Repaglinide and Metformin Hydrochloride

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Overview

What is Repaglinide and Metformin Hydrochloride?

Repaglinide and metformin hydrochloride tablets for oral use contain repaglinide, a glinide, and metformin, a biguanide.

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 CHNO 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.

Metformin hydrochloride (N,N-dimethylimidodicarbonimidic diamide hydrochloride) is a white to off-white crystalline compound with a molecular formula of CHN•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 hydrochloride is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68. The structural formula of metformin hydrochloride is:

Repaglinide and metformin hydrochloride tablets contain 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.

What does Repaglinide and Metformin Hydrochloride look like?

What are the available doses of Repaglinide and Metformin Hydrochloride?

Tablets:

What should I talk to my health care provider before I take Repaglinide and Metformin Hydrochloride?

How should I use Repaglinide and Metformin Hydrochloride?

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 glinide and metformin or who have inadequate glycemic control on a glinide alone or metformin alone.

Limitation of Use

Repaglinide and metformin hydrochloride tablets should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.

General Dosage and Administration information

Administer repaglinide and metformin hydrochloride tablets orally 2 to 3 times a day with meals up to a maximum daily dose of 10 mg repaglinide/2500 mg metformin. No more than 4 mg repaglinide/1000 mg metformin should be taken per meal.

Instruct patients to take repaglinide and metformin hydrochloride tablets within 30 minutes before meals. In patients who skip meals, instruct patients to skip the scheduled dose of repaglinide and metformin hydrochloride tablets to reduce the risk of hypogylcemia. In patients who experience hypoglycemia, the dose of repaglinide should be reduced .

Patients Inadequately Controlled with Metformin Monotherapy

The recommended starting dose of repaglinide and metformin hydrochloride tablets 1 mg repaglinide/500 mg metformin twice daily with meals. Gradually increase dose based on glycemic response to reduce the risk of hypoglycemia with repaglinide.

Patients Inadequately Controlled with Glinide Monotherapy

The recommended starting dose of metformin component of repaglinide and metformin hydrochloride tablets is 500 mg metformin twice daily with meals. Gradually increase dose based on glycemic response to reduce gastrointestinal side effects associated with metformin.

Patients Currently Using Repaglinide and Metformin Concomitantly

Initiate repaglinide and metformin hydrochloride tablets at the dose of repaglinide and metformin similar to (but not exceeding) the patient's current doses. Titrate as needed to achieve glycemic control up to the maximum daily dose.

What interacts with Repaglinide and Metformin Hydrochloride?

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What are the warnings of Repaglinide and Metformin Hydrochloride?

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What are the precautions of Repaglinide and Metformin Hydrochloride?

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What are the side effects of Repaglinide and Metformin Hydrochloride?

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What should I look out for while using Repaglinide and Metformin Hydrochloride?

ID1042

Repaglinide and metformin hydrochloride tablets are contraindicated in patients with:

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

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

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

What might happen if I take too much Repaglinide and Metformin Hydrochloride?

Repaglinide

Severe hypoglycemic reactions with coma, seizure, or other neurological impairment may occur and constitute medical emergencies requiring immediate hospitalization. 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 may 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.

Metformin

Overdose of metformin has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases 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 overdosage is suspected.

How should I store and handle Repaglinide and Metformin Hydrochloride?

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

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Clinical Information

Chemical Structure

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Clinical Pharmacology

Repaglinide and Metformin Hydrochloride Tablets

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 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.

Non-Clinical Toxicology

ID1042

Repaglinide and metformin hydrochloride tablets are contraindicated in patients with:

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

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

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

Inhibitors of CYP3A4 and CYP2D6

After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the oxycodone plasma concentration will decrease [see ], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to Oxycodone and Acetaminophen Tablets.

If concomitant use is necessary, consider dosage reduction of Oxycodone and Acetaminophen Tablets until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the Oxycodone and Acetaminophen Tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.

After stopping a CYP3A4 inducer, as the effects of the inducer decline, the oxycodone plasma concentration will increase [see ], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.

If concomitant use is necessary, consider increasing the Oxycodone and Acetaminophen Tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider Oxycodone and Acetaminophen Tablets dosage reduction and monitor for signs of respiratory depression.

Benzodiazepines and Other CNS Depressants

Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see ].

Serotonergic Drugs

If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Oxycodone and Acetaminophen Tablets if serotonin syndrome is suspected.

Monoamine Oxidase Inhibitors (MAOIs)

The use of Oxycodone and Acetaminophen Tablets is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.

If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.

Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics

Advise patient to avoid concomitant use of these drugs.

Muscle Relaxants

If concomitant use is warranted, monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Oxycodone and Acetaminophen Tablets and/or the muscle relaxant as necessary.

Diuretics

If concomitant use is warranted, monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.

Anticholinergic Drugs

If concomitant use is warranted, monitor patients for signs of urinary retention or reduced gastric motility when Oxycodone and Acetaminophen Tablets are used concomitantly with anticholinergic drugs.

Alcohol, ethyl

Oral Contraceptives

Charcoal (activated)

Beta Blockers (Propranolol)

Loop Diuretics

Lamotrigine

Probenecid

Zidovudine

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 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 post-marketing 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

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 Therefore, consider more frequent monitoring of patients.

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

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 m; 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.

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

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Reference

This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"

While we update our database periodically, we cannot guarantee it is always updated to the latest version.

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Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72

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Interactions

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