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Repaglinide and Metformin Tablets

Generic Name: repaglinide and metformin hydrochloride
Dosage Form: tablet

WARNING: LACTIC ACIDOSIS

Post-marketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (> 5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL [see WARNINGS AND PRECAUTIONS (5.1)].

Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anyhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment.

Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the full prescribing information [see DOSAGE AND ADMINISTRATION (2.2), CONTRAINDICATIONS (4), WARNINGS AND PRECAUTIONS (5.1), DRUG INTERACTIONS (7), and USE IN SPECIFIC POPULATIONS (8.6, 8.7)].

If metformin-associated lactic acidosis is suspected, immediately discontinue repaglinide and metformin hydrochloride tablets and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended [see WARNINGS AND PRECAUTIONS (5.1)].

Indications and Usage for Repaglinide and Metformin Tablets

Repaglinide and metformin hydrochloride tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus who are already treated with a meglitinide and metformin HCl or who have inadequate glycemic control on a meglitinide alone or metformin HCl alone.

Important Limitations of Use

Repaglinide and metformin hydrochloride tablets should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings.

Repaglinide and Metformin Tablets Dosage and Administration

Recommended Dosing

The dosage of repaglinide and metformin hydrochloride tablets should be individualized on the basis of the patient's current regimen, effectiveness and tolerability. Repaglinide and metformin hydrochloride tablets can be administered 2 to 3 times a day up to a maximum daily dose of 10 mg repaglinide/2500 mg metformin HCl. No more than 4 mg repaglinide/1000 mg metformin HCl should be taken per meal. Initiation and maintenance of combination therapy with repaglinide and metformin hydrochloride tablets should be individualized to the patient, and at the discretion of the health care provider. Blood glucose monitoring should be performed to determine the therapeutic response to repaglinide and metformin hydrochloride tablets.

Repaglinide and metformin hydrochloride tablets doses should usually be taken within 15 minutes prior to the meal but the timing can vary from immediately preceding the meal up to 30 minutes before the meal. Patients who skip a meal should be instructed to skip the repaglinide and metformin hydrochloride tablet dose for that meal.

Patients Inadequately Controlled with Metformin HCl Monotherapy

If therapy with a combination tablet containing repaglinide and metformin HCl is considered appropriate for a patient with type 2 diabetes mellitus inadequately controlled with metformin HCl alone, the recommended starting dose of repaglinide and metformin hydrochloride tablets is 1 mg repaglinide/500 mg metformin HCl administered twice daily with meals, with gradual dose escalation (based on glycemic response) to reduce the risk of hypoglycemia with repaglinide.

Patients Inadequately Controlled with Meglitinide Monotherapy

If therapy with a combination tablet containing repaglinide and metformin HCl is considered appropriate for a patient with type 2 diabetes mellitus inadequately controlled with repaglinide alone, the recommended starting dose of the metformin HCl component of repaglinide and metformin hydrochloride tablets should be 500 mg metformin HCl twice a day, with gradual dose escalation (based on glycemic response) to reduce gastrointestinal side effects associated with metformin HCl.

Patients Currently Using Repaglinide and Metformin HCl Concomitantly

For patients switching from repaglinide co-administered with metformin HCl, repaglinide and metformin hydrochloride tablets can be initiated at the dose of repaglinide and metformin HCl similar to (but not exceeding) the patient's current doses, then may be titrated to the maximum daily dose as necessary to achieve targeted glycemic control.

No studies have been performed examining the safety and efficacy of repaglinide and metformin hydrochloride tablets in patients previously treated with other oral antihyperglycemic agents and switched to repaglinide and metformin hydrochloride tablets. Any change in therapy should be undertaken with care and with appropriate monitoring as changes in glycemic control can occur.

2.2 Recommendations for Use in Renal Impairment

Assess renal function with an estimated glomerular filtration rate (eGFR) prior to initiation of repaglinide and metformin hydrochloride tablets and periodically thereafter.

Repaglinide and metformin hydrochloride tablets is contraindicated in patients with an eGFR below 30 mL/min/1.73 m2.

Initiation of repaglinide and metformin hydrochloride tablets in patients with an eGFR between 30 to 45 mL/min/1.73 m2 is not recommended.

In patients taking repaglinide and metformin hydrochloride tablets whose eGFR later falls below 45 mL/min/1.73 m2, assess the benefit-risk of continuing therapy. Discontinue repaglinide and metformin hydrochloride tablets if the patient's eGFR later falls below 30 mL/min/1.73 m2 [see CONTRAINDICATIONS (4) and WARNINGS AND PRECAUTIONS (5.1)].

Discontinuation for Iodinated Contrast Imaging Procedures

Discontinue repaglinide and metformin hydrochloride tablets at the time or, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with a history of liver disease, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart repaglinide and metformin hydrochloride tablets if renal function is stable [See WARNINGS AND PRECAUTIONS (5.1)].

Dosage Forms and Strengths

  • 1 mg repaglinide/500 mg metformin HCl tablets are yellow coloured, biconvex, oval shaped, film coated tablets, debossed with 'V41' on one side and 'LU' on the other side.
  • 2 mg repaglinide/500 mg metformin HCl tablets are pink coloured, biconvex, oval shaped, film coated tablets, debossed with 'V42' on one side and 'LU' on the other side.

Contraindications

Repaglinide and metformin hydrochloride tablets are contraindicated in:

  • Severe renal impairment (GFR below 30 mL/min. 1.73 m2) [see WARNINGS AND PRECAUTIONS (5.1)] .
  • Acute or chronic metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis should be treated with insulin [see WARNINGS and PRECAUTIONS (5.1)] .
  • Patients receiving gemfibrozil [see WARNINGS AND PRECAUTIONS (5.7), DRUG INTERACTIONS (7.2), CLINICAL PHARMACOLOGY (12.3)] .
  • Patients with known hypersensitivity to repaglinide, metformin HCl or any inactive ingredients in repaglinide and metformin hydrochloride tablets.

