Repaglinide + Metformin

Repaglinide + Metformin is an Anti-diabetic Agent belonging to the pharmacological class of Meglitinides Derivatives and biguanides.

Repaglinide + Metformin is approved for treating type 2 diabetes mellitus in adults. It enhances insulin release and sensitivity. The combination of drugs helps regulate blood sugar levels and is a valuable therapy alternative for those with this condition.

Repaglinide enters the bloodstream rapidly, often taking an hour to reach peak plasma concentrations, and is mainly excreted via the liver. Metformin, on the other hand, is principally eliminated through the kidneys and has a longer elimination half-life. It is absorbed more slowly, reaching peak concentrations in two to three hours.

The common side effect of Repaglinide + Metformin is low blood glucose levels (hypoglycemia).

Repaglinide + Metformin is available as tablets for convenient administration.

Repaglinide + Metformin is available in the United States, Canada, the United Kingdom, Germany, France and Australia.

Repaglinide + Metformin is an anti-diabetic Agent belonging to the pharmacological class of Meglitinides Derivatives and biguanides.

Repaglinide: Repaglinide activity depends on the presence of active cells and glucose. Repaglinide does not affect insulin release without glucose, unlike sulfonylurea insulin secretagogues. Instead, it amplifies the effects of extracellular glucose on ATP-sensitive potassium channels while having minimal impact on insulin levels during the day and nighttime. As a result, Repaglinide is more effective in lowering postprandial blood glucose levels than fasting blood glucose levels and needs to be taken for a more extended period (about one month) before fasting blood glucose levels begin to decline. Repaglinide has the most excellent insulinotropic effects at intermediate glucose concentrations (3 to 10 mmol/L), but it does not boost insulin release that has already been triggered by high glucose concentrations (more than 15 mmol/L).

Metformin: Metformin decreases hepatic glucose production, reduces glucose absorption in the intestine and improves insulin sensitivity (increases peripheral glucose uptake and utilization).

Synergistic Benefits: When controlling diabetes, metformin and repaglinide work synergistically. Metformin lowers the amount of glucose the liver produces and improves insulin sensitivity, whereas Repaglinide acts quickly to stimulate insulin release. This dual-action effect contributes to improved blood sugar regulation. The combination improves glycemic control throughout the day, particularly during meals, by addressing various facets of glucose regulation. It reduces the possibility of hypoglycemia and weight gain, which are frequently linked to other medications. Repaglinide + Metformin is an excellent combination for type 2 diabetics looking for better blood sugar control because of their synergistic action.

Data Onset of action of Repaglinide + Metformin typically occurs within 30 minutes after taking the medication.

Data duration of action of Repaglinide + Metformin effects typically lasts several hours, 4-5 hours after administration.

The Data of Tmax (time to peak concentration) of Repaglinide + Metformin typically occurs within 1 to 1.5 hours after oral administration.

The Data of Cmax of Repaglinide + Metformin is typicallywithin 1 to 1.5 hours after oral administration.

Repaglinide + Metformin is available in oral tablets.

Tablets: To be swallowed whole with water/liquid. Do not chew, crush or break it.

As the physician recommends, take the medication orally once daily, generally with a meal.

Repaglinide: It increases the amount of insulin the body produces (in the pancreas), helping treat type 2 diabetes mellitus. Insulin lowers blood glucose levels and prevents them from rising after meals.

Metformin: Metformin improves glucose tolerance by lowering basal and postprandial plasma glucose. It exerts its effect by decreasing hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis, delaying intestinal glucose absorption, and increasing insulin sensitivity by increasing peripheral glucose uptake and utilization.

Repaglinide + Metformin combination provides several therapeutic advantages to patients with type 2 diabetes. By decreasing the synthesis of glucose (Metformin) and increasing the release of insulin (Repaglinide), it lowers blood sugar. By reducing the risk of diabetes-related problems, the combination effectively controls blood sugar levels. As an adjunctive method of treating diabetes, it is beneficial for people who need better blood sugar control and for whom a single drug is insufficient.

Repaglinide + Metformin is indicated as an addition to diet and exercise in individuals with type 2 diabetes mellitus who are not responding well to meglitinide and metformin alone or who have insufficient glycemic control while using meglitinide or metformin alone.

Not for the management of diabetic ketoacidosis or type 1 diabetes.

Orally: Repaglinide + Metformin is available as a tablet that can be taken orally. Depending on the specific needs of individual patient, the recommended oral dosage for Repaglinide + Metformin is 8–12 hours apart. Although it can be administered only fifteen minutes before meals, it usually takes 15 minutes or more beforehand. The daily maximum is limited to 2500 mg of metformin and 10 mg of Repaglinide. The dosage should not exceed 1000 mg of metformin and 4 mg of Repaglinide per meal. Dosing should be individualized to meet the unique requirements of each patient, with an emphasis on both tolerability and effectiveness.

