Repaglinide

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

Repaglinide is approved for treating type 2 diabetes mellitus in adults. It helps reduce blood sugar levels by stimulating the pancreas to produce more insulin, mainly after meals, to prevent post-meal glucose rises.

Repaglinide is absorbed rapidly from the gastrointestinal tract (GIT), with peak plasma concentrations occurring within 1 hour after oral administration. It has a short elimination half-life of about 1 hour, and its primary metabolites are excreted in the bile and faeces.

Low blood sugar levels, or hypoglycemia, is Repaglinide's most common side effect. Other common side effects of this drug include diarrhoea, nausea, back discomfort, joint pain, and sinus inflammation.

Repaglinide is available in the form of oral tablets.

The molecule is available in the United States, Canada, the United Kingdom, Australia, Germany, India and Japan.

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

Repaglinide activity is dependent 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).

Repaglinide does not affect thyroid, skeletal, or cardiac muscle and appears selective for pancreatic cells.

Data duration of Repaglinide action lasting about 4 to 6 hours after each dose.

The Data of Tmax of Repaglinide typically occurs within 1 hour after oral administration.

Repaglinide is available in the form of 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; it is best taken before meals.

Treatment of Type 2 diabetes mellitus

Repaglinide can be used to treat Diabetes mellitus type 2 treatment, a disease marked by elevated blood sugar levels. Encouraging the pancreas to produce more insulin aids in lowering blood glucose levels. To boost glycemic control in those with type 2 diabetes, Repaglinide is frequently recommended, combined with a healthy diet and exercise regimen. It is commonly taken before meals to control how blood sugar levels react to food consumption.

In Treatment of Type 2 diabetes mellitus

Repaglinide increases the amount of insulin your body produces (in the pancreas). The insulin lowers your blood glucose levels and prevents them from rising after meals.

To effectively manage diabetes, the blood glucose levels must be reduced. Controlling blood sugar levels will lower the likelihood of any of the severe complications of diabetes, including kidney damage, eye damage, nerve problems, and amputation of limbs. The risk of cardiac disease and stroke can be decreased with proper diabetes management. Individuals can live longer if they take this medication consistently and follow a healthy diet and exercise routine.

It is indicated as an adjunct to exercise and diet to help individuals with type 2 diabetes mellitus (T2DM) in adults to improve their glycemic control.

Orally: Repaglinide is available as a tablet that can be taken orally. Repaglinide should be taken on an empty stomach or with food, usually 15 to 30 minutes before eating. It is best to take it regularly at a fixed time each day following the physician's prescribed schedule for regular and evenly spaced intervals because the dose and duration of therapy are individualized per specific conditions to achieve the most effective and successful treatment outcome. If a meal is skipped, the corresponding amount of Repaglinide should also be skipped to avoid the risk of hypoglycemia (low blood sugar).

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Tablets: 0.5mg, 1mg or 2mg

Repaglinide is available in the form of oral tablets.

Dose Adjustment in Adult Patients:

Diabetes Mellitus Type 2

In response to variations in meal schedules, it may be dosed two, three, or four times a day.

Starting dose

HbA1c <8%: 0.5 mg orally before each meal

HbA1c ≥8%: 1 to 2 mg orally before each meal

Dosage range

Dose range: 0.5 to 4 mg before meals

16 mg/day is the maximum permitted dosage per day.

Dosage adjustment

When glycemic control is achieved, double the dosage up to 4 mg with each meal.

Following each dose modification, wait at least a week before evaluating the reaction.

Meals skipped: To lower the risk of hypoglycemia, advise patients not to take the usual repaglinide dosage.

Reduce the daily amount of Repaglinide if hypoglycemia occurs.

Dosing Considerations

Therapy in combination

Add thiazolidinedione or metformin if monotherapy does not provide satisfactory glycemic control.

Repaglinide may be added if thiazolidinedione, in addition to metformin, is insufficient for glycemic control.

Like repaglinide monotherapy, combination therapy's starting dosage and dose modifications are the same.

Repaglinide should be used in treating Type 2 Diabetes Mellitus, along with appropriate nutritional limits.