Warnings and Precautions

Lactic Acidosis

Metformin hydrochloride

There have been post-marketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate:pyruvate ratio; metformin plasma levels generally >5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk.

If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of repaglinide and metformin hydrochloride tablets. In repaglinide and metformin hydrochloride tablets treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable, with a clearance of up to 170 mL/minute under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery.

Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue repaglinide and metformin hydrochloride tablets and report these symptoms to their healthcare provider.

For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below:

Renal Impairment: 

The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient's renal function include [see DOSAGE AND ADMINISTRATION (2.2), CLINICAL PHARMACOLOGY (12.3)]:

  • Before initiating repaglinide and metformin hydrochloride tablets, obtain an estimated glomerular filtration rate (eGFR).
  • Repaglinide and metformin hydrochloride tablets is contraindicated in patients with an eGFR less than 30 mL/minute/1.73 m2[see CONTRAINDICATIONS (4)]
  • Initiation of repaglinide and metformin hydrochloride tablets is not recommended in patients with eGFR between 30 to 45 mL/minute/1.73 m2.
  • Obtain an eGFR at least annually in all patients taking repaglinide and metformin hydrochloride tablets. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.
  • In patients taking repaglinide and metformin hydrochloride tablets whose eGFR later falls below 45 mL/min/1.73 m2, assess the benefit and risk of continuing therapy.

Drug Interactions:

The concomitant use of repaglinide and metformin hydrochloride tablets with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation [see DRUG INTERACTIONS (7)]. Therefore, consider more frequent monitoring of patients.

Age 65 or Greater:

The risk of metformin-associated lactic acidosis increases with the patient's age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients [see USE IN SPECIFIC POPULATIONS (8.5)].

Radiological Studies with Contrast:

Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop repaglinide and metformin hydrochloride tablets at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart repaglinide and metformin hydrochloride tablets if renal function is stable.

Surgery and Other Procedures: 

Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment. Repaglinide and metformin hydrochloride tablets should be temporarily discontinued while patients have restricted food and fluid intake.

Hypoxic States:

Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur, discontinue repaglinide and metformin hydrochloride tablets.

Excessive Alcohol Intake:

Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving repaglinide and metformin hydrochloride tablets.

Hepatic Impairment:

Patients with hepatic impairment have developed with cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of repaglinide and metformin hydrochloride tablets in patients with clinical or laboratory evidence of hepatic disease.

Combination with NPH-insulin

Repaglinide

Repaglinide is not indicated for use in combination with NPH-insulin.

Across seven controlled clinical trials, there were six serious adverse events (1.4%) of myocardial ischemia with repaglinide in combination with NPH-insulin compared to one event (0.3%) in patients using insulin alone [see ADVERSE REACTIONS (6.2)].

Drug Interactions

Repaglinide is partly metabolized by CYP2C8 and CYP3A4 and appears to be a substrate for active hepatic uptake transporter (organic anion transporting protein OATP1B1). Drugs that inhibit CYP2C8, CYP3A4, or OATP1B1 (e.g., cyclosporine) may increase plasma concentrations of repaglinide. Dose reduction of repaglinide may be needed [see DRUG INTERACTIONS (7.4) and CLINICAL PHARMACOLOGY (12.3)].

Gemfibrozil significantly increased repaglinide exposure. Therefore, patients should not take repaglinide and metformin hydrochloride tablets with gemfibrozil [see CONTRAINDICATIONS (4) and CLINICAL PHARMACOLOGY (12.3)].

Hypoglycemia

Most blood glucose-lowering drugs, including repaglinide, can cause hypoglycemia. Patients who have not previously been treated with a meglitinide should be started on the lowest available repaglinide component of repaglinide and metformin hydrochloride tablets to reduce the risk of hypoglycemia. Elderly, debilitated or malnourished patients and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemia. Hypoglycemia may be difficult to recognize in the elderly and in people who are taking β-adrenergic blocking drugs [see ADVERSE REACTIONS (6.1)].

Vitamin B12 Levels

In controlled clinical trials of metformin HCl of 29 weeks' duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients. This finding, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, is rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin HCl or vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on repaglinide and metformin hydrochloride tablets and any apparent abnormalities should be appropriately investigated and managed.

Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. In these patients, routine serum vitamin B12 measurements at 2- to 3- year intervals may be useful.

Loss of Control of Blood Glucose

When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a temporary loss of glycemic control may occur. At such times, it may be necessary to withhold repaglinide and metformin hydrochloride tablets and temporarily administer insulin. Repaglinide and metformin hydrochloride tablets may be reinstituted after the acute episode is resolved.

Change in Clinical Status of Patients with Previously Controlled Type 2 Diabetes

A patient with type 2 diabetes previously well-controlled on repaglinide and metformin hydrochloride tablets who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate, and metformin levels. If acidosis of either form occurs, repaglinide and metformin hydrochloride tablets must be stopped immediately and other appropriate corrective measures initiated.

Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with repaglinide and metformin hydrochloride tablets or any other oral anti-diabetic drug.

Adverse Reactions

The following adverse reactions are discussed in more detail in other sections of the labeling.

  • Lactic acidosis [see WARNINGS AND PRECAUTIONS (5.1)]
  • Hypoglycemia [see WARNINGS AND PRECAUTIONS (5.4)]
  • Vitamin B12levels[see WARNINGS AND PRECAUTIONS (5.5)]

Most Frequently Observed Adverse Reactions

Repaglinide

In clinical trials of repaglinide, hypoglycemia is the most common adverse reaction (> 5%) leading to withdrawal of patients treated with repaglinide.