Repaglinide + Metformin has various strengths, such as 1mg+500mg or 2mg+500mg.

Repaglinide + Metformin is available in the form of Oral tablets.

Initial Repaglinide + Metformin dosage should be started at a level comparable to the patient's current Repaglinide + Metformin dosage, but not higher; titrate as needed to achieve the desired glycemic control.

Initially treated insufficiently with metformin or meglitinide monotherapy: 500 mg/1 mg PO q12hr ac initially.

Depending on glycemic response, dosage may be increased gradually.

Repaglinide + Metformin should be used in treating type 2 diabetes mellitus, along with appropriate dietary restrictions.

Limit consumption of alcohol and excessive drinking, which can lead to hypoglycemia (low blood sugar)

Maintain a consistent carbohydrate intake with your meals to help regulate blood sugar levels. Avoid excessive intake of high-sugar or high-fat foods.

Avoid consuming large amounts of grapefruit or grapefruit juice, as it may affect the metabolism of Repaglinide.

While taking this combination, it is advised to stay hydrated, consume a rich-balanced diet low in saturated fats and cholesterol—and drink plenty of vegetables, whole grains, fruits, and lean proteins in meals.

The dietary restriction should be individualized as per patient requirements.

Repaglinide + Metformin may be contraindicated in the following conditions:-

The adverse reactions related to Repaglinide + Metformin can be categorized as:-

The clinically relevant drug interactions of Repaglinide + Metformin are briefly summarized here:

The most common side effects of Repaglinide + Metformin include:

Repaglinide + Metformin should be prudent in the following group of special populations.

Pregnancy Category C: Use with caution if the benefits outweigh the risks.

Regardless of medication exposure, there is an established risk of birth abnormalities, loss, or other unfavorable result in all pregnancies. With appropriate metabolic control, this background risk may be reduced. It is higher in pregnancies affected by hyperglycemia. Good metabolic control must be maintained both before and throughout pregnancy in patients with diabetes or a history of gestational diabetes. It's crucial to monitor these patients' glucose management carefully.

Metformin passes across the placenta, and its amounts in maternal plasma may be similar.

When glycemic control is maintained, a mother using metformin for type 2 diabetes mellitus or gestational diabetes has not been linked to an increased risk of birth abnormalities or unfavourable fetal/neonatal outcomes.

Metformin may be an alternate medication for certain patients needing therapy for type 2 diabetes mellitus or gestational diabetes mellitus; however, according to ADA guidelines, other medicines should be used to treat diabetes in pregnant women.

A medication-associated risk of significant birth abnormalities, miscarriage, or unfavourable maternal or fetal outcomes has not been found in the limited information from case reports and case series that are currently available.

Given Repaglinide during organogenesis at around 60 and 1 times the maximum daily clinical dose, teratogenicity was not seen in rats or rabbits.

When rat dams were exposed to Repaglinide at doses up to four times clinical exposure, the offspring showed no skeletal deformations such as shortening, bending and thickening of the humerus during the postnatal period and were less viable. These effects occurred during days 17 to 22 of gestation and during lactation.

No information is available on Repaglinide's presence in human milk, its effects on nursing infants, or its impact on milk production.

Breast milk contains metformin.

Repaglinide is not advised for usage while nursing due to the risk of hypoglycemia in breastfed infants.

As per FDA, safety and effectiveness in the pediatric population have yet to be established.

Repaglinide + Metformin proved to be safe and beneficial for the older population. However, lower starting doses and careful monitoring are frequently advised to prevent hypoglycemia, a potential problem in older persons due to age-related changes in drug metabolism.

To achieve targeted glycemic control, titrate as needed. The initial Repaglinide + Metformin dose should be started at a level comparable to the patient's existing repaglinide/metformin dosage, but not higher.

Before determining a patient's normal renal function, do not administer it to those older than 80.

Initially treated insufficiently with 500 mg/1 mg PO q12hr ac of meglitinide or metformin monotherapy.

May raise the dosage cautiously and gradually on the glycemic response.

Before determining a patient's normal renal function, do not administer it to those older than 80.

Before starting metformin, assess the eGFR.

Measure eGFR before beginning metformin therapy. If eGFR is >30 mL/min/1.73 m², treatment should not be started. If eGFR is between 30 and 45 mL/min/1.73 m², treatment should not be started.

Check eGFR once a year or more frequently if you are at risk of renal impairment (older people, for example).

When taking metformin, eGFR drops below 45 mL/min/1.73 m². The risks and advantages of continued medication should be assessed.

While taking metformin, stop the medication if your eGFR falls below 30 mL/min/1.73 m².

Hepatic impairment: Do not administer

The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of Repaglinide + Metformin.

Overconsumption of Repaglinide + Metformin could lead to severe hypoglycemia (low blood sugar), leading to symptoms such as sweating, tremors, confusion, dizziness, weakness, palpitations, and in extreme cases, loss of consciousness or seizures.