While taking Repaglinide, maintain regular meal schedules with balanced macronutrient content to help stabilize blood sugar levels. It is advised to take Repaglinide just before or up to 30 minutes before a meal. Skipping meals or delaying meals while on this medication can lead to low blood sugar (hypoglycemia).

Reduce the intake of high-sugar foods and beverages, as it can cause rapid spikes in blood sugar levels.

Avoid excessive consumption of grapefruit or its juice, as it may interact with Repaglinide.

Limit or avoid the intake of alcohol as it can interfere with blood sugar regulation.

Staying hydrated and maintaining a rich, balanced diet with appropriate fibre-rich foods like fruits, vegetables, whole grains, and lean proteins is advised to help manage your overall health and blood sugar levels effectively.

The dietary restriction should be individualized as per patient requirements.

Repaglinide may be contraindicated in the following conditions:-

• Hypersensitivity reaction to Repaglinide or any inactive ingredients
• Concomitant use of gemfibrozil results in increased repaglinide plasma concentration (8-fold increase); it may lead to severe hypoglycemia
• Diabetic ketoacidosis
• Type I diabetes mellitus

• Stress caused by an illness, a fever, trauma, or surgery; stopping if stressed.

• Repaglinide, a substrate for active hepatic uptake transporter, may accumulate in the plasma concentrations of drugs that block the organic anion transporting protein OATP1B1 (such as cyclosporine).

• Individuals with hepatic/renal insufficiency should be cautious while administrating Repaglinide.

• The use of sulfonylureas may be associated with increased cardiovascular events.

• Cautious should be taken while administrating the drug to pregnant and lactating mothers.

• Individuals at high risk for severe hypoglycemia: elderly, disabled, or undernourished; inadequacy of the adrenal or pituitary glands

• Patients using NPH-insulin concurrently have reported experiencing myocardial ischemia; nonetheless, this combination is not recommended.

• With elderly and malnourished patients, continue with caution.

It is unsafe to consume Repaglinide with alcohol.

Not recommended for use during breastfeeding.

Safe to use during pregnancy only if the possible benefit outweighs the potential risk to the foetus.

Limit alcohol or grapefruit consumption and reduce intake of high-sugar foods and beverages.

The adverse reactions related to Repaglinide can be categorized as

• Common Adverse Effects: Hypoglycemia, upper respiratory infection, headache
• Less Common Adverse Effects: Back pain, sinusitis, arthralgia, bronchitis, diarrhoea, serious CV events, chest pain, constipation
• Rare Adverse Effects: Increased LFTs, thrombocytopenia, leukopenia, hemolytic anaemia, pancreatitis, visual disturbances, anaphylactoid reactions

The clinically relevant drug interactions of Repaglinide are briefly summarized here.

• Medications That Increase Blood Sugar (Hyperglycemia): Certain medications, such as corticosteroids (e.g., prednisone), diuretics (e.g., hydrochlorothiazide), and some antipsychotic drugs (e.g., olanzapine), can raise blood sugar levels. Combined with Repaglinide, this may lead to higher blood sugar levels and reduced medication effectiveness.
• Medications That Lower Blood Sugar (Hypoglycemia): Other diabetes medications like insulin, sulfonylureas (e.g., glipizide), and certain antidiabetic drugs (e.g., metformin) can higher the risk of low blood sugar (hypoglycemia) when taken alongside Repaglinide. Close monitoring of blood sugar levels is crucial to avoid severe hypoglycemia.
• Gemfibrozil: This medication, used to lower cholesterol and triglyceride levels, can significantly increase the levels of Repaglinide in the bloodstream. It should be avoided when taking Repaglinide due to the risk of severe hypoglycemia.
• CYP2C8 and CYP3A4 Inducers: Drugs that induce the CYP3A4 and/or 2C8 enzyme systems include rifampin, barbiturates, and carbamazepine. Dosage adjustments are recommended in patients taking strong CYP3A4 or CYP2C8 inhibitors or strong CYP3A4 or CYP2C8 inducers.