Metformin HCl

Gastrointestinal reactions (e.g., diarrhea, nausea, vomiting) are the most common adverse reactions (> 5%) with metformin HCl treatment and are more frequent at higher metformin HCl doses.

Clinical Trial Experience

Because clinical trials are conducted under varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Patients with Inadequate Glycemic Control on Metformin HCl Monotherapy

Table 1 summarizes the most common adverse reactions occurring in a 6-month randomized study of repaglinide added to metformin HCl in patients with type 2 diabetes inadequately controlled on metformin HCl alone.

Table 1: Repaglinide added to metformin HCl in patients with type 2 diabetes inadequately controlled on metformin HCl alone. Adverse reaction reported (regardless of Investigator Assessment of Causality) in ≥10% of patients receiving combination therapy*

Coadministered repaglinide and metformin HCl
Metformin HCl monotherapy
Repaglinide
monotherapy

N (%)
N (%)
N (%)
No. of Patients Exposed
27
27
28
Gastrointestinal System Disorder
Diarrhea
Nausea
9(33)
5(19)
4 (15)
13(48)
8 (30)
2 (7)
10(36)
2 (7)
1 (4)
Symptomatic Hypoglycemia **
9 (33)
0 (0)
3 (11)
Headache
6 (22)
4 (15)
3 (11)
Upper Respiratory Tract Infection
3 (11)
3 (11)
3 (11)
*   Intent to treat population
** There were no cases of severe hypoglycemia (hypoglycemia requiring the assistance of another person)

Cardiovascular Events in Repaglinide Monotherapy Trials

In one-year trials comparing repaglinide to sulfonylurea drugs, the incidence of angina was 1.8% for both treatments, with an incidence of chest pain of 1.8% for repaglinide and 1.0% for sulfonylureas. The incidence of other selected cardiovascular events (hypertension, abnormal electrocardiogram, myocardial infarction, arrhythmias, and palpitations) was ≤ 1% and not different between repaglinide and the comparator drugs.

The incidence of total serious cardiovascular adverse events, including ischemia, was higher for repaglinide (51/1228 or 4%) than for sulfonylurea drugs (13/498 or 3%) in controlled clinical trials. In 1-year controlled trials, repaglinide treatment was not associated with excess mortality when compared to the rates observed with other oral hypoglycemic agent therapies such as glyburide and glipizide.

Seven controlled clinical trials included repaglinide combination therapy with NPH-insulin (n=431), insulin formulations alone (n=388) or other combinations (sulfonylurea plus NPH-insulin or repaglinide plus metformin HCl) (n=120). There were six serious adverse events of myocardial ischemia in patients treated with repaglinide plus NPH-insulin (1.4%) from two studies, and one event in patients using insulin formulations alone from another study (0.3%) [see WARNINGS AND PRECAUTIONS (5.6)].

Postmarketing Experience

The following additional adverse reactions have been identified during postapproval use. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or a causal relationship to drug exposure.

Repaglinide

Alopecia, hemolytic anemia, pancreatitis, Stevens-Johnson Syndrome, and severe hepatic dysfunction including jaundice and hepatitis.

Metformin HCL

Cholestatic, hepatocellular, and mixed hepatocellular liver injury

Drug Interactions

Carbonic Anhydrase Inhibitors

Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently causes a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with repaglinide and metformin hydrochloride tablets may increase the risk for lactic acidosis. Consider more frequent monitoring of these patients.

Drugs That Reduce Metformin Clearance

Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors such as ranolazine, vandetanib, dolutegravir, and cimetidine) could increase systemic exposure to metformin and may increase the risk for lactic acidosis [see CLINICAL PHARMACOLOGY (12.3)]. Consider the benefits and risks of concomitant use.

Alcohol

Alcohol is known to potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake while receiving repaglinide and metformin hydrochloride tablets.

CYP2C8 and CYP3A4 Inhibitors/Inducers

Repaglinide is metabolized by CYP2C8 and to a lesser extent by CYP3A4. Drugs that inhibit 2C8 (gemfibrozil, trimethoprim, deferasirox), inhibit 3A4 (itraconazole, ketaconazole), or induce CYP2C8/3A4 (rifampin) may alter the pharmacokinetics and pharmacodynamics of repaglinide. In vivo data from a study that evaluated the co-administration of gemfibrozil and repaglinide in healthy subjects showed a significant increase in repaglinide blood levels. Administration of repaglinide and metformin hydrochloride tablets and gemfibrozil to the same patient is not recommended [see WARNINGS AND PRECAUTIONS (5.3) and CLINICAL PHARMACOLOGY (12.3)].

Repaglinide exposures are increased more than 20-fold in patients taking both gemfibrozil and itraconazole [see CONTRAINDICATIONS (4) and CLINICAL PHARMACOLOGY (12.3)].

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category C.

There are no adequate and well-controlled studies in pregnant women with repaglinide and metformin hydrochloride tablets or its individual components. Because animal reproduction studies are not always predictive of human response, repaglinide and metformin hydrochloride tablets like other antidiabetic medications, should be used during pregnancy only if clearly needed.

No animal studies have been conducted with the combined products in repaglinide and metformin hydrochloride tablets. The following data are based on findings in studies performed with repaglinide or metformin individually.

