide is rapidly absorbed through the gastrointestinal tract and plasma drug concentrations increase rapidly. The plasma drug concentration peaks within 1 hour after dosing. Subsequently, plasma drug concentration decreases rapidly. No clinically relevant differences were found in the pharmacokinetics of repaglinide after administration at 0, 15 and 30 minutes before meals and on an empty stomach, respectively.
Pharmacokinetic properties of repaglinide: mean absolute bioavailability was 63% (CV 11%).
Clinical studies found large inter-individual variation (60%) in blood concentrations of repaglinide. Intra-individual variation was low to moderate (35%), therefore, repaglinide dose should be adjusted according to clinical response, but inter-individual variation does not affect the effectiveness of the drug.
Distribution
Repaglinide has a low volume of distribution of 30 L (consistent with the distribution of intracellular fluid) and a high human plasma protein binding rate (>98%).
Clearance
After the drug concentration reaches Cmax, plasma drug concentration decreases rapidly. The plasma half-life is approximately 1 hour. Repaglinide is rapidly cleared from the blood within 4-6 hours.
Repaglinide is mainly metabolized by CYP2C8, but also by CYP3A4. No clinically significant hypoglycemic effects have been observed for the metabolites.
The metabolites of Repaglinide are excreted primarily through the bile. Less than 2% of the drug in its original form is excreted in the feces, and a small proportion (approximately 8%) is excreted in the urine, primarily as metabolites.
Patients with renal insufficiency
Single versus multiple steady-state dosing
The pharmacokinetics of Repaglinide was studied in patients with type 2 diabetes mellitus with varying degrees of renal impairment. The AUC and Cmax of repaglinide were the same in patients with normal renal function and mild to moderate renal impairment (mean values 56.7ng/ml*h and 57.2ng/ml*h; 37.5ng/ml and 37.7ng/ml, respectively). There was some increase in mean AUC and Cmax values in patients with severe renal insufficiency (98.0ng/ml*hour and 50.7ng/ml, respectively), but this study showed only a weak association between repaglinide levels and creatinine clearance.
No adjustment of the starting dose is required in patients with renal insufficiency.
Caution should be exercised when increasing the dose of Repaglinide in patients with type 2 diabetes mellitus who have severe renal impairment or renal insufficiency requiring hemodialysis.
Patients with hepatic insufficiency
A single-dose, open study in 12 healthy subjects and 12 patients with chronic liver disease (CLD) using Child-Pugh classification and caffeine clearance classification demonstrated higher total blood concentrations of repaglinide and free repaglinide in patients with moderate to severe hepatic insufficiency compared to healthy subjects The correlation between AUC values and caffeine clearance was statistically significant. No differences in glycemic profiles were found in the patient groups.
When taking the same usual dose, patients with liver injury may be exposed to higher concentrations of repaglinide and metabolites compared to patients with normal liver function. Therefore, Repaglinide should not be used in patients with severe hepatic abnormalities, and the product should be used with caution in patients with hepatic impairment. There should be a long interval between dose adjustments to adequately assess the response to the drug.
Storage
Store in a dry place at 15°C-25°C.
Store in the original sealed package. Keep out of reach of children. Indicate the expiration date on the outer packaging. Do not use after the expiration date.
Packaging
Aluminum foil bubble eye package.
15 tablets/box (1.0mg, 2.0mg).
30 tablets/box (0.5mg, 1.0mg, 2.0mg).
【Expiration date】 60 months
【Execution standard
Chinese Pharmacopoeia, 2015 edition and JX20120236
[Imported drug registration certificate number
(1) 0.5mg Repaglinide tablets import drug registration number: H20130022
(2) 1.0mg Repaglinide tablets import drug registration number: H20130023
(3) 2.0mg Repaglinide Tablets Imported Drug Registration No.: H20130021
【Manufacturer
Company Name: Novo Nordisk A/S, Denmark
Novo Nordisk A/S
Production plant: Germany Boehringer Ingelheim Pharma GmbH & Co. KG production
Production Address: Binger Strasse 173, 55216 Ingelheim am Rhein, Germany
Tel: 0049 6132 770
Fax: 0049 6132 720
Phone number for company inquiries: 800 810 2299 (toll-free)
400 810 2299 (mobile)
010 65388080
Fax: 010 65056668
NovoNorm® and Novolon® are registered trademarks of Novo Nordisk Denmark
©2016
Novo Nordisk A/S
2880 Bagsvaerd, Denmark