The most common side effects of Repaglinide include:

• Pain in the stomach
• Nausea
• Low blood sugar (hypoglycemia).
• Diarrhoea
• Back pain
• The pain in one's joints
• An upper respiratory infection
• Headache
• Sinus inflammation

• Pregnancy

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

Repaglinide use during pregnancy has not been associated with an increased risk of severe birth abnormalities, miscarriage, or bad maternal or foetal outcomes, according to the scant evidence from case reports and case series.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

Pregnant women with poorly managed diabetes have an increased risk of developing diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm birth, stillbirth, and delivery complications. Significant birth abnormalities, stillbirths, and macrosomia-related morbidity are more likely in foetuses with poorly managed diabetes.

Animal Data

When given to rats or rabbits throughout the organogenesis stage, Repaglinide was not teratogenic at doses that were 60 times (for the rats) and around one time (for the rabbits) the therapeutic exposure (measured in mg/m2). Repaglinide caused skeletal deformations such as shortening, thickness, and bending of the humerus in the postnatal period in the offspring of rat mothers exposed to the drug at 22 times clinical exposure on a mg/m2 basis from days 17 to 22 of pregnancy and throughout nursing. These offspring were also less viable. This impact was not observed at dosages up to 4 times the clinical exposure (on a mg/m2 basis).

• Nursing Mothers

No information is available on Repaglinide's presence in human milk, its effects on nursing infants, or its impact on milk production. Animal milk includes the medication. A medication will likely be present in human milk if found in animal milk. Repaglinide is not advised for usage while nursing since it may induce hypoglycemia in breastfed babies.

Animal data

Detected in the rat mothers' breast milk, the pups' blood sugar levels are lower.

Studies on cross-fostering showed that, to a smaller extent than in pups treated in gestation, skeletal abnormalities might be generated in control pups fed by treated moms.

• Pediatric Use

As per the FDA, safety and effectiveness in the pediatric population have not been established.

• Geriatric Use

In clinical investigations lasting 24 weeks or more, 415 individuals were over 65, and none were over 75. There were no efficacy or adverse events differences between these participants and those under 65 in one-year, active-controlled studies. Older patients did not see an increase in hypoglycemia frequency or severity, although it is possible that some older people may be more sensitive to repaglinide treatment.

Dose Adjustment in Kidney Impairment Patients:

CrCl 40-80 mL/min: no adjustments are required

CrCl 20–40 mL/min: 0.5 mg given with meals; titrate gradually and monitor

CrCl < 20 mL/min: Insufficient data

Dose Adjustment in Hepatic Impairment Patients:

Use cautious starting and maintenance doses; wait for dosage modifications for longer intervals.

Signs and Symptoms

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

Overconsumption of Repaglinide may include hypoglycemia (low blood sugar) and, in severe cases, unconsciousness or seizures.

Management

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

Hypoglycemic symptoms without loss of consciousness or neurologic symptoms should be immediately addressed with oral glucose and dose and/or meal schedule changes.

In severe cases, glucagon injection or intravenous dextrose may be needed.

Management typically involves supportive measures that may include addressing associated symptoms or complications.

If hypoglycemia (low blood sugar) occurs, appropriate measures should be taken to raise blood glucose levels, such as administering glucose or high-sugar foods and beverages.

Maintain a healthy lifestyle through proper nutritional diet, regular physical activity, and stress management. These factors can help improve blood sugar control and reduce the risk of hypoglycemia.

Pharmacodynamics:

The cellular membrane's potential influences insulin production by pancreatic cells. The activity of ATP-sensitive potassium channels (ABCC8) in cell membranes and extracellular glucose concentrations have an inverse relationship, which controls membrane potential. A cell's GLUT2 (SLC2A2) transporters allow extracellular glucose to enter—glucose's cellular metabolism results in ATP production. ATP-sensitive potassium channels are inhibited by high ATP concentrations, which depolarize the membrane. ATP-sensitive potassium channels activate and cause membrane repolarization when the extracellular glucose concentration is low. The membrane depolarizes in response to high glucose concentrations, which opens L-type calcium channels and causes ATP-sensitive potassium channels to shut. The calcium ion inflow stimulates the exocytosis of insulin granules. Repaglinide causes ATP-sensitive potassium channels to be inhibited in a glucose-dependent manner, which enhances insulin release.