Repaglinide

Repaglinide was not teratogenic in rats at doses 40 times, and rabbits approximately 0.8 times the clinical exposure (on a mg/m2 basis) throughout pregnancy. Offspring of rat dams exposed to repaglinide at 15 times clinical exposure on a mg/m2 basis during days 17 to 22 of gestation and during lactation developed nonteratogenic skeletal deformities consisting of shortening, thickening, and bending of the humerus during the postnatal period. This effect was not seen at doses up to 2.5 times clinical exposure (on a mg/m2 basis) on days 1 to 22 of pregnancy or at higher doses given during days 1 to 16 of pregnancy. Relevant human exposure has not occurred to date and therefore the safety of repaglinide administration throughout pregnancy or lactation cannot be established.

Metformin HCl

Metformin HCl alone was not teratogenic in rats or rabbits at doses up to 600 mg/kg/day. This represents an exposure of approximately two and six times the near-maximal efficacious human daily dose of 2000 mg of the metformin HCl component of repaglinide and metformin hydrochloride tablets based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin.

Nursing Mothers

No studies in lactating animals have been conducted with the repaglinide and metformin hydrochloride tablets fixed dose combination. In studies performed with individual components, both repaglinide and metformin are excreted into milk of lactating rats.

Repaglinide

In rat reproduction studies, measurable levels of repaglinide were detected in the breast milk of the dams and lowered blood glucose levels were observed in the pups. Cross fostering studies indicated that skeletal changes could be induced in control pups nursed by treated dams, although this occurred to a lesser degree than those pups treated in utero.

Metformin HCl

Studies in lactating rats with metformin HCl show that it is excreted into milk and reaches levels comparable to those in plasma.

It is not known whether repaglinide or metformin are excreted in human milk. Repaglinide and metformin hydrochloride tablets are not recommended in nursing mothers because it may potentially cause hypoglycemia in nursing infants.

Pediatric Use

Safety and effectiveness of repaglinide and metformin hydrochloride tablets in pediatric patients have not been established. Repaglinide and metformin hydrochloride tablet is not recommended for use in children.

Geriatric Use

Healthy volunteers treated with repaglinide 2 mg before each of 3 meals, showed no significant differences in repaglinide pharmacokinetics between the group of patients <65 years of age and those ≥65 years of age.

In patients with advanced age, repaglinide and metformin hydrochloride tablets should be carefully titrated to establish the minimum dose for adequate glycemic effect. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of lactic acidosis. Assess renal function more frequently in elderly patients. [see WARNINGS AND PRECAUTIONS (5.1), CONTRAINDICATIONS (4), CLINICAL PHARMACOLOGY (12.3)].

Renal Impairment

Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. Repaglinide and metformin hydrochloride tablets are contraindicated in severe renal impairment, patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m2. [See DOSAGE AND ADMINISTRATION (2.2), CONTRAINDICATIONS (4), WARNINGS AND PRECAUTIONS (5.1) and CLINICAL PHARMACOLOGY (12.3)]

Hepatic Impairment

Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. Repaglinide and metformin hydrochloride tablets is not recommended in patients with hepatic impairment. [See WARNINGS AND PRECAUTIONS (5.1)]

Overdosage

Repaglinide and Metformin Hydrochloride Tablets

No data are available with regard to overdose of repaglinide and metformin hydrochloride tablets. Findings related to the individual active substances are listed below.

Repaglinide

In a clinical trial, dizziness, headache, and diarrhea were reported in subjects receiving increasing doses of repaglinide up to 80 mg a day for 14 days. Hypoglycemia did not occur when meals were given with these high doses.

Hypoglycemic symptoms without loss of consciousness or neurologic findings should be treated aggressively with oral glucose and adjustments in drug dosage and/or meal patterns. Close monitoring should continue until the physician is assured that the patient is out of danger. Patients should be closely monitored for a minimum of 24 to 48 hours, since hypoglycemia may recur after apparent clinical recovery. There is no evidence that repaglinide is dialyzable using hemodialysis. Severe hypoglycemic reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute medical emergencies requiring immediate hospitalization. If hypoglycemic coma is diagnosed or suspected, the patient should be given a rapid intravenous injection of concentrated (50%) glucose solution. This should be followed by a continuous infusion of more dilute (10%) glucose solution at a rate that will maintain the blood glucose at a level above 100 mg/dL.

Metformin HCl

Overdose of metformin HCl has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin HCl has been established. Lactic acidosis has been reported in approximately 32% of metformin HCl overdose cases [see WARNINGS AND PRECAUTIONS (5.1)]. Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin HCl overdosage is suspected.

Repaglinide and Metformin Tablets Description

Repaglinide and metformin hydrochloride tablets contain two oral antihyperglycemic drugs used in the management of type 2 diabetes: repaglinide and metformin HCl. The concomitant use of repaglinide and metformin HCl has been previously approved based on clinical trials in patients with type 2 diabetes inadequately controlled on exercise, diet, and metformin HCl alone.

Repaglinide, S(+)2-ethoxy-4(2((3-methyl-1-(2-(1-piperidinyl) phenyl)-butyl) amino)-2-oxoethyl) benzoic acid, is chemically unrelated to the oral sulfonylurea insulin secretagogues. Repaglinide is a white to off-white powder with molecular formula C27H36N2O4 and a molecular weight of 452.6 with the structural formula as shown below. Repaglinide is freely soluble in methanol and ethanol. The pKa of repaglinide in acid is 3.9, and the pKa in amine is 6.0.