There is no specific antidote or treatment for excessive intake of Repaglinide + Metformin. However, immediate medical attention is essential. Repaglinide + Metformin should be terminated immediately when an overdose is suspected or if any unusual symptoms occur after intake.

If the patient is conscious and can swallow safely, administer oral glucose (e.g., glucose gel or tablets). If they cannot eat or are severely hypoglycemic, administer intravenous (IV) dextrose.

Supportive care may include the management of symptoms, such as providing fluids and electrolytes if necessary and administering antiemetic medications for nausea and vomiting. In cases of severe hypoglycemia, medical professionals will closely monitor and manage the patient until their condition stabilizes.

Repaglinide: Repaglinide activity depends on the presence of active cells and glucose. Repaglinide does not affect insulin release without glucose, unlike sulfonylurea insulin secretagogues. Instead, it amplifies the effects of extracellular glucose on ATP-sensitive potassium channels while having minimal impact on insulin levels during the day and nighttime. As a result, Repaglinide is more effective in lowering postprandial blood glucose levels than fasting blood glucose levels and needs to be taken for a more extended period (about one month) before fasting blood glucose levels begin to decline. Repaglinide has the most excellent insulinotropic effects at intermediate glucose concentrations (3 to 10 mmol/L), but it does not boost insulin release that has already been triggered by high glucose concentrations (more than 15 mmol/L).

Metformin: Metformin is an antihyperglycemic medication that lowers basal and postprandial plasma glucose levels in people with type 2 diabetes, improving their glucose tolerance. Its pharmacologic modes of action are distinct from those of other oral antihyperglycemic medication groups. Metformin increases peripheral glucose uptake and utilization, which lowers intestinal glucose absorption, reduces hepatic glucose synthesis, and enhances insulin sensitivity. Metformin, unlike sulfonylureas, does not result in hyperinsulinemia or hypoglycemia in either type 2 diabetes patients or healthy persons. Metformin medication does not alter insulin secretion, although it may reduce the plasma insulin response throughout the day and insulin levels while fasting.

Repaglinide: Following oral administration, it is rapidly and entirely absorbed. Peak plasma concentrations are observed within an hour (between 0.5 and 1.4 hours). There is around 56% absolute bioavailability. The biological action peaks in 3-3.5 hours, and higher plasma insulin levels last 4-6 hours. The area under the curve (AUC) for Repaglinide is 18.0 to 18.7 (ng/mL/h) when a single 2 mg dosage is administered to healthy subjects.

Metformin: Slowly and incompletely absorbed from the gastrointestinal tract. Food slightly delays and decreases the extent of absorption. Absolute bioavailability: 50-60%. Time to peak plasma concentration: 2-3 hours (immediate-release); 7 hours, range: 4-8 hours (extended-release).

Bioavailability: 50-60% (Metformin [fasted])

Repaglinide: After intravenous (IV) dosing, the volume of distribution at steady state (Vss) and whole-body clearance (CL) in healthy participants were 31 L and 38 L/h, respectively—more than 98% of the proteins bound to human serum albumin.

Metformin: Concentrates in the liver, kidney and gastrointestinal tract. It crosses the placenta and then enters breast milk (small amounts). Volume of distribution: 654 ± 358 L.

Protein-bound: Negligible (Metformin)

Repaglinide: Cytochrome P450 3A4 and 2C9 rapidly metabolize Repaglinide by oxidizing and dealkylating it to produce the primary dicarboxylic acid derivative (M2). The aromatic amine derivative (M1) is produced by further oxidation. Repaglinide's carboxylic acid group can be glucuronidated to produce an acyl glucuronide (M7). Other unidentified metabolites have also been found. There is no apparent hypoglycemia action in repaglinide metabolites.

Metformin: Excreted unchanged in the urine and did not undergo specific hepatic metabolism (no metabolites have been found in humans) or biliary excretion.

Repaglinide: Within 96 hours of administering a single oral dosage of 14C-repaglinide, 90% of the radiolabel was found in the faeces and 8% in the urine. Only 0.1% of the dosage is excreted as the parent chemical in the urine. 60% of the dosage delivered comprised the primary metabolite (M2). In faeces, less than 2% of the parent drug was found.

Metformin: With a plasma elimination half-life of roughly 6.2 hours, 90% of the absorbed medication is excreted via the renal pathway during the first 24 hours following oral administration. The elimination half-life of blood is roughly 17.6 hours, indicating that the erythrocyte bulk could constitute a distribution compartment.

Metformin decreases hepatic glucose synthesis and increases insulin sensitivity, while Repaglinide enhances the pancreas' insulin release. This combination helps in efficient blood sugar regulation.

Repaglinide is an insulin secretagogue with an immediate half-life that can be given before meals. This maintains blood sugar rises after meals under control and within the desired range.