Pharmacokinetics:

Absorption

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.

Bioavailability: 56%

Onset: 15-60 min (increased insulin levels)

Duration: 4-6 hr

Peak plasma time: 1 hr

Distribution

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.

Protein-bound: >98%

Vd: 31 L

Metabolism

Cytochrome P450 3A4 and 2C9 rapidly metabolise Repaglinide by oxidising 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.

Metabolized extensively in the liver by CYP3A4 and CYP2C8

Metabolites: Oxidized dicarboxylic acid, aromatic amine, acyl glucuronide (inactive)

Elimination

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.

Half-life: 1 hr

Total body clearance: 38 L/hr

Excretion: Feces (90%); urine (8%)

• Kawamori, Ryuzo et al. “Clinical study of repaglinide efficacy and its safety in type 2 diabetes mellitus patients with blood glucose levels inadequately controlled by sitagliptin.” Journal of diabetes investigation vol. 7,2 (2016): 253-9. doi:10.1111/jdi.12384
• Goldberg, R B. et al. “A randomized placebo-controlled trial of repaglinide in treating type 2 diabetes.” Diabetes care vol. 21,11 (1998): 1897-903. doi:10.2337/diacare.21.11.1897
• J. Ma, L. Y. Liu, P. H. Wu, Y. Liao, T. Tao, W. Liu, "Comparison of Metformin and Repaglinide as Monotherapy in the Treatment of New-Onset Type 2 Diabetes Mellitus in China", Journal of Diabetes Research, vol. 2014, Article ID 294017, 6 pages, 2014. https://doi.org/10.1155/2014/294017
• Landgraf, R., Bilo, H. & Müller, P. A comparison of Repaglinide and glibenclamide in treating type 2 diabetic patients previously treated with sulphonylureas. E J Clin Pharmacol 55, 165–171 (1999). https://doi.org/10.1007/s002280050613

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 104-week carcinogenicity trial, male rats were more likely to develop benign liver and thyroid adenomas and thyroid adenomas at doses up to 120 mg/kg/day, or about 90 times the clinical exposure in mg/m2. There was no indication that female rats were carcinogenic. Lower doses of 30 mg/kg/day and 60 mg/kg/day, which are more than 20 and 45 times, respectively, clinical exposures on a mg/m2 basis, did not result in more excellent higher thyroid and liver tumour rates in male rats. Mice were used in a 104-week carcinogenicity research at doses up to 500 mg/kg/day, around 187 times the clinical exposure on a mg/m2 basis. Yet, no indication of carcinogenicity was discovered in mice.

Repaglinide was found to be non-genotoxic in a variety of in vivo and in vitro experiments, including the Ames test for bacterial mutagenesis, the forward cell mutation assay in V79 cells (HGPRT), the chromosomal aberration assay in human lymphocytes, the unscheduled and replicating DNA synthesis in rat liver, and the in vivo mouse and rat micronucleus tests.

Repaglinide was given to male and female rats at dosages of up to 300 and 80 mg/kg/day in research on rat reproduction. Despite being over 60 times clinical exposure on a mg/m2 basis, fertility had no unfavourable impacts.

• Inform patients that repaglinide tablets can result in hypoglycemia, and educate them and their carers about self-management techniques, such as glucose monitoring and hypoglycemia treatment. Alert patients to the possibility that hypoglycemia will affect their focus and quickness of response. An enhanced frequency of blood glucose monitoring is advised in individuals who are more likely to have hypoglycemia and those with diminished symptom awareness.
• Repaglinide tablets should be taken by patients 30 minutes or less before meals. Patients should be advised to skip their repaglinide dosage if they miss a meal.
• Patients should be informed of potential repaglinide tablet drug interactions and those with other medications.

• https://www.ncbi.nlm.nih.gov/books/NBK559305/
• https://www.ncbi.nlm.nih.gov/books/NBK548879/
• https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm
• https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020741s041s042lbl.pdf
• https://www.ema.europa.eu/en/medicines/human/EPAR/repaglinide-teva