Structural formula of Repaglinide

Metformin HCl (N,N-dimethylimidodicarbonimidic diamide hydrochloride) is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents. Metformin HCl is a white to off-white crystalline compound with a molecular formula of C4H11N5•HCl and a molecular weight of 165.63. Metformin HCl is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin HCl is 12.4. The pH of a 1% aqueous solution of metformin HCl is 6.68. The structural formula of metformin HCl is:

Structural formula of Metformin HCl

Repaglinide and metformin hydrochloride tablets are available as tablets for oral administration containing 1 mg repaglinide with 500 mg metformin HCl (1 mg/500 mg) or 2 mg repaglinide with 500 mg metformin HCl (2 mg/500 mg) formulated with the following inactive ingredients: hypromellose 6cp, magnesium stearate, meglumine, microcrystalline cellulose, polacrillin potassium, poloxamer 188, polyethylene glycol, povidone, sorbitol, talc and titanium dioxide. Iron oxide yellow is present in the 1 mg/500 mg repaglinide and metformin hydrochloride tablets. Iron oxide red and propylene glycol are present in the 2 mg/500 mg repaglinide and metformin hydrochloride tablets.

Repaglinide and Metformin Tablets - Clinical Pharmacology

Mechanism of Action

Repaglinide and Metformin Hydrochloride Tablets

Repaglinide and metformin hydrochloride tablets combines two anti-hyperglycemic agents with different mechanisms of action to improve glycemic control in patients with type 2 diabetes.

Repaglinide lowers blood glucose levels by stimulating the release of insulin from the pancreas. This action is dependent upon functioning beta (β) cells in the pancreatic islets.

Repaglinide closes ATP-dependent potassium channels in the β-cell membrane by binding at characterizable sites. This potassium channel blockade depolarizes the β -cell, which leads to an opening of calcium channels. The resulting increased calcium influx induces insulin secretion. The ion channel mechanism is highly tissue selective with low affinity for heart and skeletal muscle.

Metformin is an anti-hyperglycemic agent, which improves glucose tolerance in patients with type 2 diabetes by lowering both the basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.

Pharmacokinetics

Repaglinide and Metformin Hydrochloride Tablets

The results of a bioequivalence study in healthy subjects (Table 2) demonstrated that repaglinide/metformin HCl 1 mg/500 mg and 2 mg/500 mg combination tablets are bioequivalent to co-administration of corresponding doses of repaglinide and metformin HCl as individual tablets. Repaglinide dose proportionality was demonstrated for repaglinide and metformin hydrochloride tablets (2 mg/500 mg) and repaglinide and metformin hydrochloride tablets (1 mg/500 mg).

Table 2. Mean (SD) Pharmacokinetic Parameters for Repaglinide and Metformin

Treatment:

A = 2 mg/500 mg repaglinide and metformin hydrochloride tablet

B = 2 mg repaglinide tablet + 500 mg metformin HCl tablet

C = 1 mg/500 mg repaglinide and metformin hydrochloride tablet



Pharmacokinetic Parameter
Treatment
N
AUC (ngh/mL)
Cmax (ng/mL)
Repaglinide



A
55
34.5 (13.3)
26.0 (13.7)
B
55
35.0 (13.2)
23.7 (12.5)
C
55
17.6 (6.6)
12.9 (6.9)
Metformin



A
55
6041.9 (1494.6)
838.8 (210.2)
B
55
5871.6 (1352.6)
805.9 (160.3)
C
55
5948.9 (1442.0)
799.4 (174.6)

Absorption and Bioavailability:

Repaglinide

After single and multiple oral doses in healthy subjects or in patients with type 2 diabetes, peak plasma drug levels (Cmax) occur within 1 hour (Tmax). Repaglinide is eliminated from the blood stream with a half-life of approximately 1 hour. The mean absolute bioavailability is 56%. When repaglinide was given with food, the mean Tmax was not changed, but the mean Cmax and AUC (area under the time/plasma concentration curve) were decreased 20% and 12.4%, respectively.

Metformin HCl

The absolute bioavailability of a 500 mg metformin HCl tablet given under fasting conditions is approximately 50% to 60%. Studies using single oral doses of metformin HCl tablets of 500 mg to 1,500 mg, and 850 mg to 2,550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination. Food decreases the extent of and slightly delays the absorption of metformin, as shown by approximately a 40% lower peak concentration (Cmax), a 25% lower area under plasma concentration (AUC) and a 35-minute prolongation of time to peak plasma concentration (Tmax) following administration of a single 850 mg tablet of metformin HCl with food, compared to the same tablet strength administered fasting. The clinical relevance of these decreases is unknown.

Distribution:

Repaglinide

After intravenous (IV) dosing in healthy subjects, the volume of distribution at steady state (Vss) was 31 L, and the total body clearance (CL) was 38 L/h. Protein binding and binding to human serum albumin was greater than 98%.

Metformin HCl

The apparent volume of distribution (V/F) of metformin following single oral dose of 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of metformin HCl, steady state plasma concentrations of metformin are reached within 24 to 48 hours and are generally < 1 mcg/mL. During controlled clinical trials, maximum metformin plasma levels did not exceed 5 mcg/mL, even at maximum doses.

Metabolism and Elimination:

Repaglinide

Repaglinide is completely metabolized by oxidative biotransformation and direct conjugation with glucuronic acid after either an intravenous or oral dose. The major metabolites are an oxidized dicarboxylic acid (M2), the aromatic amine (M1), and the acyl glucuronide (M7). The cytochrome P-450 enzyme system, specifically 2C8 and 3A4, have been shown to be involved in the N-dealkylation of repaglinide to M2 and the further oxidation to M1. Metabolites do not contribute to the glucose-lowering effect of repaglinide. Within 96 hours after dosing with 14C-repaglinide as a single, oral dose, approximately 90% of the radiolabel was recovered in the feces and approximately 8% in the urine. Only 0.1% of the dose is cleared in the urine as parent compound. The major metabolite (M2) accounted for 60% of the administered dose. Less than 2% of parent drug was recovered in feces. Repaglinide appears to be a substrate for active hepatic uptake transporter (organic anion transporting protein OATP1B1).

Metformin HCl

Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) or biliary excretion. Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.

Specific Populations:

Renal Impairment

Repaglinide:

Single-dose and steady-state pharmacokinetics of repaglinide were compared between patients with type 2 diabetes and normal renal function (CrCl > 80 mL/min), mild to moderate renal function impairment (CrCl = 40 to 80 mL/min), and severe renal function impairment (CrCl = 20 to 40 mL/min). Both AUC and Cmax of repaglinide were similar in patients with normal and mild to moderately impaired renal function (mean values 56.7 ng/mL*hr vs 57.2 ng/mL*hr and 37.5 ng/mL vs 37.7 ng/mL, respectively). Patients with severely reduced renal function had elevated mean AUC and Cmax values (98.0 ng/mL*hr and 50.7 ng/mL, respectively), but this study showed only a weak correlation between repaglinide levels and creatinine clearance.

Metformin HCl:

In patients with decreased renal function, the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased [see CONTRAINDICATIONS (4) and WARNINGS AND PRECAUTIONS (5.1)].

Hepatic Impairment

Repaglinide:

A single-dose, open-label study was conducted in 12 healthy subjects and 12 patients with chronic liver disease (CLD) classified by Child-Pugh scale and caffeine clearance. Patients with moderate to severe impairment of liver function had higher and more prolonged serum concentrations of both total and unbound repaglinide than healthy subjects (AUChealthy: 91.6 ng/mL*hr; AUCcld patients:368.9 ng/mL*hr; Cmax, healthy: 46.7 ng/mL; Cmax, CLD patients: 105.4 ng/mL). AUC was statistically correlated with caffeine clearance. No difference in glucose profiles was observed across patient groups. Patients with impaired liver function may be exposed to higher concentrations of repaglinide and its associated metabolites than would patients with normal liver function receiving usual doses. Therefore, repaglinide should generally be avoided in patients with impaired liver function.

Metformin HCl:

No pharmacokinetics studies with metformin HCl have been conducted in patients with hepatic impairment.

Geriatric Patients

Healthy volunteers treated with repaglinide 2 mg before each of 3 meals, showed no significant differences in repaglinide pharmacokinetics between the group of patients <65 years of age and those ≥65 years of age.

Limited data from controlled pharmacokinetic studies of metformin HCl in healthy elderly subjects suggest that total plasma clearance is decreased, the half-life is prolonged, and Cmax is increased, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function [see WARNINGS AND PRECAUTIONS (5.2)].

Drug Interactions:

Table 3: Effect of Other Drugs on AUC and Cmaxof Metformin

Unless indicated all drug interactions were observed with single dose co-administration

*single and multiple dose co-administration

↑ indicates increase

↓ indicates decrease

Study Drug*
Metformin AUC
Metformin Cmax
Cimetidine
40% ↑
60% ↑
Furosemide
15% ↑
22% ↑
Nifedipine
9% ↑
20% ↑
Propranolol-metformin
10% ↓
6%  ↓
Ibuprofen-metformin
5% ↑
7% ↑
Table 4: Effect of Other Drugs on AUC and Cmax of Repaglinide

Unless indicated all drug interactions were observed with single dose of 0.25 mg repaglinide

1Coadministration of gemfibrozil with repaglinide and metformin hydrochloride tablets is not recommended [see WARNINGS AND PRECAUTIONS (5.7) and DRUG INTERACTIONS (7.2)]

2 Single dose of 2 mg repaglinide was administered

32 mg repaglinide was administered TID for 4 days

4 Single dose of 4 mg repaglinide was administered

5 Two doses, twelve hours apart, healthy volunteers

6Single dose of 0.5 mg repaglinide was administered

↑ indicates increase

↓ indicates decrease

* Indicates data are from published literature

Study Drug
Dose Other Drug
Duration 
Repaglinide


Other Drug
AUC
Cmax
Clarithromycin*
250 mg BID
4 days
40% ↑
67% ↑
Cyclosporine
100 mg5
1 day
2.5 fold ↑
1.8 fold ↑
Deferasirox*
30 mg/kg QD6 
4 days  
2.3 fold ↑  
62% ↑  
Fenofibrate
200 mg QD
5 days
0%
18% ↑
Gemfibrozil*1
600 mg BID
3 days
8.1 fold ↑
2.4 fold ↑
Itraconazole*
100 mg BID
3 days
1.4 fold↑
1.5 fold ↑
GemfibrozilItraconazole 
Co-administration*1
Gem: 600 mg BID; Itra: 100 mg BID
3 days
19 fold ↑
2.8 fold ↑
Ketoconazole2 200 mg QD
4 days
15% ↑
16% ↑
Levonorgestrel/ethinyl Estradiol3
(0.15 mg/0.03 mg) Combination tablet QD
21 days
1.4% ↓
20% ↑
Nifedipine*3 
10 mg TID
4 days
10% ↓
5 % ↓
Rifampin*4 600 mg QD
6 to 7 days
32 to 80% ↓
17 to 79% ↓
Simvastatin3
20 mg QD
4 days
2% ↑
26% ↑
Trimethoprim*
160 mg BID
3 days
61% ↑
41% ↑
Table 5: Effect of Metformin or Repaglinide on AUC and Cmaxof Other Drugs

1. When administered with metformin

2 Co-administration of a combination tablet (0.15 mg levonorgestrel/0.03 mg ethinyl estradiol) once daily for 21 days with 2 mg repaglinide administered TID (days 1 to 4) and a single dose on day 5.

↓ indicates decrease

↑ indicates increase

Other Drugs
AUC
Cmax
Furosemide1
12% ↓
31%↓
Ethinyl Estradiol2
20% ↑
20% ↑
Fenofibrate
0%
18% ↑

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Repaglinide and Metformin Hydrochloride Tablets

No animal studies have been conducted with the combined products in repaglinide and metformin hydrochloride tablets to evaluate carcinogenesis, mutagenesis and impairment of fertility. The following data are based on findings in studies performed with the individual components.

Repaglinide

In a 104-week carcinogenicity study in rats at doses up to 120 mg/kg/day, the incidences of benign adenomas of the thyroid and liver were increased in male rats. The higher incidences of thyroid and liver tumors in male rats were not seen at lower dose of 30 mg/kg/day and 60 mg/kg/day respectively (which are over 15 and 30 times, respectively, clinical exposures on a mg/m2 basis).

In a 104-week carcinogenicity study in mice at doses up to 500 mg/kg/day, no evidence of carcinogenicity was found in mice (which is approximately 125 times clinical exposure on a mg/m2 basis).

Repaglinide was non-genotoxic in a battery of in vivo and in vitro studies: Bacterial mutagenesis (Ames test), in vitro forward cell mutation assay in V79 cells (HGPRT), in vitro chromosomal aberration assay in human lymphocytes, unscheduled and replicating DNA synthesis in rat liver, and in vivo mouse and rat micronucleus tests.

In a rat fertility study, repaglinide was administered to male and female rats at doses up to 300 and 80 mg/kg/day, respectively. No adverse effects on fertility were observed (which are over 40 times clinical exposure on a mg/m2 basis).

Metformin HCl

In a 104-week carcinogenicity study in rats at doses up to 900 mg/kg/day, the incidences of benign stromal uterine polyps were increased in female rats at 900 mg/kg/day (which is approximately four times the maximal recommended human daily dose of 2000 mg of metformin HCl component of repaglinide and metformin hydrochloride tablets on a mg/m2 basis).

In a 91-week carcinogenicity study in mice at doses up to 1500 mg/kg/day, no evidence of carcinogenicity was found in mice (which is approximately four times the maximal recommended human daily dose of 2000 mg of metformin HCl component of repaglinide and metformin hydrochloride tablets on a mg/m2 basis).

There was no evidence of a mutagenic potential of metformin HCl alone in the following in vitro tests: Ames test (S. typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative.

In a rat fertility study, metformin HCl was administered to male and female rats at doses up to 600 mg/kg/day. No adverse effects on fertility were observed (which is approximately three times the maximal recommended human daily dose of 2000 mg of metformin HCl component of repaglinide and metformin hydrochloride tablets on a mg/m2basis).

Clinical Studies

Patients with Inadequate Glycemic Control on Metformin HCl Monotherapy

In a double-blind, clinical trial, 83 patients with type 2 diabetes and inadequate glycemic control on metformin HCl monotherapy were randomized to add-on repaglinide, repaglinide monotherapy, or continued treatment with metformin HCl monotherapy. The repaglinide dosage was titrated for 4 to 8 weeks, followed by a 3-month dose maintenance period. Repaglinide add-on to metformin HCl resulted in a statistically significant improvement in HbA1c and fasting plasma glucose compared to the monotherapy arms (Table 6). In this study where metformin HCl dosage was kept constant, repaglinide add-on to metformin HCl resulted in a greater reduction in HbA1c and fasting plasma glucose at a lower daily repaglinide dosage than in the repaglinide monotherapy group (dose sparing with respect to repaglinide). However, the repaglinide add-on to metformin HCl group had a higher incidence of hypoglycemia than the repaglinide monotherapy group [see ADVERSE REACTIONS (6.2)]. The 2 repaglinide treatment arms experienced weight gain, whereas the metformin HCl monotherapy arm had weight loss.

Table 6. Repaglinide as Add-on to Metformin HCl: Mean Changes from Baseline in Glycemic Parameters and Body Weight After 4 to 5 Months of Treatment1

Repaglinide add-on to Metformin HCl
Repaglinide monotherapy
Metformin HCl monotherapy
N
27
28
27
Median Final Dose (mg/day)
6 (repaglinide)
1500 (metformin HCl)
12
1500
HbA1c (%)



Baseline
8.3
8.6
8.6
Change from baseline
-1.4*
-0.4
-0.3
Fasting plasma glucose (mg/dL)



Baseline
184
174
194
Change from baseline
-39*
+9
-5
Weight (kg)



Baseline
93
87
91
Change from baseline
2.4#
3.0
-0.9
1: based on intent-to-treat analysis
*: p< 0.05, for pairwise comparisons with repaglinide and metformin HCl monotherapy.
#: p< 0.05, for pairwise comparisons with metformin HCl monotherapy.

How Supplied/Storage and Handling

Repaglinide and metformin hydrochloride tablets are supplied as biconvex tablets available in 1 mg/500 mg (yellow) and 2 mg/500 mg (pink) strengths. 1 mg/500 mg tablets are debossed with 'V41' on one side and 'LU' on the other side and 2 mg/500 mg tablets are debossed with 'V42' on one side and 'LU' on the other side. The tablets are colored to indicate strength.

1 mg repaglinide/500 mg metformin HCl tablets
(yellow)
Bottles of 100
Bottles of 500
Bottles of 1000 
NDC 68180-490-01
NDC 68180-490-02
NDC 68180-490-03
2 mg repaglinide/500 mg metformin HCl tablets
(pink)
Bottles of 100
Bottles of 500
Bottles of 1000
NDC 68180-491-01
NDC 68180-491-02
NDC 68180-491-03

Store at 25°C (77° F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

Protect from moisture. Keep bottles tightly closed.

Dispense in tight containers with safety closures.

Patient Counseling Information

Physician Instructions

Patients should be informed of the potential risks and advantages of repaglinide and metformin hydrochloride tablets and of alternative modes of therapy. They should also be informed about the importance of adherence to dietary instructions, of a regular exercise program, and of regular testing of blood glucose, HbA1c, renal function, and hematologic parameters. The risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development and concomitant administration of other glucose-lowering drugs should be explained to patients and family members. Medication requirements may change during periods of stress such as fever, trauma, infection, or surgery, due to loss of glycemic control. Patients should be advised to seek medical advice promptly.

The risks of lactic acidosis, its symptoms, and conditions that predispose to its development, as noted in the WARNINGS AND PRECAUTIONS (5.1), should be explained to patients. Patients should be advised to discontinue repaglinide and metformin hydrochloride tablets immediately and to promptly notify their health practitioner if unexplained hyperventilation, myalgia, malaise, unusual somnolence, or other nonspecific symptoms occur. Once a patient is stabilized on any dose level of repaglinide and metformin hydrochloride tablets, gastrointestinal symptoms, which are common during initiation of metformin HCl therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease. Instruct patients to inform their doctor that they are taking repaglinide and metformin hydrochloride tablets prior to any surgical or radiological procedure, as temporary discontinuation of repaglinide and metformin hydrochloride tablets may be required until renal function has been confirmed to be normal [see WARNINGS AND PRECAUTIONS (5.1)].

Patients should be instructed to take repaglinide and metformin hydrochloride tablets with meals. Doses are usually taken within 15 minutes prior to the meal but the timing can vary from immediately preceding the meal up to 30 minutes before the meal. Patients who skip a meal should be instructed to skip the repaglinide and metformin hydrochloride tablets dose for that meal.

Patients should be counseled against excessive alcohol intake, either acute or chronic, while receiving repaglinide and metformin hydrochloride tablets.

Laboratory Tests

Initial and periodic monitoring of hematologic parameters (e.g., hemoglobin/hematocrit and red blood cell indices) and renal function (serum creatinine) should be performed, at least on an annual basis. Vitamin B12 deficiency should be excluded if megaloblastic anemia is detected.

Manufactured for:

Lupin Pharmaceuticals, Inc.

Baltimore, Maryland 21202

United States

Manufactured by:

Lupin Limited

Goa 403 722

INDIA

Revised: June 21, 2017                                                                                                  ID#: 252006

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

Repaglinide and Metformin Hydrochloride Tablets

1 mg/500 mg – Bottle of 100s

NDC 68180-490-01

Repaglinide and Metformin Hydrochloride Tablets

2 mg/500 mg – Bottle of 100s

NDC 68180-491-01

REPAGLINIDE AND METFORMIN HYDROCHLORIDE 
repaglinide and metformin hydrochloride tablet
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:68180-490
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
METFORMIN HYDROCHLORIDE (METFORMIN) METFORMIN HYDROCHLORIDE 500 mg
REPAGLINIDE (REPAGLINIDE) REPAGLINIDE 1 mg
Inactive Ingredients
Ingredient Name Strength
CELLULOSE, MICROCRYSTALLINE  
FERRIC OXIDE YELLOW  
HYPROMELLOSE 2910 (6 MPA.S)  
MAGNESIUM STEARATE  
MEGLUMINE  
POLACRILIN POTASSIUM  
POLOXAMER 188  
POLYETHYLENE GLYCOLS  
POVIDONE  
SORBITOL  
TALC  
TITANIUM DIOXIDE  
Product Characteristics
Color YELLOW (yellow) Score no score
Shape OVAL (biconvex) Size 5mm
Flavor Imprint Code V41;LU
Contains     
Packaging
# Item Code Package Description
1 NDC:68180-490-01 100 TABLET in 1 BOTTLE
2 NDC:68180-490-03 1000 TABLET in 1 BOTTLE
3 NDC:68180-490-02 500 TABLET in 1 BOTTLE
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA200624 12/10/2015
REPAGLINIDE AND METFORMIN HYDROCHLORIDE 
repaglinide and metformin hydrochloride tablet
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:68180-491
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
METFORMIN HYDROCHLORIDE (METFORMIN) METFORMIN HYDROCHLORIDE 500 mg
REPAGLINIDE (REPAGLINIDE) REPAGLINIDE 2 mg
Inactive Ingredients
Ingredient Name Strength
CELLULOSE, MICROCRYSTALLINE  
FERRIC OXIDE RED  
HYPROMELLOSE 2910 (6 MPA.S)  
MAGNESIUM STEARATE  
MEGLUMINE  
POLACRILIN POTASSIUM  
POLOXAMER 188  
POLYETHYLENE GLYCOLS  
POVIDONE  
PROPYLENE GLYCOL  
SORBITOL  
TALC  
TITANIUM DIOXIDE  
Product Characteristics
Color PINK (pink) Score no score
Shape OVAL (biconvex) Size 5mm
Flavor Imprint Code V42;LU
Contains     
Packaging
# Item Code Package Description
1 NDC:68180-491-01 100 TABLET in 1 BOTTLE
2 NDC:68180-491-03 1000 TABLET in 1 BOTTLE
3 NDC:68180-491-02 500 TABLET in 1 BOTTLE
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA200624 12/10/2015
Labeler - Lupin Pharmaceuticals, Inc. (089153071)
Registrant - LUPIN LIMITED (675923163)
Establishment
Name Address ID/FEI Operations
LUPIN LIMITED 677600414 manufacture(68180-490, 68180-491), pack(68180-490, 68180-491)
Revised: 06/2017
 
Lupin Pharmaceuticals, Inc.
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